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Use of antibacterial prophylaxis for patients with neutropenia. Australian Consensus Guidelines 2011 Steering Committee.
Abstract
The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by this group because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. Recent evidence has demonstrated non-significant but consistent, improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. However, the consensus was that this evidence was not strong enough to recommend prophylaxis. The evidence base for FQ prophylaxis is presented alongside current consensus opinion to guide the appropriate and judicious use of these agents. Due consideration is given to patient risk, as it pertains to specific patient populations, as well as the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. The potential costs and consequences of emerging FQ resistance, particularly among Escherichia coli, Clostridium difficile and Gram-positive organisms, are considered. As FQ prophylaxis has been advocated in some chemotherapy protocols, specific regard is given to whether FQ prophylaxis should be used to support these regimens. The group also provides recommendations for monitoring and surveillance of emerging resistance in those centres that have adopted FQ prophylaxis.
... ICC was interpreted as follows: 0?0.2 indicates 'poor' agreement; 0.3?0.4 indicates 'fair' agreement; 0.5?0.6 indicates 'moderate' agreement; 0.7?0.8 indicates 'strong' agreement; and >0.8 indicates 'almost perfect' agreement.[10]Results Eight clinical practice guidelines were identified through the electronic and manual literature search and met the inclusion criteria for analysis.[11][12][13][14][15][16][17][18][19][20][21]The CPGs were all published between 2003 and 2013 and were largely endorsed by professional societies. ...
... The average standardized scores for the other domains were as such: 'scope and purpose' 53.4; 'stakeholder involvement' 53.1; 'rigour of development' 52.7; and 'clarity of presentation' 55.4, all of possible 100 points. Three guidelines (37.5%) were endorsed by appraisers as 'recommended without revision',[11,13,14]and two guidelines (25.0%) were considered to be 'recommended with alterations',[15][16][17][18]21]while three others (37.5%) were endorsed to be 'not recommended for adoption into clinical practice'.[12,19,20]One guideline showed 'fair' inter-rater reliability,[13]one showed 'moderate' reliability,[11]and four showed 'strong' reliability,[12,14,19,21]while two other guidelines showed 'almost perfect' agreement,[15? ...
... The highest ranked domain across all guidelines was editorial independence, and the lowest was applicability. Five guidelines were deemed usable in practice, with or without modifications to the current form.[11,[13][14][15][16][17][18]21]The other three guidelines, which represent the oldest guidelines as per the date of publication, were not recommended for endorsement.[12,19,20]Some ...
... Moreover, the benefit of the prophylaxis with fluoroquinolones (FQs) in settings with high FQs-resistance rates has been questioned. 17,18 Finally, healthcare costs are increased in case of infections with resistant bacteria due to prolonged hospitalization and expensive antibiotic treatments. 19,20 Fluconazole prophylaxis has significantly reduced infections caused by Candida spp, making Aspergillus the most frequent fungal pathogen during prolonged neutropenia. ...
... 5,8,[97][98][99] On the contrary, the Australian Consensus Guidelines recommend to consider the use of prophylaxis only for outpatients receiving HSCT and in palliative care patients with bone marrow failure. 18 All these recommendations are based on the results of 2 large randomized, double-blinded and placebo-controlled trials, published in 2005, which assessed the efficacy of levofloxacin during neutropenia in patients undergoing chemotherapy for solid cancers or acute leukemia. 100,101 Although both of them reported a significant reduction in febrile episodes and infections, no survival benefit was observed. ...
... Resistant GN are frequent in the intestinal flora of patients receiving FQs prophylaxis, and FQs were linked to the proliferation of MRSA, C. difficile, VRE, and ESBLs. 18,106 A comprehensive cancer center in the United States documented a rising proportion of FQsresistant E. coli, from less than 15% in the 1990s to 46% in 2009. 107 The data on FQs resistance have led some centers to discontinue prophylaxis, and most of the cohorts reported no increase in the mortality, despite an increase in BSIs in some of them. ...
Bloodstream infections (BSI) are among the most frequent complications in neutropenic cancer patients and, if caused by Gram-negative rods, are associated with high mortality. Thus, fever during neutropenia warrants prompt empirical antibiotic therapy which should be active against the most frequent Gram-negatives. In the last decade, there has been a worldwide increase in multidrug resistant (MDR) strains. In these cases, the traditional choices such as oral therapy, ceftazidime, cefepime, piperacillin-tazobactam, or even carbapenems, might be ineffective. Therefore novel de-escalation approach has been proposed for patients who are at high risk for infections due to MDR bacteria. It consists of starting antibiotics which cover the most probable resistant strain but it is narrowed down after 72 hours if no MDR pathogen is isolated. With increasing bacterial resistance, the benefit of fluoroquinolone prophylaxis during prolonged neutropenia remains to be confirmed. Antibiotic stewardship and infection control programs are mandatory in every cancer center.
... Recommendations can only be "strong" or "weak" (based on whether the desirable effects of the recommendation outweigh the undesirable effects) 21 and the quality of evidence can only have 4 levels: high, moderate, low, and very low (based on how likely it is that future research will change the estimate of the effect or even the direction of the effect). 22 Once the basic concept is accepted, the classification is easy to follow and logical: an intervention that is potentially lifesaving may get a strong recommendation even when the evidence supporting it is of low quality (eg, empirical addition of antifungal therapy in children with persistent FN 20 ) and, conversely, very-high-quality evidence may generate only a weak recommendation if the undesirable consequences have not been fully explored (eg, fluoroquinolone prophylaxis in afebrile patients who are expected to remain neutropenic for Ն 7 days, supported by metaanalyses but rejected by the Australian guidelines 23 ). Critical appraisal of the evidence is essential, but leaves room for subjectivity. ...
... Australian guidelines recommend avoiding antibacterial prophylaxis in general and consider it only for stem cell transplantation patients and palliative patients with BM failure. 23 Antifungal prophylaxis. Antifungal prophylaxis recommendations are particularly complex in all guidelines because they require an assessment of the risk of Candida versus mold (mainly Aspergillus) infection. ...
... [27][28][29][30] The low quality of many of the studies included in the meta-analyses, the lack of an effect on mortality in any single trial (including the latest and more influential 31 ), and the paucity of long-term data on bacterial resistance and patient colonization with resistant pathogens are the arguments for the Australian guidelines to not recommend its routine use. 23 Antifungal prophylaxis. There is convincing evidence that fluconazole reduces the rates of invasive candidiasis 32 and death 33 in patients at high risk of fungal infection. ...
Applying the principles of evidence-based medicine to febrile neutropenia (FN) results in a more limited set of practices than expected. Hundreds of studies over the last 4 decades have produced evidence to support the following: (1) risk stratification allows the identification of a subset of patients who may be safely managed as outpatients given the right health care environment; (2) antibacterial prophylaxis for high-risk patients who remain neutropenic for ≥ 7 days prevents infections and decreases mortality; (3) the empirical management of febrile neutropenia with a single antipseudomonal beta-lactam results in the same outcome and less toxicity than combination therapy using aminoglycosides; (4) vancomycin should not be used routinely empirically either as part of the initial regimen or for persistent fever, but rather should be added when a pathogen that requires its use is isolated; (5) empirical antifungal therapy should be added after 4 days of persistent fever in patients at high risk for invasive fungal infection (IFI); the details of the characterization as high risk and the choice of agent remain debatable; and (6) preemptive antifungal therapy in which the initiation of antifungals is postponed and triggered by the presence, in addition to fever, of other clinical findings, computed tomography (CT) results, and serological tests for fungal infection is an acceptable strategy in a subset of patients. Many practical management questions remain unaddressed.
... The chance of infection during neutropenia increases over time; therefore, severity and duration of neutropenia are unequivocal risk factors for the development of infection following chemotherapy [5,6]. In line with other guidelines [4,19,20], we recommend to stratify neutropenic patients into two different risk groups according to the anticipated duration of neutropenia. Patients likely to develop prolonged neutropenia (> 7 days) should be considered as high-risk patients (A-I), whereas patients with estimated duration of neutropenia of seven days or less should not be considered at high risk (A-I), unless additional risk factors are present (B-II) [21,22] (Table 2). ...
... The prevalence of colonization due to ESBL Enterobacteriaceae increases worldwide, while prior colonization with ESBL-producing pathogens in hematologic/oncologic patients constitutes an important risk factor for subsequent development of ESBL-associated blood stream infections [50,51,55]. Concerns about resistance development therefore led some experts to vote against antibacterial prophylaxis in neutropenic patients [19,24]. ...
Hematologic and oncologic patients with chemo- or immunotherapy-related immunosuppression are at substantial risk for bacterial infections and Pneumocystis jirovecii pneumonia (PcP). As bacterial resistances are increasing worldwide and new research reshapes our understanding of the interactions between the human host and bacterial commensals, administration of antibacterial prophylaxis has become a matter of discussion. This guideline constitutes an update of the 2013 published guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). It gives an overview about current strategies for antibacterial prophylaxis in cancer patients while taking into account the impact of antibacterial prophylaxis on the human microbiome and resistance development. Current literature published from January 2012 to August 2020 was searched and evidence-based recommendations were developed by an expert panel. All recommendations were discussed and approved in a consensus conference of the AGIHO prior to publication. As a result, we present a comprehensive update and extension of our guideline for antibacterial and PcP prophylaxis in cancer patients.
... them, ciprofloxacin) demonstrated a significant decrease in anaerobic bacteria colonizing the gut and an increase in potentially pathogenic aerobic enterococci (46). The recognition of this phenomenon let many international guidelines recommend the implementation of a systematic monitoring of vancomycin resistant enterococci, methicillin-resistant S. aureus, FQ-resistant Gram-negatives and C. difficile infections, in order to adapt prophylactic (and therapeutic) strategies to local epidemiological data (22,41,(47)(48)(49). What still remains unknown is the proportion of resistant strains above which a prophylaxis should be not administered any longer or at least the drug adopted should be changed: a study conducted in a center where FQ prophylaxis is normally adopted evidenced an increase in the number of cancer patients per year colonized or infected by FQ-resistant E. coli. ...
... After a 6-month period of discontinuation, the FQ-prophylaxis resumption seemed to be anyway effective to prevent bacteriemias by resistant E. coli (45). Moreover, lower rates of febrile episodes and bloodstream infections should be weighted with the lack of benefits on the overall mortality and relevant changes in local ecology (47,48,50). Besides selection of resistant strains, FQ administration may cause other adverse events, especially at gastrointestinal, musculoskeletal and neurologic levels, also because of interactions with other drugs assumed by cancer patients (51). ...
Antibiotics are frequently administered for prophylaxis of fever in neutropenic children with cancer. This strategy is mainly derived from adults’ data, and various pediatric studies evidenced the effectiveness of antibiotics (e.g. fluorquinolones) in the prevention of febrile neutropenia. However, only two pediatric randomized, double blind, placebo‐controlled trials have been performed, with a total of 262 leukemic children enrolled, and no other one was ever powered for analyzing effectiveness over other infectious complications.
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... Patients with an expected duration of neutropenia between 6 and 10 days were classified as intermediate risk group. Other guidelines divide the patients into two risk groups with neutropenia of more or less than 7 days based on two recently published clinical trials [1,101112. Importantly, none of these classifications are based on prospective studies. However, judging the risk of an individual patient on his expected duration of neutropenia has become clinical practice in many centers. ...
... One of the main concerns regarding antibiotic prophylaxis in any patient population is the development or selection of multidrug-resistant pathogens. This has led some experts to withhold a recommendation for antibiotic prophylaxis in neutropenic cancer patients [11] . Regarding the risk of the emergence of resistance, several issues need to be considered: ...
Bacterial infections are the most common cause for treatment-related mortality in patients with neutropenia after chemotherapy. Here, we discuss the use of antibacterial prophylaxis against bacteria and Pneumocystis pneumonia (PCP) in neutropenic cancer patients and offer guidance towards the choice of drug. A literature search was performed to screen all articles published between September 2000 and January 2012 on antibiotic prophylaxis in neutropenic cancer patients. The authors assembled original reports and meta-analysis from the literature and drew conclusions, which were discussed and approved in a consensus conference of the Infectious Disease Working Party of the German Society of Hematology and Oncology (AGIHO). Antibacterial prophylaxis has led to a reduction of febrile events and infections. A significant reduction of overall mortality could only be shown in a meta-analysis. Fluoroquinolones are preferred for antibacterial and trimethoprim-sulfamethoxazole for PCP prophylaxis. Due to serious concerns about an increase of resistant pathogens, only patients at high risk of severe infections should be considered for antibiotic prophylaxis. Risk factors of individual patients and local resistance patterns must be taken into account. Risk factors, choice of drug for antibacterial and PCP prophylaxis and concerns regarding the use of prophylactic antibiotics are discussed in the review.
... In a recent meta-analysis, fluoroquinolone prophylaxis had reduced mortality in neutropenic patients [17], whereas two large trials failed to demonstrate a similar benefit [18,19]. As such, variations exist between guidelines, with some supporting antibiotic prophylaxis [20] and others recommending against it [21]. Resistance selection is the most considered adverse event associated with prophylaxis. ...
Bloodstream infections (BSI) are life-threatening complications for onco-hematologic patients. Fluoroquinolones prophylaxis (FQP) was recommended for patients with neutropenia. Later, it was correlated with increased resistance rates among this population and its role became debated. While the role of FQ prophylaxis is still being studied, its cost-effectiveness is also unknown. The objective of this study was to evaluate the costs and effects associated with two alternative strategies (FQP vs. no prophylaxis) for patients with hematological malignancies undergoing allogenic stem cell transplant (HSCT). A decision-tree model was built integrating retrospectively collected data from a single transplant center, part of a tertiary teaching hospital in Northern Italy. Probabilities, costs and effects were considered in the assessment of the two alternative strategies. Probabilities of colonization, BSIs, extended-spectrum beta lactamase (ESBL) and Klebsiella pneumoniae carbapenemase (KPC) BSIs and mortality associated with infection, as well as median duration of length of stay (LOS) were calculated based on data collected between 2013 and 2021. The center applied the strategy of FQP between 2013 and 2016, and of no prophylaxis between 2016 and 2021. Data on 326 patients were collected during the considered time period. Overall, the rates of colonization, BSI, KPC/ESBL BSI, and mortality were 6.8% (95% confidence interval (CI) 2.7–13.5), 42% (9.9–81.4) and 20.72 (16.67–25.26), respectively. A mean bed-day cost of 132€ was estimated. Considering no prophylaxis vs. prophylaxis, the difference in costs ranged between additional 33.61 and 80.59€ per patient, whereas the difference in effects ranged between 0.11 and 0.03 life-years (LYs) lost (around 40 and 11 days). Given the small differences in terms of costs and effects between the two strategies, no prophylaxis seems an appropriate choice. Furthermore, this analysis did not consider the broader effect on hospital ecology of multiple doses of FQP, which could provide further support for the strategy of no prophylaxis. Our results suggest that the necessity for FQP in onco-hematologic setting should be determined based on local antibiotic resistance patterns.
... 7,8 More recently, some international guidelines still recommended FQ prophylaxis in patients who are at high risk for febrile neutropenia (National Institute for Health and Care Excellence -NICE, 9 German Society of Hematology and Medical Oncology -DGHO, 10 American Society of Clinical Oncology -ASCO and IDSA, 11 National Comprehensive Cancer Network -NCCN). 12 By contrast, Australian guidelines gave a low level (grade C) of recommendation for antibacterial prophylaxis in high-risk patients; 13 similarly, the European Society for Medical Oncology (ESMO) guidelines on the management of febrile neutropenia discourage the use of antimicrobial, including FQ, for prophylaxis. 14 In 2017 the ECIL group analyzed the emergence of antimicrobial resistance in gram-negative rods and questioned the recommendations for FQ prophylaxis, underscoring the need for up-to-date, evidence-based data on local epidemiology. ...
Background:
Acute myeloid leukemia (AML) patients are at high risk of infections during post-induction neutropenia. Recently, the role of antibacterial prophylaxis has been reconsidered due to concerns about the emergence of multi-resistant pathogens. The aim of the present study was to evaluate the impact of avoiding prophylaxis on the rate of induction death (primary endpoint), neutropenic fevers, bloodstream infections (BSIs), resistant pathogens BSIs and septic shocks (secondary endpoints).
Methods:
We performed a retrospective single-center study including 373 AML patients treated with intensive induction chemotherapy, divided into two groups according to levofloxacin prophylaxis given (group A, gA) or not (group B, gB).
Results:
Neutropenic fever was observed in 91% of patients in gA and 97% in gB (OR 0.35, IC95% 0.08 - 1.52, p=0162). The rate of BSIs was 27% in gA compared to 34% in gB (OR 0.69, 0.38 - 1.25, p=0.222). The induction death rate was 5% in gA and 3% in gB (OR 1.50, 0.34 - 6.70, p=0.284). Fluoroquinolones (FQ) resistant pathogens were responsible for 59% of total BSIs in gA and 22% in gB (OR 5.07, 1.87 - 13.73, p=0.001); gram-negative BSIs due to multi-drug resistant organisms were 31% in gA and 36% in gB (OR 0.75, 0.15 - 3.70, p=0.727).
Conclusions:
Despite its limitations (retrospective nature, single-center, different cohort size), the present study showed that avoiding levofloxacin prophylaxis was not associated with an increased risk of induction death. The cumulative incidence of neutropenic fever was higher in non-prophylaxis group, while no difference was observed for BSIs. In the prophylaxis group we observed a higher incidence of FQ-resistant organisms.
... Thurshy et al. reported implementation of a whole hospital sepsis clinical pathway in cancer patients, with a significant reduction in ICU admissions, post-sepsis hospital length of stay, and sepsis-related mortality (reduced from 16 to 5%) [68]. This strategy of early sepsis recognition was further implemented across 26 other hospitals across Australia, and they have since abandoned the use of quinolone prophylaxis [69]. Improving mortality of bacteremia to less than 5% with an early recognition of sepsis pathway may shift the risk-benefit analysis of quinolone prophylaxis. ...
Purpose of review
Bacterial sepsis is a leading cause of morbidity and mortality among pediatric cancer patients receiving intensive chemotherapy. While there are treatment guidelines for empiric antimicrobial therapy for fever with neutropenia, the role of prophylactic antibacterial agents has been widely debated and is less well-defined.
Recent findings
Demonstrable benefits of fluoroquinolone prophylaxis (specifically levofloxacin) include prevention of bacteremia and potentially fevers during neutropenia, though with limited if any impact on mortality. However, the risks of using antibacterial prophylaxis include antimicrobial over-utilization, antimicrobial resistance, Clostridioides difficile colitis, and stool dysbiosis with associated risk of graft versus host disease and mortality.
Summary
This review article outlines the current literature and provides guidance for decisions about levofloxacin prophylaxis in the pediatric oncology population.
... Differences in surveys preclude direct comparison; however, use of antibacterial prophylaxis appears to be higher in the United States than elsewhere, reflecting different approaches in other countries [18]. The European Society of Medical Oncology (ESMO) and Australian guidelines discourage use of fluoroquinolones for prophylaxis due to lack of evidence of mortality benefit and concern regarding antimicrobial resistance [23,24]. Although 2 prior meta-analyses including studies from 1973 to 2010 found that antibacterial prophylaxis significantly reduced the risk of allcause mortality, a meta-analysis including studies from 2006 to 2014 did not find any effect of fluoroquinolone prophylaxis on mortality [25][26][27]. ...
Background
Contemporary information regarding fever and neutropenia (FN) management, including approaches to antibacterial prophylaxis, empiric therapy, and de-escalation across United States (US) cancer centers is lacking.
Methods
A self-administered, electronic, cross-sectional survey of antimicrobial stewardship physicians and pharmacists at US cancer centers. The survey ascertained institutional practices and individual attitudes on FN management in high-risk cancer patients. A 5-point Likert scale assessed individual attitudes.
Results
Providers from 31 of 86 hospitals (36%) responded, and FN management guidelines existed in most (29/31, 94%) hospitals. Antibacterial prophylaxis was recommended in 27/31 (87%) hospitals with levofloxacin as the preferred agent (23/27, 85%). Cefepime was the most recommended agent for empiric FN treatment (26/29, 90%). Most institutional guidelines (26/29, 90%) recommended against routine addition of empiric gram-positive agents except for specific scenarios. Eighteen of 29 (62%) hospitals explicitly provided guidance on de-escalation of empiric, systemic antibacterial therapy; however, timing of de-escalation was variable according to clinical scenario. Among 34 individual respondents, a majority agreed with use of antibiotic prophylaxis in high-risk patients (25, 74%). Interestingly, only 10 (29%) respondents indicated agreement with the statement that benefits of antibiotic prophylaxis outweigh potential harms.
Conclusion
Most US cancer centers surveyed had institutional FN management guidelines. Antibiotic de-escalation guidance was lacking in nearly 40% of centers, with heterogeneity in approaches when recommendations existed. Further research is needed to inform FN guidelines on antibacterial prophylaxis and therapy de-escalation.
... There is also considerable literature showing that the emergence of antimicrobial resistance and the spread of multidrug-resistant pathogens are associated with the use of antibiotic prophylaxis [8][9][10][11]. Putting the extensive use of prophylaxis in the context of increasing antibiotic resistance, Australian guidelines advise against the routine use of prophylaxis for neutropenia [12]. In view of the pharmacovigilance reports, the U.S. Food and Drug Administration has attended to the issue of antibiotic toxicity and released warnings against unnecessary use of antibiotics due to their association with disabling and potentially permanent side effects that involve the central nervous system, nerves, peripheral neuropathy, muscles, joints, tendinitis, tendon rupture, confusion, and hallucinations [13]. ...
Purpose
The efficacy of prophylactic antimicrobial treatment renders challenges in patients with leukemias receiving chemotherapy. The study aimed to compare differences in C-reactive protein (CRP) and procalcitonin (PCT) at presentation and the immediate outcome measures of post-chemotherapy NF between patients with and without antimicrobial prophylaxis.
Methods
A 5-year observational study included 282 NF episodes in 133 leukemia patients requiring hospital care from January 2014 to May 2019. We collected demographic characteristics, laboratory data of blood cell counts and inflammatory biomarkers, and immediate outcome measures of NF, including microbiologically diagnosed infections, presence of predominant pathogens, required modification of antibiotics during NF, adverse medical complications, total fever duration, and deaths. We evaluated data between patients with and without prophylaxis.
Results
Of patients, 77.3%, 68.4%, and 20.6% had antibiotic prophylaxis, antifungal prophylaxis, and no prophylaxis, respectively. There were totally 15 deaths—13 with antibiotic prophylaxis and 10 with antifungal prophylaxis. CRP, PCT, and immediate outcome measures of NF did not show significant differences between those with and without antimicrobial prophylaxis. Although between-group differences showed no statistical significance, higher median fever duration, CRP and PTC values, and higher proportions of NF requiring modification of antibiotics were found more frequently in those with antimicrobial prophylaxis than in those without.
Conclusion
The benefits of using antimicrobial prophylaxis were less supported. Enhancing diagnostic laboratory and medical complication surveillance and periodic evaluation of institutional data during post-chemotherapy neutropenia and NF in relation to antimicrobial prophylaxis is promising in providing insights to redefine the risk–benefit accounts of using prophylaxis.
... The use of FQ has also been linked to the proliferation of several other MDROs such as MRSA, VRE and C. difficile. 146,147 However, patients at high risk of FN should be considered for antimicrobial prophylaxis, including patients with acute leukemias. The risk stratifications should be based on patient characteristics, i.e., advanced age, performance status, nutritional status, prior FN, comorbidity, and their underlying leukemia. ...
Acute leukemia is a group of aggressive malignant diseases, associated with a high degree of both morbidity and mortality. An important cause of both the latter is infectious complications. Patients with acute leukemia are highly susceptible to diseases both due to factors related to the disease itself, factors attributed to treatment and specific individual risk factors in each individual patient. Patients with chemotherapy induced neutropenia are at particularly high risk, and microbiological agents include viral, bacterial and fungal agents. The etiology is often unknown in infectious complications, although adequate patient evaluation and sampling have diagnostic, prognostic and treatment-related consequences. Bacterial infections include a wide range of potential microbes, both Gram-negative and Gram-positive species, while fungal infections include both mold and yeast. A recurring problem is increasing resistance to antimicrobial agents, and in particular this applies to methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) and extended spectrum beta-lactamase resistance (ESBL). Treatment of sepsis in leukemia patients includes the use of broad-spectrum antibiotics and international guidelines regarding treatment have been developed. Nevertheless, one should implant knowledge of local microbiological epidemiology and resistance conditions in treatment decisions. In this review, we discuss infectious diseases in acute leukemia with major focus on febrile neutropenia and sepsis, and we problematize the diagnostic, prognostic, and therapeutic aspects of infectious complications in this patient group.
... Two recent guidelines invite the readers to interpret the data in the light of the lack of significant benefit on mortality, and despite a possible reduction in the rate of infection and fever episodes in some settings, they do not recommend FQ prophylaxis [15,16]. This cautious policy is in agreement with what we, on behalf of the ECIL group, have recently published [8]. ...
Yeshurun et al. reported the results of retrospective study with historical control in patients with multiple myeloma and lymphoma undergoing autologous transplant. The rates of bacteraemia and fever were lower during the period of ciprofloxacin prophylaxis with no effect on mortality. In the era of multidrug resistance (MDR), the efficacy of fluoroquinolone prophylaxis might be lower in settings with high level of resistance. Additionally, the benefit of fluoroquinolone prophylaxis on mortality should not be expected since the morality is mainly associated with infections due to MDR currently associated with MDR strains which could not be prevented by fluoroquinolone prophylaxis.
... 11 The increase in antimicrobialresistant Gram-negative bacilli questions the utility, preferred agent and duration of antimicrobial prophylaxis during chemotherapy-induced neutropenia. 8,[14][15][16] Oral third-generation cephalosporins have antibacterial activity against Gram-negative bacteria and Gram-positive penicillinaseproducing bacteria. [17][18][19] Oral third-generation cephalosporins have been substituted as neutropenic prophylaxis on a case-bycase basis when a fluoroquinolone could not be administered due to intolerances, allergies, history of adverse drug reactions or drug-drug interactions. ...
Background:
There is demonstrated benefit with fluoroquinolones as infection prophylaxis in neutropenic patients; however, side effects, drug interactions and increasing resistance necessitate investigation of alternative therapies.
Objectives:
To compare the incidence of febrile neutropenia in high-risk patients with haematological malignancy receiving a fluoroquinolone with those receiving an oral third-generation cephalosporin (OTGC) as antibacterial prophylaxis during chemotherapy-induced neutropenia.
Methods:
A retrospective, matched, single-centre study comparing clinical and microbiological outcomes in acute leukaemia patients receiving fluoroquinolones versus OTGCs as antibacterial prophylaxis after chemotherapy.
Results:
A total of 120 patients (levofloxacin n = 80, OTGC n = 40) were included and matched. The 30 day incidence of febrile neutropenia was 89.7% (95% CI = 82.4-93.9). The rates of febrile neutropenia were similar between antimicrobials (OTGC versus levofloxacin HR = 0.90, 95% CI = 0.54-1.52, P = 0.70). The most frequent site of infection was the bloodstream (line related) (n = 24, 62%) and the majority (n = 28, 72%) of infections were caused by Gram-positive organisms. Groups were similar in terms of site of infection (P = 0.91) and morphology of recovered microorganisms (P = 0.74). There were significantly more cultures positive for Enterobacter spp. in the OTGC group (P = 0.043). Three patients died during follow-up (from first dose up to 30 days after the last dose) (30 day survival = 99.2%, 95% CI = 97.5-100), with only two of the reported deaths attributable to infection.
Conclusions:
These findings demonstrate comparable rates of febrile neutropenia and culture positivity with an increase in cultures positive for Enterobacter spp. when OTGCs are compared with levofloxacin for antibacterial prophylaxis during chemotherapy-induced neutropenia. Further prospective, randomized investigation is warranted.
... Guidelines conclude that the evidence is not sufficient to recommend prophylactic use of antibiotics [18]. In contrast, in other guidelines, such as the IDSA [5], ESMO [19], ASCO [20], and NCCN [21], prophylactic use of fluoroquinolone was recommended for high-risk patients who are going to be neutropenia for more than 7 days. ...
Background: Febrile neutropenia is one of the most serious adverse events in patients with hematological malignancies and chemotherapy. The routine use of fluoroquinolone prophylaxis in patients with hematological malignancies is controversial. Therefore, we prospectively evaluated the efficacy and safety of prophylactic use of garenoxacin for febrile neutropenia. Patients and Methods: Consecutive adult patients with hematological malignancies who were at risk for chemotherapy-induced neutropenia lasting more than seven days were eligible for present study. They received oral garenoxacin (400 mg daily) from the neutrophil count decreased to less than 1000/μl and continued until the neutropenia had resolved. The primary endpoint was incidence of febrile neutropenia, and the secondary endpoints were the type and incidence of adverse events. Results: We enrolled 46 consecutive patients (median age, 59 years). The underlying diseases comprised acute myeloid leukemia (n = 17), acute lymphoblastic leukemia (n = 3), malignant lymphoma (n = 23), and multiple myeloma (n = 3). There were 23 febrile neutropenia episodes and 2 episodes of bacteremia. There were no grade 3 or 4 adverse events; however serum creatinine levels were significantly elevated after garenoxacin administration. The overall prophylactic efficacy of garenoxacin was 50%, and there were no infection-related deaths. Conclusions: Prophylactic use of garenoxacin is effective and safe in patients with hematological malignancies. (Clinical trial registration number: UMIN000004979).
... Some authors recommend that uoroquinolone prophylaxis should be abandoned because it is probably ine ective-when resistance rates among Escherichia coli is greater than 20%. 70,71 Unfortunately, this is exactly the case in many hematologic centers throughout the world. ...
... Therefore monotherapy is clearly effective to treat a patient with fever without any localization or microbiological documentation, but it could be not adequate in the presence of a potentially lifethreatening Gram-negative bacteremia (due to P. aeruginosa, or other Gram-negatives). A 20% proportion of resistant strains had been suggested as cut off to stop fluoroquinolone prophylaxis for febrile neutropenia in cancer patients [4,14,15], but no indication is available for therapy. Noteworthy, the presence of a 10-20%, or higher, proportion of resistant strains is recommended to avoid use of an antibiotic and change therapeutic strategy in the treatment of community acquired intraabdominal infections [16], while this proportion is reduced to 5% to identify the best treatment strategies for gonococcal infections [17]. ...
ABSTRACT Background: Monotherapy is recommended as the first choice for initial empirical therapy of febrile neutropenia, but local epidemiological and antibiotic susceptibility data are now considered pivotal to design a correct management strategy.
To evaluate the proportion of Gram-negative rods isolated in bloodstream infections in children with cancer resistant to antibiotics recommended for this indication.
The in vitro susceptibility to ceftazidime, piperacillin-tazobactam, meropenem and amikacin of Gram-negatives isolated in bacteremic episodes in children with cancer followed at the Istituto "Giannina Gaslini", Genoa, Italy in the period of 2001-2013 was retrospectively analyzed using the definitions recommended by EUCAST in 2014. Data were analyzed for any single drug and to the combination of amikacin with each β-lactam. The combination was considered effective in absence of concomitant resistance to both drugs, and not evaluated by means of in vitro analysis of antibiotic combinations (e.g., checkerboard).
A total of 263 strains were evaluated: 27% were resistant to piperacillin-tazobactam, 23% to ceftazidime, 12% to meropenem and 13% to amikacin. Concomitant resistance to β-lactam and amikacin was detected in 6% of strains for piperacillin-tazobactam, 5% for ceftazidime and 5% for meropenem. During the study period there was a nonsignificant increase in the proportions of strains resistant to β-lactams indicated for monotherapy, and also increase in the resistance to combined therapies.
in an era of increasing resistance to antibiotics guideline-recommended monotherapy could be not appropriate for initial empirical therapy of febrile neutropenia. Strict local survey on etiology and antibiotic susceptibility is mandatory for a correct management of this complication in cancer patients.
... Thus, our results indicated substantial hospital cost savings mainly with non-chemotherapy drugs associated with pemetrexed singlet when compared to the two platinum-based doublets. In addition, patients receiving chemotherapy regimens associated with a higher risk of neutropenia or leukopenia are often given prophylactic treatment and may be treated more aggressively to improve treatment tolerance and prevent life-threatening infection [21,22]. Thus, the effects associated with prophylactic treatment and aggressive AE management would be accounted for in hospital costs of supportive care, which included both medications and non-drug care for prevention and management of hematologic AEs. ...
Purpose
To compare supportive care costs associated with second-line chemotherapy for advanced non-squamous non-small cell lung cancer (advNS-NSCLC) in Chinese patients.
Methods
This retrospective cohort study included patients receiving pemetrexed or docetaxel-based second-line chemotherapy for advNS-NSCLC in four Chinese hospitals from 2007 to 2012. The best matched pairs between pemetrexed and other regimens were identified using propensity score methods for head-to-head comparisons of supportive care costs per treatment cycle. Linear regression analyses were performed to rank log10 scale of supportive care costs per treatment cycle associated with chemotherapy by tumor response and hematologic toxicity.
Results
384 patients were included to create propensity score-matched treatment groups for pemetrexed singlet versus docetaxel singlet, platinum/pemetrexed, and platinum/docetaxel, respectively. Pemetrexed singlet was associated with significantly less supportive care costs per treatment cycle than the two doublets (platinum/pemetrexed: median difference −RMB 9,877, p = 0.003; platinum/docetaxel: median difference −RMB 8,370, p = 0.009; 1 RMB = 0.16 USD) but not docetaxel singlet in matched patients. Of the four studied chemotherapy regimens, pemetrexed singlet was associated with the lowest log10 scale of supportive care costs per treatment cycle in patients with tumor control (coefficient relative to docetaxel singlet −1.049, p < 0.001) or leukopenia (coefficient relative to docetaxel singlet −0.991, p = 0.034).
Conclusion
Pemetrexed singlet cost significantly less for supportive care than pemetrexed or docetaxel-based doublets when treating Chinese patients with AdvNS-NSCLC in the second-line setting. Pemetrexed singlet was also associated with significantly less supportive care costs per treatment cycle than docetaxel singlet in patients with tumor control or leukopenia.
... Trials have shown the efficacy of antibiotic prophylaxis in reducing the incidence of bacterial infections [10]. The IDSA [1], ESMO [5], ASCO [6], and NCCN [7] recommend antibacterial prophylaxis with a fluoroquinolone for high-risk patients (who are going to be neutropenic for >7 days), although the Australian Consensus Guidelines consider that the evidence was not strong enough to recommend antibiotic prophylaxis, except for stem cell transplantation patients and palliative patients with BM failure [11]. ...
Febrile neutropenia is one of the most serious complications in patients with haematological malignancies and chemotherapy. A prompt identification of infection and empirical antibiotic therapy can prolong survival. This paper reviews the guidelines about febrile neutropenia in the setting of hematologic malignancies, providing an overview of the definition of fever and neutropenia, and categories of risk assessment, management of infections, and prophylaxis.
... 23 En términos generales se recomiendan como profilaxis antibiótica las fluoroquinolonas (levofloxacino y ciprofloxacino), sobre todo en pacientes con leucemia que recibirán diversos regímenes intensivos de quimioterapia. 24 Su indicación se reduce, principalmente, en áreas con mayor resistencia a quinolonas 25 y en los pacientes con consumo crónico. 26 En nuestra serie, la sensibilidad de las Pseudomonas aisladas a las quinolonas es aún moderada a diferencia de Escherichia coli en la que sólo se registró 9% de cepas susceptibles a ciprofloxacino. ...
RESUMEN Antecedentes: la frecuencia de aislamiento de bacterias en pacientes con neutropenia es baja; Escherichia coli, Pseudomonas aeruginosa y las diferentes especies de Staphylococcus son las más frecuentes. Material y método: estudio prospectivo, longitudinal, observacional y prolectivo en el que se analizaron los resultados de la toma de cultivos semanales (nasal, faríngeo, sangre, urocultivo y coprocultivo) de pacientes con leucemia aguda durante la etapa de inducción en un periodo de nueve meses. Resultados: se estudiaron 67 casos, en su mayoría de leucemia linfoblástica aguda (n=55). Las bacterias aisladas con mayor frecuencia fueron las grampositivas (56%) [S epidermidis (32%], seguidas de las gramnegativas (Escherichia coli (14.7%]). Los principales sitios de aislamiento fueron la cavidad nasal, la faringe y la sangre. La frecuencia de Pseudomonas aeruginosa fue de 3%. La resistencia a los antibióticos se observó, principalmente, para ciprofloxacino, en especial de Pseudomonas aeruginosa (67%) a diferencia de piperacilina-tazobactam y cefepime en donde la sensibilidad fue, incluso, de 85%. Escherichia coli fue la más sensible a imipenem, meropenem y amikacina (95, 50 y 86%, respectivamente). Todos los estafilococos tuvieron alta sensibilidad a vancomicina (> 90%). Conclusión: la estrategia de toma semanal de cultivos incrementó la frecuencia de aislamiento de bacterias (86.6 %); la cavidad nasal fue el sitio de donde más se aislaron y E. coli la bacteria más aislada. La sensibilidad a piperacilina-tazobactam, cefepime y los carbapenem sigue siendo alta, lo que sustenta su utilidad como tratamientos de primera línea en pacientes con neutropenia febril. Palabras clave: leucemia aguda, cultivos bacterianos, neutropenia, cáncer. ABSTRACT Background: The frequency of bacteria isolates in patients with febrile neutropenia is low. Escherichia coli, Pseudomonas aeruginosa and the different species of Staphylococcus are the most frequent. Material and methods: Retrospective, Observational and Prolective study. The results of weekly cultures (nasal cavity, pharynx, blood) of patients with acute leukemia during the induction phase studied. Results: 67 patients were studied, mostly ALL (n=55). The most frequent bacteria were Gram-positive (56%) [Staphylococcus epidermidis (32%), followed by Gram-negative (Escherichia coli [14.7%]). The main site where bacteria were isolated was the nasal cavity followed by pharynx and blood. The frequency of Pseudomonas aeruginosa was 3% unlike Piperacillin-Tazobactam and Cefepime in which the sensitivity was 85%. For Escherichia coli the main sensitivity were for imipenem, meropenem and amikacin (95, 50 y 85% respectively). All Staphylococci were sensitive to vancomycin (>90%). Conclusion: Weekly samples strategy increases the frequency of bacterial isolates (86.6%), the nasal cavity being the main site. When we exclude these cases, E coli was the most frequent bacteria. Sensitivity to Piperacillin-Tazobactam, Cefepime and Carbapenems is high which supports its use as first-line treatment in febrile neutropenia.
... In our experience the cost of antibacterial prophylaxis with regard to evolving resistance is a major concern.[99, 100] Australian consensus guidelines for management of haematology patients recommended against routine antibacterial prophylaxis for gram-negative bacteraemia, in particular, fluoroquinolones [101]. ...
Infections due to resistant and multi-drug-resistant (MDR) organisms in haematology patients and hematopoietic stem cell transplant recipients are an increasingly complex problem of global concern. We outline the burden of illness and epidemiology of resistant organisms such as gram-negative pathogens, vancomycin-resistant Enterococcus faecium (VRE), and Clostridium difficile in haematology cohorts. Intervention strategies aimed at reducing the impact of these organisms are reviewed: infection prevention programs, screening and fluoroquinolone prophylaxis. The role of newer therapies (e.g. linezolid, daptomycin and tigecycline) for treatment of resistant and MDR organisms in haematology populations is evaluated, in addition to the mobilization of older agents (e.g. pristinamycin and fosfomycin) and potential benefit of combination regimens.
... There are two predominant bacterial infection risk reduction strategies in HSCTs: 1) Prophylactic strategy where antibiotics are prescribed prior to the onset of neutropenia and 2) Empiric strategy where antibiotics are prescribed only at the onset of fever. Although there is evidence that bacterial prophylaxis is associated with improved clinical outcomes [9], its widespread use remains debated, given concerns regarding increased drug toxicity and antibiotic resistance [10][11][12][13]. Further, an empiric strategy may also be suboptimal as life-threatening septicemia may precede the development of fevers. ...
Empirical antibiotics at the onset of febrile neutropenia are one of several strategies for management of bacterial infections in patients undergoing Hematopoietic Stem Cell Transplant (HSCT) (empiric strategy). Our HSCT program aims to perform HSCT in an outpatient setting, where an empiric antibiotic strategy was employed. HSCT recipients began receiving intravenous antibiotics at the onset of neutropenia in the absence of fever as part of our institutional policy from 01 Jan 2009; intravenous Prophylactic strategy. A prospective study was conducted to compare two consecutive cohorts [Year 2008 (Empiric strategy) vs. Year 2009 (Prophylactic strategy)] of patients receiving HSCT. There were 238 HSCTs performed between 01 Jan 2008 and 31 Dec 2009 with 127 and 111 in the earlier and later cohorts respectively. Infection-related mortality pre- engraftment was similar with a prophylactic compared to an empiric strategy (3.6% vs. 7.1%; p = 0.24), but reduced among recipients of autologous HSCT (0% vs. 6.8%; p = 0.03). Microbiologically documented, blood stream infections and clinically documented infections pre-engraftment were reduced in those receiving a prophylactic compared to an empiric strategy, (11.7% vs. 28.3%; p = 0.001), (9.9% vs. 24.4%; p = 0.003) and (18.2% vs. 33.9% p = 0.007) respectively. The prophylactic use of intravenous once-daily ceftriaxone in patients receiving outpatient based HSCT is safe and may be particularly effective in patients receiving autologous HSCT. Further studies are warranted to study the impact of this Prophylactic strategy in an outpatient based HSCT program.
... Patients with febrile neutropenia are often treatment-experienced and, therefore, have a higher incidence of colonization and invasive infections with multidrug-resistant organisms (MDROs) [42,44]. Widespread use of prophylactic antibiotics in this patient group has also been implicated in the selection of resistant isolates [45][46][47]. ...
Purpose of review:
Febrile neutropenia presents a clinical challenge in which timely and appropriate antibiotic exposure is crucial. In the context of altered pharmacokinetics and rising bacterial resistance, standard antibiotic doses are unlikely to be sufficient. This review explores the potential utility of altered dosing approaches of β-lactam antibiotics to optimize treatment in febrile neutropenia.
Recent findings:
There is a dynamic relationship between the antibiotic, the infecting pathogen, and the host. Great advancements have been made in the understanding of the pharmacokinetic changes in critical illness and the pharmacodynamic relationships of antibiotics in these settings.
Summary:
Antibiotic treatment in febrile neutropenia is becoming increasingly difficult. Patients are of higher acuity, receive more intensive chemotherapy regimens leading to prolonged neutropenia, and are often exposed to multiple antibiotic courses. These patients display significant variability in antibiotic clearances and increases in volume of distribution compared with standard ward-based patients. Rising antibiotic resistance and a lack of new antibiotics in production have prompted alternative dosing strategies based on pharmacokinetic/pharmacodynamic data, such as extended or continuous infusions of β-lactam antibiotics, to maximize the likelihood of treatment success. A definitive study that describes a mortality benefit of such dosing regimens remains elusive and the theoretical advantages require testing in well designed clinical trials.
Background Prophylaxis with fluoroquinolones (FQ) is commonly used in patients with acute leukemia (AL) during neutropenia. This practice is supported by an older meta-analysis reporting reduced mortality using FQ prophylaxis. Later meta-analyses have failed to reproduce this finding, presumably due to higher background FQ resistance rates limiting their effectiveness. Summary This article reviews the pros and cons of FQ prophylaxis mainly in patients with AL. Most current guidelines do not support universal prophylaxis but rather recommend a selective approach, weighing the benefits against the risks. This recommendation is based on the lack of mortality benefit reported in more recent meta-analyses. FQ prophylaxis was demonstrated to reduce bacteremia and febrile neutropenia episodes, although mostly in trials performed in low resistance settings (<20%), whereas current FQ resistance rates may reach 30-60%. Other disadvantages of FQ include potential adverse events, antibiotic resistance development, cost, increase in Gram-positive infections and resistant Gram-negative infections following prophylaxis, Clostridioides difficile infection, and an effect on gut microbiota. Key messages Taking the above into consideration, alternative approaches other than universal FQ prophylaxis should be considered. Centers with high FQ resistance rates may consider either withholding prophylaxis or providing selective prophylaxis for high-risk patients screened negative for FQ-resistant bacteria.
Background
The use of fluoroquinolones to prevent infections in neutropenic patients with cancer or undergoing hematopoietic stem cell transplantation (HSCT) is a controversial issue, with international guidelines providing conflicting recommendations. Although potential benefits are clear, concerns revolve around efficacy, potential harms, and antimicrobial resistance (AMR) implications.
Discussion
Fluoroquinolone prophylaxis reduces neutropenic fever (NF) bloodstream infections and other serious bacterial infections, based on evidence from systematic reviews, randomized controlled trials, and observational studies in adults and children. Fluoroquinolone prophylaxis may also reduce infection‐related morbidity and healthcare costs; however, evidence is conflicting. Adverse effects of fluoroquinolones are well recognized in the general population; however, studies in the cancer cohort where it is used for a defined period of neutropenia have not reflected this. The largest concern for routine use of fluoroquinolone prophylaxis remains AMR, as many, but not all, observational studies have found that fluoroquinolone prophylaxis might increase the risk of AMR, and some studies have suggested negative impacts on patient outcomes as a result.
Conclusions
The debate surrounding fluoroquinolone prophylaxis calls for individualized risk assessment based on patient characteristics and local AMR patterns, and prophylaxis should be restricted to patients at the highest risk of serious infection during the highest risk periods to ensure that the risk‐benefit analysis is in favor of individual and community benefit. More research is needed to address important unanswered questions about fluoroquinolone prophylaxis in neutropenic patients with cancer or receiving HSCT.
Overview
Patients with cancer have an increased risk of developing infections, owing both to their underlying disease and its treatment. This risk appears to be greatest in patients with hematologic malignancies and in hematopoietic cell transplant recipients. This is due primarily to the development of various immunologic defects such as neutropenia and impaired cellular and/or humoral immunity, each associated with a unique spectrum of infection. Newer therapeutic modalities for the treatment of some cancers are changing the spectrum of infections as are the increasing use of catheters and other medical devices. While bacterial infections are documented most often, opportunistic fungal and viral infections are being encountered with increasing frequency. The morbidity and mortality of infections in cancer patients is generally greater than in the general population. Thus, early diagnosis and the prompt administration of appropriate therapy are of paramount importance. Antimicrobial resistance among these pathogens has become a worldwide problem, which can only be partially tackled by the development of novel agents. Consequently, the importance of conducting frequent epidemiologic surveillance in order to detect local epidemiologic shifts and of infection prevention, infection control, and antimicrobial stewardship cannot be emphasized enough. The number of cancer survivors is steadily increasing. Many of these patients remain immunosuppressed for substantial periods of time. Keeping these survivors healthy and infection free will continue to be a challenge for years to come.
Safe outpatient management of acute leukaemia consolidation cycles may enable substantial savings in admission costs. Safety involves the prompt administration of antibiotics in patients with neutropenic fever. Our unit in a metropolitan tertiary referral hospital analysed a cohort of patients spanning a 10-year period, with two key observations: (i) a high proportion of patients living a substantial distance from hospital and (ii) the high incidence and generally prompt onset of fever after severe neutropenia, suggesting this broad applicability of this approach is unfeasible without addressing travel issues and potentially reducing and/or delaying neutropenic fever with prophylactic antibiotics.
Purpose of review:
Our aim is to review recent literature on antibiotic use in patients with neutropenia.
Recent findings:
Prophylactic antibiotics are associated with risks and have limited mortality benefit. While early antibiotic use in febrile neutropenia (FN) is critical, early de-escalation or discontinuation may be safe in many patients.
Summary:
With an increasing understanding of potential risks and benefits of use and improved risk assessment, paradigms of antibiotic use in neutropenic patients are changing.
Currently there are no guidelines on a safe neutrophil count(ANC) for intravenous antibiotic(IVAB) cessation and hospital discharge in patients recovering after febrile neutropenia(FN). We assessed the safety in selected patients after recent FN of prompt IVAB cessation and hospital discharge. Safety was defined as no fever recurrence after IVAB cessation and readmission in the 10-days post-discharge for infections.A retrospective, single center audit conducted on 92 adult hematology patients admitted with de novo acute myeloid leukemia (AML) for intensive chemotherapy or for an autograft. Most admissions (n = 128/141;91%) were complicated by FN. Half of FN episodes ceased IVAB promptly with a median(range) ANC of 0.6(0.1-4.9x109/L); none of these episodes had recurrent fever requiring IVAB resumption. Prompt discharge occurred in 45% overall. Subsequent unplanned readmission rates were low.In afebrile, stable AML and autograft patients without medico-social barriers to discharge, IVAB can be ceased and hospital discharges safely done ≤24h of ANC ≥ 0.2x109/L.
Overview
Patients with cancer have increased risk of developing infections, owing both to their underlying disease and its treatment. This risk appears to be greatest in patients with hematologic malignancies and in hematopoietic cell transplant (HCT) recipients. This is due primarily to the development of various immunologic defects such as neutropenia and impaired cellular and/or humoral immunity, each associated with a unique spectrum of infection. Newer therapeutic modalities for the treatment of some cancers are changing the spectrum of infections as are the increasing use of catheters and other medical devices. While bacterial infections are documented most often, opportunistic fungal and viral infections are being encountered with increasing frequency. The morbidity and mortality of infection in cancer patients are generally greater than in the general population. Thus, early diagnosis and the prompt administration of appropriate therapy are of paramount importance. Antimicrobial resistance among these pathogens has become a worldwide problem, which can only be partially tackled by the development of novel agents. Consequently, the importance of conducting frequent epidemiologic surveillance in order to detect local epidemiologic shifts and of infection prevention, infection control, and antimicrobial stewardship cannot be emphasized enough. The number of cancer survivors is steadily increasing. Many of these patients remain immunosuppressed for substantial periods of time. Keeping these survivors healthy and infection free will continue to be a challenge for years to come.
Background
Infection related mortality (IRM) is the most common non-relapse mortality reported post allogeneic hematopoietic cell transplantation (HCT). Information on the incidence and timing of specific infective organisms and the risk factors for IRM is essential to developing prevention strategies.
Objective
This report provides the first account of IRM in adults and children undergoing HCT in Australia.
Study Design
Between 2013 and 2018, 2705 adult and 689 pediatric first HCTs were identified from the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) database, with 1075 (39.7%) total overall deaths in adults and 134 (19.4%) in children. Demographics and causes of death including infectious etiology and causative organisms were extracted from the database for adults and children for analysis.
Results
At day 100 and 1-year post-HCT, IRM was the leading cause of early post-HCT mortality in adults, accounting for 6.2% and 9.8%, respectively; in children IRM was the leading cause of post-HCT mortality at day 100 at 2.5%, and the second highest cause of post-HCT mortality at 1-year post-HCT at 4.9%, following relapse at 5.8%. In adults, older age, transplantation not in a first complete remission (non-CR1), the use of ATG or alemtuzumab, CMV serostatus D+/R- and acute Graft Versus Host Disease (aGVHD) were significant risk factors for IRM. However, in children, age >5 years old, Acute Lymphocytic Leukemia (ALL) primary disease and mismatched unrelated or haploidentical donor sources predicted IRM. Of the deaths where an infectious etiology was reported in adults (52.4%), 49.3% were attributed to bacteria, 25.3% to fungus, 21.7% to viruses, and 3.6% to Post-Transplant Lymphoproliferative Disorder (PTLD). The most common organisms were Pseudomonas spp., Enterococcus spp., Candida spp., Aspergillus spp. and cytomegalovirus (CMV). In children where an infectious etiology was reported (64%), 13% were attributed to bacteria, 26% to fungus, 45% to viruses, and 16% to PTLD.
Conclusions
This report highlights that IRM was the leading cause of death early post-HCT in Australia. Strategies to reduce IRM, such as individualized pre-transplant infection risk assessment, rapid diagnostics and prevention management strategies should be explored to determine if these outcomes can be improved. In addition, improving the completeness and accuracy of reported data, particularly the infectious pathogens, could assist in directing management strategies to reduce IRM in HCT.
La leucemia aguda ha sido reconocida como una enfermedad compleja y rápidamente fatal desde su primera descripción hace 150 años. Librada a su historia natural, la leucemia mieloide aguda lleva a la muerte en pocos meses. Las infecciones son la principal causa de muerte, siendo la bacteriemia y la neumonía las más frecuentes.Los avances ocurridos en los últimos 50 años, como el advenimiento de quimioterapias efectivas, la mejor comprensión de la patogénesis de las complicaciones infecciosas en el paciente neutropénico, la disponibilidad de agentes anti infecciosos de amplio espectro y la mejoría en los cuidados de soporte contribuyeron a mejorar esta situación.En relación a otras enfermedades oncohematológicas, la leucemia mieloide aguda registra la mayor incidencia de eventos febriles, siendo el período de mayor riesgo el de la inducción a la remisión.La fiebre de origen desconocido, la multirresistencia bacteriana y las infecciones fúngicas invasivas constituyen un desafío para el equipo de trabajo.El uso de profilaxis antibacteriana y antifúngica no reemplaza a las medidas de prevención de carácter institucional.
Background
Patients with cancer are at high risk for infection, but the epidemiology of healthcare‐associated Staphylococcus aureus bacteraemia (HA‐SAB) and Clostridioides difficile infection (HA‐CDI) in Australian cancer patients has not previously been reported.
Aims
To compare the cumulative aggregate incidence and time trends of HA‐SAB and HA‐CDI in a predefined cancer cohort with a mixed statewide patient population in Victoria, Australia.
Methods
All SAB and CDI events in patients admitted to Victorian healthcare facilities between 1st July 2010 and 31st December 2018 were submitted to the Victorian Healthcare Associated Infection Surveillance System Coordinating Centre. Descriptive analyses and multilevel mixed‐effects Poisson regression modelling were applied to a standardised data extract.
Results
In total, 10,608 and 13,118 SAB and CDI events were reported across 139 Victorian healthcare facilities, respectively. Of these, 89 (85%) and 279 (88%) were healthcare‐associated in the cancer cohort compared to 34% (3,561/10,503) and 66% (8,403/12,802) in the statewide cohort. The aggregate incidence was more than two‐fold higher in the cancer compared to the statewide cohort for HA‐SAB (2.25 [95% CI: 1.74‐2.77] vs. 1.11 [95% CI: 1.07‐1.15] HA‐SABs/10,000 OBDs) and three‐fold higher for HA‐CDI (6.26 [95% CI: 5.12‐7.41] vs. 2.31 [95% CI: 2.21‐2.42] HA‐CDIs/10,000 OBDs). Higher quarterly diminishing rates were observed in the cancer cohort than the statewide data for both infections.
Conclusions
Our findings demonstrate a higher burden of HA‐SAB and HA‐CDI in a cancer cohort when compared with state data and highlight the need for cancer‐specific targets and benchmarks to meaningfully support quality improvement.
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Patients with hematological malignancies are at increased risk for infections caused by disease-related and therapy-induced immunosuppression.(Akova et al. 2005; Crawford et al. 2008) With the change in practice over the last five decades, a significant improvement in the outcome of hematological malignancies with serious infections has been noted. The expected mortality rate was higher than 60% in neutropenic patients in the 1960s.(Hersh et al. 1965) The incidence has dropped to less than 5% with current practice.(Homsi et al. 2000) Antimicrobial prophylaxis is one of the most successful strategies in reducing infection-associated morbidity and mortality in hematological malignancy patients.(Verhoef 1993) Antimicrobial prophylaxis aims to prevent infectious morbidity and all its consequences, including hospitalization, quality of life, cost of treatment, treatment-related adverse events, and death.
Purpose of review:
Data on the infectious complications of anti-CD19 chimeric antigen receptor-modified T-cell (CAR-T-cell) therapies are scant. The approaches to preventing and managing infections among CAR-T-cell recipients are extrapolated from those of patients with other hematological malignancies. Understanding the incidence and risk factors of infections in these patients will improve clinical outcomes.
Recent findings:
Infections occur in 23-42% of CAR-T-cell recipients and are most frequent in the first month after infusion, declining sharply thereafter. Risk factors include preinfusion (e.g., prior hematopoietic cell transplant, underlying malignancy) and postinfusion variables (e.g., cytokine release syndrome [CRS], neutropenia). Neutropenic fever after CAR-T-cell therapy is nearly universal but is confounded by CRS. The timeline of infections can be divided into preinfusion (because of the preparative regimen); 0-30 days after infusion, when bacterial infections predominate; and 30 days onwards, when respiratory viral infections predominate. Fungal and herpesviridae infections are uncommon.
Summary:
Recent studies have shed light on the epidemiology of infections after CAR-T-cell therapy. Future efforts should focus on identifying modifiable risk factors for infection, defining neutropenic fever in the setting of CRS, determining the benefit of antimold prophylaxis, and identifying the optimal approach to viral monitoring, vaccination, and immunoglobulin replacement.
Aims:
Multidrug-resistant (MDR) bacteria are an emerging cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The aim of the study was to analyze the incidence, clinical characteristics and survival from bacterial infections caused by MDR pathogens in pediatric HSCT recipients.
Methods and results:
Between 2012 and 2017, among 971 transplanted patients, bacterial infections were found in 416 children. Overall, there were 883 bacterial episodes, including 85.8% after allo-HSCT and 14.2% after auto-HSCT. MDR strains were responsible for half of the total number of bacterial episodes. Over 50% of MDR pathogens were Enterobacteriaceae causing mainly gut infections or urinary tract infections.
Conclusions:
Regarding HSCT type, we did not find differences in the profile of MDR bacterial infections between allo- and auto-HSCT recipients. However, survival in MDR and non-MDR infections was comparable.
Significance and impact of study:
The large sample size enables unique analysis and makes our data more applicable to other pediatric HSCT centers. In case of the absence of local epidemiological data, presented clinical characteristic of MDR-caused infections may be used to optimize the prophylactic strategies, early identification of infectious complications of MDR etiology, and thus promptly initiate adequate antibiotic therapy and further improve patients' outcome.
According to the definition of the National Cancer Institute, supportive care (SC) includes early and multidisciplinary management of symptoms of the disease, treatment-related side effects and diverse psychological, social and spiritual problems of the affected person. The aims of supportive care usually mingle with palliative care, which will be discussed separately. The main goal of supportive care is to improve or at least maintain the patient’s quality of life during cancer treatment. This is why SC is focused not only on the physical but also on the emotional, social and all other problems, which are important in normal life. There is a separate chapter on the psychological impacts of breast cancer (Chap. 20, Holcombe) so this chapter will focus on the physical elements of SC with special reference to chemotherapy issues and thromboembolic complications.
Objectives:
Fluoroquinolone (FQ) prophylaxis was recommended in 2005 by European Conference on Infections in Leukemia (ECIL) for patients with prolonged neutropenia. In consideration of a worldwide increase in antibiotic resistance, the issue of FQ prophylaxis during neutropenia was re-evaluated.
Methods:
Literature review of randomised controlled trials (RCT) and observational studies published in years 2006-2014 was performed. Their results were analysed in meta-analysis. Meta-regression model was applied to evaluate whether the rates of FQ resistance in community and hospital settings influenced the efficacy of FQ prophylaxis. The impact of FQ prophylaxis on colonisation and infection with resistant bacteria was reviewed.
Results:
Two RCTs and 12 observational studies were identified. FQ prophylaxis did not have effect on mortality (pooled OR 1.01, 95%CI 0.73-1.41), but was associated with lower rate of bloodstream infections (BSI) (pooled OR 0.57, 95%CI 0.43-0.74) and episodes of fever during neutropenia (pooled OR 0.32, 95%CI 0.20-0.50). No effect of the background rate of FQ resistance on the efficacy of FQ prophylaxis was observed. In few studies, FQ prophylaxis resulted in an increased colonisation or infection with FQ- or multi-drug resistant strains.
Conclusions:
The possible benefits of FQ prophylaxis on BSI rate, but not on overall mortality, should be weighed against its impact in terms of toxicity and changes in local ecology in single centres.
Patients undergoing intensive chemotherapy for acute myeloid leukemia are at high risk for bacterial infections during therapy-related neutropenia. However, the use of specific antibiotic regimens for prophylaxis in afebrile neutropenic acute myeloid leukemia patients is controversial. This was a retrospective evaluation of 172 acute myeloid leukemia patients who received 322 courses of myelosuppressive chemotherapy and had an expected duration of neutropenia of >7 days. The patients were allocated to antibiotic prophylaxis groups and treated with colistin or ciprofloxacin through 2 different hematological services at our hospital as available. The infection rate was reduced from 88.6% to 74.2% through antibiotic prophylaxis (vs. without prophylaxis, p=0.04). A comparison of both antibiotic drugs revealed a trend towards fewer infections associated with ciprofloxacin prophylaxis (69.2% vs. 79.5% in the colistin group, p=0.07), as determined by univariate analysis. This result was confirmed through multivariate analysis (OR 0.475, 95%CI 0.236-0.958; p=0.041). The prophylactic agents did not differ with regard to the microbiological findings (p=0.6, n.s.). Of note, the use of ciprofloxacin was significantly associated with an increased rate of infections with pathogens that are resistant to the antibiotic used for prophylaxis (79.5% vs. 9.5% in the colistin group, p<0.0001). The risk factors for higher infection rates were the presence of a central venous catheter (p<0.0001), mucositis grade III/IV (p=0.0039), and induction/relapse courses (vs. consolidation, p<0.0001). Concluding, ciprofloxacin prophylaxis appears to be of particular benefit during induction and relapse chemotherapy for acute myeloid leukemia. To prevent and control drug resistance, it may be safely replaced by colistin during consolidation cycles of acute myeloid leukemia therapy.
Multidrug-resistant (MDR) bacteria, particularly Gram negatives, such as Enterobacteriaceae resistant to third-generation cephalosporins or carbapenems and MDR Pseudomonas aeruginosa, are increasingly frequent in hematology patients. The prevalence of different resistant species varies significantly between centers. Thus, the knowledge of local epidemiology is mandatory for deciding the most appr-opriate management protocols. In the era of increasing antibiotic resistance, empirical therapy of febrile neutropenia should be individualized. De-escalation approach is recommended in case of severe clinical presentation in patients who are at high risk for infection with a resistant strain. Targeted therapy of an MDR Gram negative usually calls for a combination treatment, although no large randomized trials exist in this setting. Infection control measures are the cornerstone of limiting the spread of MDR pathogens in hematology units.
Purpose
Guidelines generally do not recommend oral antimicrobials for prophylaxis against chemotherapy-related infections in patients with solid tumors. Evidence on antimicrobial prophylaxis use, and associated chemotherapy-related infection risk, in US clinical practice is limited.
Methods
A retrospective cohort design and data from two US private healthcare claims repositories (2008–2011) were employed. Study population included adults who received myelosuppressive chemotherapy for non-metastatic cancer of the breast, colon/rectum, or lung, or for non-Hodgkin’s lymphoma. For each subject, the first chemotherapy course was characterized, and within the first course, each chemotherapy cycle and chemotherapy-related infection episode was identified. Use of prophylaxis with oral antimicrobials and colony-stimulating factors in each cycle also was identified.
Results
A total of 7116 (22% of all) non-metastatic breast cancer, 1833 (15%) non-metastatic colorectal cancer, 1999 (15%) non-metastatic lung cancer, and 1949 (21%) non-Hodgkin’s lymphoma patients received antimicrobial prophylaxis in ≥1 cycle. Mean number of antimicrobial prophylaxis cycles during the course among these patients was typically <2, with little difference across cancers and chemotherapy regimens. Fluoroquinolones were the most commonly received class of antimicrobials, accounting for 20%–50% all antimicrobials administered. Among subjects who received first-cycle antimicrobial prophylaxis, chemotherapy-related infection risk in that cycle ranged from 3% to 6% across cancer types. Among patients who received first-cycle antimicrobial prophylaxis and developed chemotherapy-related infections, 38%–67% required inpatient care. Chemotherapy-related infection risk in subsequent cycles with antimicrobial prophylaxis was comparable.
Conclusion
The results of this study suggest that use of antimicrobial prophylaxis during myelosuppressive chemotherapy is far from uncommon in clinical practice. The results also suggest that an important minority of cancer chemotherapy patients receiving antimicrobial prophylaxis still develop serious infection requiring hospitalization.
The emergence of resistance has been demonstrated in cancer treatment centers where prophylaxis with fluoroquinolone is used.
Considering the importance of epidemiological monitoring as a strategy in choosing protocols involving antibiotics, this study aimed to evaluate the emergence of quinolone resistance and changes in the local epidemiology in a hematopoietic stem cell transplant service.
For this study, 60 positive cultures before the prophylactic use of levofloxacin (period A: 2007-2008) and 118 cultures after starting the use of prophylactic levofloxacin (period B: 2010-2011) were evaluated.
Resistance increased for all the different types of bacteria isolated (from 46.0% to 76.5%; p-value = 0.0002). Among Gram-negative bacteria, resistance increased from 21.4% to 60.7% (p-value = 0.0163) and among Gram-positive bacteria, it increased from 55.6% to 82.9% (p-value = 0.0025). The use of levofloxacin increased from 19.44 defined daily doses per 1,000 patient-days in period A to 166.64 in period B. The use of broad spectrum antibiotics remained unchanged. Considering bacteria associated with infection, 72 and 76 were isolated in periods A and B, respectively. There was a reduction in the rate of Gramnegative bacteria in cultures associated with infection (3.81 vs. 2.00 cultures/1,000 patientdays; p-value = 0.008).
The study of prophylaxis with levofloxacin demonstrated that there was a decrease in infections by Gram-negative bacteria; however, bacterial resistance increased, even though the use of broad-spectrum antibiotics remained unchanged. Constant monitoring of local epidemiology combined with research on clinical outcomes is needed to evaluate the effectiveness of prophylaxis.
Purpose:
To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia.
Methods:
A literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus.
Results:
Forty-seven articles from 43 studies met selection criteria.
Recommendations:
Antibacterial and antifungal prophylaxis are only recommended for patients expected to have < 100 neutrophils/μL for > 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcott's rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empirical antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.
Background:
Fluoroquinolones reduce occurrence of fever in adult cancer patients who develop neutropenia, but there has been no randomized controlled trial in children, and there are only a few studies considering resistance in intestinal floral after ciprofloxacin has been used.
Methods:
Children younger than 18 years with acute lymphoblastic leukemia or lymphoma scheduled to undergo chemotherapy were randomized to receive oral ciprofloxacin 20mg/kg/day or placebo from the beginning of their chemotherapy. Rectal swab cultures were taken before and at 1 and/or 2 weeks after the intervention.
Results:
Of the total of 95 patients, 45 and 50 patients received ciprofloxacin and placebo, respectively. Of the 71 patients who developed neutropenia, the proportion of children who developed fever was significantly lower in the ciprofloxacin group than in the placebo group (17/34 [50.0%] versus 27/37 [73.0%]; absolute difference in risk, -23.0%; 95% confidence interval: -45.0% to -0.9%; P = 0.046). Ciprofloxacin significantly reduced the occurrence of febrile episodes in patients with acute lymphoblastic leukemia in the induction phase of chemotherapy, but not in patients with lymphoma or in the consolidation phase of chemotherapy. Adverse effects were not different between the groups. After intervention, the percentages of Escherichia coli and Klebsiella pneumoniae susceptible to ciprofloxacin were significantly lower in the ciprofloxacin group.
Conclusion:
Ciprofloxacin can prevent fever in neutropenic patients with acute lymphoblastic leukemia during the induction phase of chemotherapy with good tolerance and no serious side effects. Due to the selective pressure of intestinal flora resistance to ciprofloxacin, the long-term effectiveness needs further investigation.
Antibiotic prophylaxis has been found to have multiple benefits in patients receiving intensive chemotherapy at high risk for infection. Interest continues in identifying what additional groups of high-risk patients might potentially benefit from its use. However, concerns about the potential emergence of antibiotic resistance have led to multiple recent studies exploring this issue.
The use of antibiotic prophylaxis in pediatric leukemia, myelodysplastic syndromes, and hematopoietic stem cell transplant populations has been evaluated in recent studies. Several centers have noted increased rates of antibiotic resistance in patients receiving prophylaxis.
Several single-center studies have emphasized the concern for the emergence of antibiotic resistance associated with the routine use of fluoroquinolone prophylaxis. The potential for antibiotic resistance continues to be worrisome and warrants further ongoing studies.
The current consensus guidelines were developed to standardize the clinical approach to the management of neutropenic fever in adult cancer patients throughout Australian treating centres. The three areas of clinical practice covered by the guidelines, the process for developing consensus opinion, and the system used to grade the evidence and relative strength of recommendations are described. The health economics implications of establishing clinical guidance are also discussed. © 2011 The Authors. Internal Medicine Journal
BACKGROUND
Infection remains the major cause of morbidity and mortality in patients with neutropenia, and the beneficial effects of oral prophylaxis remain controversial.METHODS
From 1993 to December 1999, the authors analyzed the clinical and microbiologic outcomes of 144 episodes of febrile neutropenia among adult patients with acute leukemia.RESULTSForty-three consecutive episodes occurred among patients who were on ciprofloxacin prophylaxis during 1993–1996 (ciprofloxacin group), and 101 subsequent episodes occurred among patients who were not exposed to ciprofloxacin prophylaxis (control group). There were no differences in clinical presentation, antibiotic treatment received for the episode, or a worse outcome between groups. The rate of bacteremia was similar (12 of 43 patients [28%] vs. 26 of 101 patients [26%], respectively). There was a trend toward a higher rate of Gram positive bacteremia in the control group (12 of 101 patients [12%] vs. 2 of 43 patients [5%]) and a higher rate of Gram negative bacteremia in the ciprofloxacin group (11 of 43 patients [26%] vs. 15 of 101 patients [15%]). Resistance to fluoroquinolones was greater in Escherichia coli blood isolates from patients in the ciprofloxacin group (7 of 8 patients vs. 2 of 9 patients; P = 0.02).CONCLUSIONS
The current results suggest that fluoroquinolone prophylaxis for patients with febrile neutropenia may be abandoned safely in areas with a high prevalence of ciprofloxacin-resistant enterobacteria. Cancer 2003;97:419–24. © 2003 American Cancer Society.DOI 10.1002/cncr.11044
We identified 1,805 gram-negative organisms in cultures of urine samples obtained over a 10-month period from residents of 63 longterm care facilities. The prevalence of fluoroquinolone resistance in Escherichia coli was 51% (446 of 874 isolates), whereas the prevalences of ceftazidime and imipenem resistance in Klebsiella species were 26% and 6% (84 and 19 of 323 isolates), respectively. The prevalence of resistance varied significantly by facility type, size, and geographic location. © 2009 by The Society for Healthcare Epidemiology of America. All rights reserved.
To describe the predictive factors for the isolation of fluoroquinolone-resistant or extended- spectrum beta-lactamase (ESBL)-producing Escherichia coli and their impact on bacteraemia outcome.
Analysis of E. coli bacteraemia episodes prospectively collected through a blood culture surveillance programme from January 1991 to December 2007.
Out of 18 080 episodes, 4758 (26%) E. coli bacteraemias were reported in the period of study. Mortality was noted in 440 cases (9%). Fluoroquinolone-resistant strains were reported in 1300 (27%) cases and ESBL-producing strains in 211 cases (4%). One hundred and seventy-eight strains out of 211 (84%) ESBL-producing E. coli were isolated since 2001. The two main independent risk factors for mortality were shock (OR: 10.28, P < 0.001) and inappropriate empirical therapy (OR: 4.83, P < 0.001). Inappropriate empirical therapy was significantly more frequent for infections caused by fluoroquinolone-resistant strains (n = 203, 16%, P < 0.001) and ESBL-producing strains (n = 110, 52%, P < 0.001). Independent factors associated with the isolation of a fluoroquinolone-resistant strain were: nosocomial origin (OR: 1.61, P < 0.001); urinary catheterization (OR: 2.44, P < 0.001); and previous therapy with a fluoroquinolone (OR: 7.41, P < 0.001). The independent risk factors associated with the isolation of an ESBL-producing strain were: nosocomial origin (OR: 1.68, P = 0.03); urinary catheterization (OR: 1.88, P = 0.001); and previous beta-lactam antibiotic therapy (OR: 2.81, P < 0.001).
Inappropriate empirical therapy was the strongest independent factor that we could modify to improve mortality in E. coli bacteraemia and was more frequent in cases caused by fluoroquinolone-resistant or ESBL-producing strains. Nosocomial acquisition, urinary catheterization and previous therapy with a fluoroquinolone or beta-lactam were predictive factors for infection with an antibiotic-resistant strain.
The prevalence of fluoroquinolone (FQ) resistance in Escherichia coli has increased markedly in recent years. Despite the important role of gastrointestinal tract colonization with FQ-resistant E. coli (FQREC), the prevalence of and risk factors for FQREC colonization among the general hospitalized patient population have not been described, to our knowledge. The objective of this study was to identify the prevalence of and risk factors for FQREC colonization among hospitalized patients.
Three-year case-control study. Case patients (ie, all subjects with FQREC colonization) were compared with control patients (ie, all subjects without FQREC colonization).
Two large medical centers within an academic health system.
All patients hospitalized at the 2 study hospitals.
Three annual fecal surveillance surveys were conducted. All patients colonized with FQREC (levofloxacin minimum inhibitory concentration, >or=8 microg/mL) were identified.
Of the 774 subjects, 89 (11.5%) were colonized with FQREC. Although there was a significant association between prior FQ use and FQREC colonization on bivariable analysis (odds ratio [OR], 2.02 [95% confidence interval {CI}, 1.14-3.46]; P=.01), there was statistically significant effect modification by year of study (P=.005). In multivariable analyses, after controlling for the hospital and for the duration of hospitalization prior to sampling, the association between FQ use and FQREC colonization was as follows: adjusted OR (aOR), 0.97 (95% CI, 0.29-3.23) in 2002; aOR, 1.41 (95% CI, 0.57-3.50) in 2003; and aOR, 9.87 (95% CI, 3.67-26.55) in 2004.
The association between prior FQ use and FQREC colonization varied significantly by study year, suggesting that the clinical epidemiology of resistant organisms may change over time. Furthermore, in the context of recent work showing significant changes in FQREC prevalence as well as changes in FQ resistance mechanisms (specifically, efflux overexpression) over the same time period, these results suggest a previously unrecognized complexity in the relationship between the clinical and molecular epidemiology of FQ resistance.
We studied 122 stool samples collected from 25 patients with hematologic malignancies who received prophylactic norfloxacin. Fecal samples were obtained at admission and twice weekly thereafter during prophylaxis. Fluoroquinolone-resistant Escherichia coli strains were isolated from the feces of 10 (40%) of the patients; two patients had fluoroquinolone-resistant E. coli strains prior to beginning norfloxacin treatment, and in the other eight patients, the strains appeared subsequently. One patient developed fluoroquinolone-resistant E. coli bacteremia after 10 days of norfloxacin administration.
A prospective study of Klebsiella pneumoniae bacteremia was performed in 12 hospitals in 7 countries. Of 452 episodes of bacteremia, 25 (5.5%) were caused by K. pneumoniae that was resistant in vitro to ciprofloxacin. Extended-spectrum β-lactamase (ESBL) production was detected in 15 (60%) of
25 ciprofloxacin-resistant isolates, compared with 68 (16%) of 427 ciprofloxacin-susceptible strains (P = .0001). Multivariate analysis revealed that risk factors for ciprofloxacin resistance in K. pneumoniae included prior receipt of a quinolone (P = .0065) and an ESBL-producing strain (P = .012). In all, 18% of ESBL-producing isolates were also ciprofloxacin-resistant. Pulsed-field gel electrophoresis showed
that 11 of the 15 ciprofloxacin-resistant ESBL-producing strains belonged to just 4 genotypes, suggesting that patient-to-patient
transmission of such strains occurred. The close relationship between ESBL production and ciprofloxacin resistance is particularly
worrisome because the first reported instance of plasmid-mediated ciprofloxacin resistance has been in an isolate of K. pneumoniae also possessing an ESBL.
Oropharyngeal samples from 60 hospitalized patients (30 fluoroquinolone [FQ]-treated and 30 non-FQ-treated patients) and 30
untreated nonhospitalized healthy control subjects yielded 20 isolates of viridans group streptococci with reduced susceptibility
to FQ, mostly from the hospitalized patients. An efflux phenotype was commonly encountered, expressed either alone or with
topoisomerase mutations. Interspecies transfer of the efflux phenotype was demonstrated via transformation of Streptococcus pneumoniae R6 with DNA fromS. mitis and S. oralis.
This article, prepared by the Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guidelines Panel, updates guidelines established a decade ago by the Infectious Disease Society of America for the use of antimicrobial agents to treat neutropenic patients with unexplained fever [1].
In Europe, antimicrobial resistance of invasive pathogens has been monitored since 1998 by the European Antimicrobial Resistance Surveillance System (EARSS). The goal of this study is to analyse the susceptibility data of invasive Escherichia coli collected by 27 Spanish laboratories in 2001. Each laboratory identified strains and tested their susceptibility using its own methods. To assess the comparability of susceptibility test results, a quality assurance exercise was performed. We report data from 1962 invasive isolates of E. coli: 1959 from blood and three from cerebrospinal fluid, corresponding to the same number of patients. Resistance to ampicillin, co-trimoxazole, ciprofloxacin and gentamicin was found in 58.46%, 32.91%, 17.19% and 6.39% of isolates, respectively. Extended-spectrum beta-lactamase (ESBL) production was detected in 30 strains (1.55%). Ciprofloxacin resistance was higher in isolates from men and in-patients than in those from women and out-patients (P < 0.001). Resistance to ampicillin and co-trimoxazole was more widespread in children than in adults: 70.37% versus 57.87% (P = 0.01) and 41.84% versus 32.53% (P = 0.05). Non-significant differences in resistance to fluoroquinolones were observed between isolates from children (11.1%) and adults (17.54%), despite the fact that fluoroquinolones are not administered to children. Significantly, resistance to non-beta-lactam antibiotics (co-trimoxazole, ciprofloxacin and gentamicin) was more prevalent in ampicillin-resistant strains and ESBL-producing strains than in ampicillin-susceptible strains and non-ESBL-producing strains. Multidrug resistance was present in 13.92% of isolates; the most prevalent phenotype was resistance to ampicillin, co-trimoxazole and ciprofloxacin, which was detected in 59.36% of multiresistant strains and in 8.22% of strains overall.
Previous surveillance studies have documented increasing rates of antimicrobial resistance in US intensive care units (ICUs) in the early 1990s.
To assess national rates of antimicrobial resistance among gram-negative aerobic isolates recovered from ICU patients and to compare these rates to antimicrobial use.
Participating institutions, representing a total of 43 US states plus the District of Columbia, provided antibiotic susceptibility results for 35 790 nonduplicate gram-negative aerobic isolates recovered from ICU patients between 1994 and 2000.
Each institution tested approximately 100 consecutive gram-negative aerobic isolates recovered from ICU patients. Organisms were identified to the species level. Susceptibility tests were performed, and national fluoroquinolone consumption data were obtained.
The activity of most antimicrobial agents against gram-negative aerobic isolates showed an absolute decrease of 6% or less over the study period. The overall susceptibility to ciprofloxacin decreased steadily from 86% in 1994 to 76% in 2000 and was significantly associated with increased national use of fluoroquinolones.
This study documents the increasing incidence of ciprofloxacin resistance among gram-negative bacilli that has occurred coincident with increased use of fluoroquinolones. More judicious use of fluoroquinolones will be necessary to limit this downward trend.
Antibiotic resistance typically confers a biological fitness cost on bacteria that can be manifested as a decreased growth rate in culture media and experimental animals. However, there are limited experimental data on the relative fitness of resistant and susceptible bacteria during growth in their natural environment.
We have developed a human competition model to investigate the relative fitness of antibiotic-resistant and -susceptible bacteria.
A non-epidemic Staphylococcus epidermidis strain was isolated from skin, and a rifampicin-resistant (RifR) clone was selected. The RifR marker was used to distinguish the inoculated strains from the resident population of coagulase-negative staphylococci. The RifR strains were further selected for resistance to ciprofloxacin (CipR) and fusidic acid (FusR). A 1:1 mix of susceptible and resistant bacteria was applied on the forearms of 12 volunteers. Competition was monitored by sampling bacteria from skin and determining their relative numbers.
Resistance to ciprofloxacin due to parC mutations did not decrease the growth rate in vitro, and the CipR/CipS ratio was close to 1 during day 1 and 3 in the in vivo competition experiments. In contrast, fusidic acid resistance due to fusA mutations resulted in a decrease in the growth rate in vitro and a considerable loss of fitness in the competition. The FusR/FusS ratio diminished from 1.3 to 0.023 in 3 days.
These data show that human volunteers can be used as a simple and relevant model to study the biological cost of resistance.
To determine whether fluoroquinolone exposure is a risk factor for the isolation of Staphylococcus aureus and whether the effect is different for methicillin-resistant S. aureus (MRSA) versus methicillin--susceptible S. aureus (MSSA), we studied two case groups. The first case group included 222 patients with nosocomially acquired MRSA. The second case group included 163 patients with nosocomially acquired MSSA. A total of 343 patients admitted concurrently served as controls. Outcome measures were the adjusted odds ratio (OR) for isolation of MRSA and MSSA after fluoroquinolone exposure. Exposure to both levofloxacin (OR 5.4; p <0.0001) and ciprofloxacin (OR 2.2; p < 0.003) was associated with isolation of MRSA but not MSSA. After adjustment for multiple variables, both drugs remained risk factors for MRSA (levofloxacin OR 3.4; p <0.0001; ciprofloxacin OR 2.5; p = 0.005) but not MSSA. Exposure to levofloxacin or ciprofloxacin is a significant risk factor for the isolation of MRSA, but not MSSA.
Similar to many hospitals worldwide, Aberdeen Royal Infirmary has had an outbreak of methicillin-resistant Staphylococcus aureus (MRSA). In this setting, the outbreak is attributable to two major clones. The relationships between antimicrobial use and MRSA prevalence were analyzed by time-series analysis. From June 1997 to December 2000, dynamic, temporal relationships were found between monthly %MRSA and previous %MRSA, macrolide use, third-generation cephalosporin use, and fluoroquinolone use. This study suggests that use of antimicrobial drugs to which the MRSA outbreak strains are resistant may be an important factor in perpetuating the outbreak. Moreover, this study confirmed the ecologic effect of antimicrobial drug use (i.e., current antimicrobial use) may have an effect on resistance in future patients. Although these results may not be generalized to other hospitals, they suggest new directions for control of MRSA, which has thus far proved difficult and expensive.
To compare rates of in vitro fluoroquinolone resistance of bacterial isolates obtained from inpatients of two haematology-oncology services with high and low fluoroquinolone consumption.
Two hospitals with consistently high (A) and low (B) fluoroquinolone use in their haematology-oncology services between the years 1999 and 2002 were identified in a hospital antibiotic use surveillance project. Rates of in vitro resistance to fluoroquinolones in inpatients of the services were determined for Escherichia coli and coagulase-negative staphylococcal bloodstream isolates, and also for Pseudomonas aeruginosa and Staphylococcus aureus isolates from any site.
Fluoroquinolone resistance of E. coli was significantly higher in hospital A than in hospital B, but there was no such correlation between fluoroquinolone use and resistance rates for P. aeruginosa and staphylococci.
The impact of antibiotic consumption on the prevalence of resistance may differ widely between different pathogens. Interventions using ecological analyses of the relationship between hospital antibiotic use and resistance need to consider pathogen-specific dynamics in the emergence and control of bacterial resistance.
We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer.
We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival.
At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P<0.001); rates of febrile neutropenia were 24.7 percent and 2.5 percent, respectively (P<0.001). Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC (P=0.05); no deaths occurred as a result of infection. Two patients in each group died during treatment. Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group. Quality-of-life scores decreased during chemotherapy but returned to baseline levels after treatment.
Adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.
Few long-term multicenter investigations have evaluated the relationships between aggregate antimicrobial drug use in hospitals and bacterial resistance. We measured fluoroquinolone use from 1999 through 2003 in a network of US hospitals. The percentages of fluoroquinolone-resistant Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) were obtained from yearly antibiograms at each hospital. Univariate linear regression showed significant associations between a hospital's volume of fluoroquinolone use and percent resistance in most individual study years (1999-2001 for P. aeruginosa, 1999-2002 for S. aureus). When the method of generalized estimating equations was used, a population-averaged longitudinal model incorporating total fluoroquinolone use and the previous year's resistance (to account for autocorrelation) did not show a significant effect of fluoroquinolone use on percent resistance for most drug-organism combinations, except for the relationship between levofloxacin use and percent MRSA. The ecologic relationship between fluoroquinolone use and resistance is complex and requires further study.
Since 2002, an epidemic of Clostridium difficile-associated-diarrhea (CDAD) associated with a high case-fatality rate has involved >30 hospitals in the province of Quebec, Canada. In 2003, a total of 55% of patients with CDAD at our hospital had received fluoroquinolones in the preceding 2 months. It has been suggested that massive use of proton pump inhibitors might have facilitated this epidemic.
To delineate the risk of CDAD associated with specific classes of antibiotics and whether this is modulated by concomitant use of proton pump inhibitors and other drugs altering gastric acidity or gastrointestinal motility, we conducted a retrospective cohort study of patients hospitalized in a teaching hospital in Sherbrooke, Canada, during the period of January 2003 through June 2004. We obtained data on 7421 episodes of care corresponding to 5619 individuals. Patients were observed until they either developed CDAD or died or for 60 days after discharge from the hospital. Adjusted hazard ratios (AHRs) were calculated using Cox regression.
CDAD occurred in 293 patients. Fluoroquinolones were the antibiotics most strongly associated with CDAD (AHR, 3.44; 95% confidence interval [CI], 2.65-4.47). Almost one-fourth of all inpatients received quinolones, for which the population-attributable fraction of CDAD was 35.9%. All 3 generations of cephalosporins, macrolides, clindamycin, and intravenous beta-lactam/beta-lactamase inhibitors were intermediate-risk antibiotics, with similar AHRs (1.56-1.89). Proton pump inhibitors (AHR, 1.00, 95% CI, 0.79-1.28) were not associated with CDAD.
Administration of fluoroquinolones emerged as the most important risk factor for CDAD in Quebec during an epidemic caused by a hypervirulent strain of C. difficile.
Recent experience with influenza, the severe acute respiratory syndrome (also known as SARS), avian influenza, and community-acquired methicillin-resistant Staphylococcus aureus has demonstrated how old pathogens can emerge with increased virulence and challenge scientists to explain their rebirth, clinicians to care for patients, and infection-control personnel to prevent their spread. Clostridium difficile appears to illustrate these challenges. It already has some distinctive features: it causes disease almost exclusively in the presence of exposure to antibiotics, it is the only anaerobe that poses a nosocomial risk, and it produces toxin in vivo only in the colon. About 3 percent of healthy adults . . .
In March 2003, several hospitals in Quebec, Canada, noted a marked increase in the incidence of Clostridium difficile-associated diarrhea.
In 2004 we conducted a prospective study at 12 Quebec hospitals to determine the incidence of nosocomial C. difficile-associated diarrhea and its complications and a case-control study to identify risk factors for the disease. Isolates of C. difficile were typed by pulsed-field gel electrophoresis and analyzed for binary toxin genes and partial deletions in the toxin A and B repressor gene tcdC. Antimicrobial susceptibility was evaluated in a subgroup of isolates.
A total of 1703 patients with 1719 episodes of nosocomial C. difficile-associated diarrhea were identified. The incidence was 22.5 per 1000 admissions. The 30-day attributable mortality rate was 6.9 percent. Case patients were more likely than matched controls to have received fluoroquinolones (odds ratio, 3.9; 95 percent confidence interval, 2.3 to 6.6) or cephalosporins (odds ratio, 3.8; 95 percent confidence interval, 2.2 to 6.6). A predominant strain, resistant to fluoroquinolones, was found in 129 of 157 isolates (82.2 percent), and the binary toxin genes and partial deletions in the tcdC gene were present in 132 isolates (84.1 percent).
A strain of C. difficile that was resistant to fluoroquinolones and had binary toxin and a partial deletion of the tcdC gene was responsible for this outbreak of C. difficile-associated diarrhea. Exposure to fluoroquinolones or cephalosporins was a risk factor.
Infection control programs were created three decades ago to control antibiotic-resistant healthcare-associated infections, but there has been little evidence of control in most facilities. After long, steady increases of MRSA and VRE infections in NNIS System hospitals, the Society for Healthcare Epidemiology of America (SHEA) Board of Directors made reducing antibiotic-resistant infections a strategic SHEA goal in January 2000. After 2 more years without improvement, a SHEA task force was appointed to draft this evidence-based guideline on preventing nosocomial transmission of such pathogens, focusing on the two considered most out of control: MRSA and VRE.
Medline searches were conducted spanning 1966 to 2002. Pertinent abstracts of unpublished studies providing sufficient data were included.
Frequent antibiotic therapy in healthcare settings provides a selective advantage for resistant flora, but patients with MRSA or VRE usually acquire it via spread. The CDC has long-recommended contact precautions for patients colonized or infected with such pathogens. Most facilities have required this as policy, but have not actively identified colonized patients with surveillance cultures, leaving most colonized patients undetected and unisolated. Many studies have shown control of endemic and/or epidemic MRSA and VRE infections using surveillance cultures and contact precautions, demonstrating consistency of evidence, high strength of association, reversibility, a dose gradient, and specificity for control with this approach. Adjunctive control measures are also discussed.
Active surveillance cultures are essential to identify the reservoir for spread of MRSA and VRE infections and make control possible using the CDC's long-recommended contact precautions.
Background:
Bacterial infections are a major cause of illness and death in patients who are neutropenic after chemotherapy treatment for cancer. Trials have shown the efficacy of antibiotic prophylaxis in decreasing the incidence of bacterial infections but not in reducing mortality rates.
Purpose:
To evaluate whether antibiotic prophylaxis in neutropenic patients reduces mortality and incidence of infection and to assess related adverse events.
Data sources:
The Cochrane Cancer Network register of trials (2004), The Cochrane Library (Issue 4, 2004), EMBASE (1980-2004), MEDLINE (1966-2004), and references of identified studies.
Study selection:
Randomized, controlled trials comparing antibiotic prophylaxis with placebo or no intervention or another antibiotic in afebrile neutropenic patients.
Data extraction:
Two reviewers independently appraised the quality of trials and extracted data.
Data synthesis:
Ninety-five trials performed between 1973 and 2004 met inclusion criteria. Fifty-two trials addressed quinolone prophylaxis. Antibiotic prophylaxis significantly decreased the risk for death when compared with placebo or no treatment (relative risk, 0.67 [95% CI, 0.55 to 0.81]). All prophylactic antibiotics were associated with an increased risk for adverse events (relative risk, 1.69 [CI, 1.14 to 2.50]). Fluoroquinolone prophylaxis reduced the risk for all-cause mortality (relative risk, 0.52 [CI, 0.35 to 0.77]), as well as infection-related mortality, fever, clinically documented infections, and microbiologically documented infections. Fluoroquinolone prophylaxis increased the risk for harboring bacilli resistant to the specific drug after treatment and adverse events, but these results were not statistically significant (relative risks, 1.69 [CI, 0.73 to 3.92]) and 1.30 [CI, 0.61 to 2.76], respectively).
Limitations:
Most trials involved patients with hematologic cancer. Data on all-cause mortality were missing in 10 of 50 trials comparing prophylaxis with no prophylaxis. Effect estimates were larger in trials of unclear methodologic quality compared with trials of adequate methodologic quality.
Conclusions:
Antibiotic prophylaxis for neutropenic patients undergoing cytotoxic therapy reduces mortality. Mortality was substantially reduced when analysis was limited to fluoroquinolones. Antibiotic prophylaxis, preferably with a fluoroquinolone, should be considered for neutropenic patients.
An abundance of new evidence regarding treatment strategies for neutropenic fever is likely to contribute to variability in practice across institutions and clinicians alike.
To describe current clinical practices in Australia, by surveying haematologists, oncologists and infectious diseases physicians involved in cancer care.
Clinician members from Australian professional associations, accounting for the vast majority of Australian cancer specialists, were invited to participate in an electronic survey, comprising of a clinical case-based questionnaire. Clinical practice areas explored were: use of risk-assessment and empiric antibiotic strategies across various treatment settings; use of anti-bacterial prophylaxis; and use of granulocyte-colony stimulating factors for established neutropenic fever and for secondary prophylaxis.
A total of 252 clinicians returned responses (approximately 30% response rate). The majority (>70%) were representative of practices in public, major city, tertiary referral hospitals. Less than half of clinicians were aware of risk-assessment tools and less than quarter currently used ambulatory care strategies. If adequate resources were made available, more than 80% were willing to use risk-assessment tools and 60% more clinicians were likely to use ambulatory care strategies. Most clinicians prescribed dual therapy parenteral antibiotics, even for clinically stable patients (53% haematologists, 56% oncologists). Granulocyte-colony stimulating factor was used frequently as secondary prophylaxis in the breast cancer case (91%), follicular lymphoma case (59%) and non-small cell lung cancer case (31%). Fluoroquinolone prophylaxis was infrequently prescribed (19% oncologists, 30% haematologists).
Evidence-practice gaps were identified around the use of risk-assessment-based empiric therapy, and help to inform better clinical guidance.
As part of Meropenem Yearly Susceptibility Test Information Collection/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and aminoglycosides was noted over the 10-year span (P < 0.0001), which was significantly reduced compared with the average susceptibility of all sites. Introduction of quinolone prophylaxis has led to a significant decline in susceptibility of E. coli to all quinolones. The organisms remain susceptible to carbapenems, cefepime, and piperacillin/tazobactam. Periodic surveillance allows for detection of resistance patterns and adjustment of empiric antibiotic choice in patients at high risk for infection.
The objective of this study was to determine the effect of antibiotic use (including prophylaxis) on the emergence of multidrug-resistant (MDR) breakthrough bacteremia in cancer patients.
In this retrospective study, the authors identified all bacteremia episodes from July 2005 to December 2006 at their tertiary cancer center and compared the bacteria types and antimicrobial resistance in isolates from patients who had received antimicrobial agents as therapy or prophylaxis (breakthrough infections) with those from patients who had not received antimicrobial agents (nonbreakthrough bacteremia).
Breakthrough bacteremia was more likely to be associated with MDR Escherichia coli (P = .002), MDR Pseudomonas aeruginosa (P = .02), and vancomycin-resistant enterococci (P = .01). Multivariate analysis revealed that breakthrough bacteremia was associated with hematologic malignancies and neutropenia (odds ratios, 9.9 and 3.0, respectively). Fluoroquinolone use was associated significantly with the emergence of methicillin-resistant Staphylococcus aureus (P = .04), MDR E. coli (P < .001), and MDR P. aeruginosa (P = .05). A strong association was observed between fluoroquinolone use and breakthrough bacteremia in multivariate analysis (odds ratio, 22; P < .001). Patients who had received vancomycin were more likely to have vancomycin-resistant enterococci bloodstream isolates than patients who had not received antibacterial agents (P < .001).
Breakthrough infections were more common in neutropenic patients and in patients who had hematologic malignancies. The isolation of MDR organisms was associated strongly with the use of fluoroquinolones. The current findings demonstrated the importance of using a comprehensive approach to the prevention of MDR bacterial infections, including the initiation of antibiotic stewardship programs.
Imipenem-resistant Pseudomonas aeruginosa (IRPA) is an emerging problem. The causal role of antibiotic selective pressure versus patient-to-patient transmission has not been assessed using a large cohort.
Patients who were admitted to the medical and surgical intensive care units (ICUs) at the University of Maryland Medical Center from 2001 through 2006 had multiple perianal culture samples collected. Using pulsed-field gel electrophoresis (PFGE), the number of patients who acquired IRPA as a result of patient-to-patient transmission was determined. We also analyzed a subset of patients who had a previous surveillance culture that grew an imipenem-susceptible P. aeruginosa (ISPA) and a subsequent culture that grew IRPA.
Our cohort consisted of 7071 patients. Three hundred patients were colonized with IRPA. 151 patients had positive culture findings at ICU admission, and 149 patients acquired an IRPA. Among the patients who acquired IRPA, 46 (31%) had a PFGE pattern similar to that for another isolate, and 38 (26%) were found to be colonized with an ISPA on the basis of earlier culture results. Of the 38-patient subset, 28 (74%) had identical PFGE patterns.
Our data showed that, of those cases of IRPA acquisition, 46 (31%) were defined as cases of patient-to-patient transmission, and 28 (19%) were cases of acquisition by the patients' endogenous flora.
The unrelenting rise in antimicrobial resistance is of great concern. The urgency of the problem is compounded by the recognition that fewer new antimicrobial agents are introduced each year [1]. Past efforts to curb resistance have been largely unsuccessful. It is important to note that what attention has been focused on emerging resistance, has been primarily directed toward gram-positive organisms (e.g., methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE)). Indeed, the few antimicrobial agents introduced in recent years have targeted treatment of multidrug resistant gram-positive organisms.
In the period April-September 2005, an outbreak of Clostridium difficile infection (CDI) due to PCR ribotype 027 occurred among 50 patients in a 341-bed community hospital in Harderwijk, The Netherlands. A retrospective case-control study was performed to identify risk factors specific for CDI, using a group of patients with CDI (n = 45), a group of randomly selected control patients without diarrhoea (n = 90), and a group of patients with non-infectious diarrhoea (n = 109). Risk factors for CDI and for non-CDI diarrhoea were identified using multiple logistic regression analysis. Independent risk factors for CDI were: age above 65 years (OR 2.6; 95% CI 1.0-5.7), duration of hospitalization (OR 1.04 per additional day; 95% CI 1.0-1.1), and antibiotic use (OR 12.5; 95% CI 3.2-48.1). Of the antibiotics used, cephalosporins and fluoroquinolones were identified as the major risk factors for development of CDI. The risk of developing CDI was particularly high in people receiving a combination of a cephalosporin and a fluoroquinolone (OR 57.5; 95% CI 6.8-483.6). The main factors affecting the risk of non-CDI diarrhoea were proton-pump inhibitors, immunosuppressive drugs, underlying digestive system disease, previous surgery, and gastric tube feeding. The outbreak ended only after implementation of restricted use of cephalosporins and a complete ban on fluoroquinolones, in addition to general hygienic measures, cohorting of patients in a separate ward, education of staff, and intensified environmental cleaning. The results of this study support the importance of appropriate antimicrobial stewardship in the control of hospital outbreaks with C. difficile PCR ribotype 027.
This study evaluated the prevalence of fluoroquinolone usage and investigated the association between usage and resistance in respiratory isolates of Streptococcus pneumoniae in Canada. Fluoroquinolone susceptibility testing was conducted on S. pneumoniae collected from 25 medical centres across Canada over nine study years. Fluoroquinolone prescriptions and consumption figures were derived from data in the IMS Health, Canada CompuScript Audit. Between 1997 and 2006, 11825 S. pneumoniae isolates were collected. Ciprofloxacin resistance rates increased significantly (P<0.01) during the study from 0% to 4.5% in children (0-15 years), from 0.2% to 5.4% in adults (16-64 years) and from 1.4% to 11.6% in the elderly (> or = 65 years). Outpatient ciprofloxacin and respiratory fluoroquinolone prescriptions increased by 55.6% (38.2 prescriptions/1000 population to 59.4 prescriptions/1000 population; P<0.01) and 416.2% (5.3 prescriptions/1000 to 27.4 prescriptions/1000; P<0.01), respectively. Ciprofloxacin and respiratory fluoroquinolone consumption increased by 10.6% [1.1 defined daily doses (DDDs)/1000/day to 1.2 DDDs/1000/day; P=0.02] and 38.2% (0.5 to 0.7 DDDs/1000/day; P=0.02), respectively, from 2001 to 2006. A strong association between ciprofloxacin use and resistance (R(2)=0.89) was identified. Fluoroquinolone resistance in S. pneumoniae increased significantly in Canada from 1997 to 2006 in conjunction with increased ciprofloxacin and respiratory fluoroquinolone consumption. Ciprofloxacin usage appears to be the biggest driver of resistance; however, total fluoroquinolone usage is also important.
Febrile neutropenia causes significant morbidity and mortality in patients receiving antineoplastic chemotherapy. Antibiotic prophylaxis reduces the incidence of fever during chemotherapy, but its routine use remains controversial for patients at low risk of neutropenic infection. This article reviews recent research to clarify the issue.
Randomized controlled trials and meta-analyses demonstrate that antibiotic prophylaxis reduces the incidence of febrile neutropenia and infection-related mortality both in patients receiving high-dose chemotherapy and in those receiving moderately myelosuppressive chemotherapy for solid tumours. The evidence that antibiotic prophylaxis results in adverse patient outcomes, through colonization or infection with resistant microorganisms is limited and unconvincing. Retrospective reanalysis of trial data indicates that for patients on moderately myelosuppressive out-patient chemotherapy, the greatest risk of infection and the greatest prophylactic benefit is on the first cycle.
Current guidelines recommend that antibiotic prophylaxis is considered in all patients at high and intermediate risk of febrile neutropenia. Clinical evidence now also supports antibiotic prophylaxis for low-risk patients. The impact of antibiotic prophylaxis during cyclical out-patient chemotherapy on microbial resistance should be determined. The hypothesis that, for low-risk patients, prophylaxis should be targeted to first chemotherapy cycles to retain efficacy but limit antibiotic exposure should be tested.
The distribution of Staphylococcus epidermidis resistant to ciprofloxacin and/or gentamicin was studied in an isolation unit for patients undergoing bone marrow transplantation. During 1 week all such strains colonizing patients or staff members or found on the clothes of staff or in the air were investigated. Antibiograms and plasmid profiles were used for epidemiological typing. Thirty-one different antibiograms were found. A few strains were widely spread and dominated quantitatively. Staff colonization was 23%, but contamination of their clothes was 82%. Two strains which colonized three of the patients were widely spread in the air. They were found in the corridor and in every patient room, even where the patient was not colonized. The main source of the environmental contamination seems to have been patients. Possible routes of infection were direct airborne transmission as well as passive transfer via staff.
An extensive survey of the in-vitro susceptibility of clinical isolates of Staphylococcus aureus to 18 antimicrobial agents was conducted over three separate periods during 1986-1987 in 14 teaching hospitals in major Australian cities. The survey aimed to document the prevalence of resistance to a wide variety of drugs that are important as antistaphylococcal agents or as epidemiological markers. More than 7500 isolates were examined. Nationally, the prevalence of resistance was 85.3% to penicillin G, 14.4% to methicillin, 14.0% to amoxycillin/clavulanate, 9% to cephalothin, 5.4% to cephamandole, 9.9% to cefotaxime, 25.0% to erythromycin, 11.2% to clindamycin, 21.7% to tetracycline, 13.0% to gentamicin, 1.9% to amikacin, 5.8% to chloramphenicol, 18.3% to trimethoprim, 0.6% to rifampicin, 3.0% to fusidic acid and 1.2% to novobiocin. For none of the strains was resistance to vancomycin confirmed by minimal-inhibitory-concentration determination. A high proportion of the resistances was harboured in methicillin-resistant Staph. aureus, except for resistance to penicillin G, erythromycin and tetracycline. The prevalence of methicillin resistance varied widely among the states: 25.2% in Queensland, 23.5% in Victoria, 12.6% in New South Wales/the Australian Capital Territory, 11.3% in South Australia and 0.4% in Western Australia. Isolates from blood cultures were slightly-more susceptible to antimicrobial agents than were isolates from other body sites. Six common profiles of resistance to penicillin G, methicillin, erythromycin, clindamycin and tetracycline accounted for more than 95% of the isolates that were tested against all five agents. Vancomycin remains the most important antistaphylococcal drug in areas where resistance to methicillin is common.
Escherichia coli with high-level fluoroquinolone resistance were isolated from feces and/or various body sites of 16 cancer patients who were on oral fluoroquinolone prophylaxis. Population analysis of fecal isolates in 11 patients showed that fluoroquinolone-resistant E. coli was the only aerobic gram-negative bacillus present and exhibited a relatively homogenous fluoroquinolone MIC distribution. Molecular typing by pulsed field gel electrophoresis of chromosomal DNA digests or by random amplified polymorphic DNA fingerprinting confirmed the clonal nature of gastrointestinal tract colonization with E. coli. Genotyping of ten colonies picked from the same fecal culture demonstrated identical strains in four of four patients examined. Identical genotypes from the same patient were isolated over prolonged periods of time in 12 of 12 cases examined, with one patient (with the longest follow-up of 14 months) who lost his initial genotype and became persistently colonized with a new genotype. In the 11 patients who developed infection due to fluoroquinolone-resistant E. coli, molecular typing also indicated that fecal colonization was associated with, and presumably preceded infection due to an indistinguishable genotype of fluoroquinolone-resistant E. coli.
A total of 510 isolates of Micrococcaceae, 500 of staphylococci and 10 micrococci, detected in 485 (3.3%) of 14,860 consecutive blood cultures obtained from patients at a Swedish university hospital and 2 local hospitals were identified to species level and investigated for antibiotic susceptibility. The 5 most frequently isolated species were Staphylococcus epidermidis (54.8%), S. aureus (28.0%), S. hominis (3.4%), S. warneri (3.2%) and S. haemolyticus (2.8%). All isolates of S. aureus were oxacillin sensitive. Great diversity in antibiotic resistance among coagulase negative staphylococci between hospitals and different ward units in the university hospital was observed. The frequency of antimicrobial resistance among S. epidermidis correlated with the antibiotic consumption at different ward units, in particular for ciprofloxacin (p < 0.001) and co-trimoxazole (p < 0.004). The study emphasizes the importance of monitoring antibiotic consumption and resistance patterns of nosocomial staphylococci in order to avoid emergence and spread of multi-resistant bacteria within the hospital environment.
Infection remains the major cause of morbidity and mortality in patients with neutropenia, and the beneficial effects of oral prophylaxis remain controversial.
From 1993 to December 1999, the authors analyzed the clinical and microbiologic outcomes of 144 episodes of febrile neutropenia among adult patients with acute leukemia.
Forty-three consecutive episodes occurred among patients who were on ciprofloxacin prophylaxis during 1993-1996 (ciprofloxacin group), and 101 subsequent episodes occurred among patients who were not exposed to ciprofloxacin prophylaxis (control group). There were no differences in clinical presentation, antibiotic treatment received for the episode, or a worse outcome between groups. The rate of bacteremia was similar (12 of 43 patients [28%] vs. 26 of 101 patients [26%], respectively). There was a trend toward a higher rate of Gram positive bacteremia in the control group (12 of 101 patients [12%] vs. 2 of 43 patients [5%]) and a higher rate of Gram negative bacteremia in the ciprofloxacin group (11 of 43 patients [26%] vs. 15 of 101 patients [15%]). Resistance to fluoroquinolones was greater in Escherichia coli blood isolates from patients in the ciprofloxacin group (7 of 8 patients vs. 2 of 9 patients; P = 0.02).
The current results suggest that fluoroquinolone prophylaxis for patients with febrile neutropenia may be abandoned safely in areas with a high prevalence of ciprofloxacin-resistant enterobacteria.
In many countries, fluoroquinolones are among the most commonly used antibacterial drugs. Concerns about bacterial resistance to these and other frequently used drugs have been raised by the medical and scientific communities. While fluoroquinolone resistance has not yet developed among many bacteria, emergence of resistance in Escherichia coli would be a problem as multiple resistances to other antibiotics is now a common problem. This paper examines trends in resistance to fluoroquinolones in Escherichia coli through analysis of data collected from Australian institutions between 1997 and 2001. During the study period, norfloxacin and ciprofloxacin were the most frequently tested fluoroquinolones in Australian laboratories. An examination of results for strains tested simultaneously against both drugs indicated that testing against either drug accurately predicted resistance or susceptibility for the other (99.7% agreement). Over 400,000 tests were performed to determine the fluoroquinolone susceptibility of E. coil. Data were analysed by the test method used (Calibrated Dichotomous Sensitivity (CDS) or National Committee for Clinical Laboratory Standards (NCCLS)). The data indicate that fluoroquinolone resistance in E. coli has not yet emerged as a significant problem in Australia, but there are some indications of low level increases in resistance rates. Norfloxacin results are likely to be a better guide to fluoroquinolone resistance in this species using this method of surveillance.
An annual survey of antimicrobial resistance in clinical isolates of Staphylococcus aureus was conducted in 21 Australian teaching hospital microbiology laboratories in eight major cities from 1989 to 1999. A total of 19,000 isolates were tested for susceptibility to 18 antimicrobials, with 3795 being methicillin-resistant (MRSA). Resistance to ciprofloxacin in MRSA increased from 4.9% to 75.9%. The proportion of MRSA resistant to erythromycin decreased significantly (99.0%-88.9%), as did that to trimethoprim (98.4%-82.4%) and to tetracycline (96.5%-80.1%). The proportion of MRSA isolated increased in Sydney, Melbourne, Canberra, Adelaide, Perth, and Darwin, but not in Brisbane. The proportion in Hobart peaked in 1994. MRSA in Perth were predominantly non-multiresistant (nmMRSA) throughout the survey (i.e., resistant to less than three of eight indicator antibiotics) due mainly to local strains that originated in the community. The proportion of nmMRSA increased to modest levels in the other cities. In eastern cities, this was due to the appearance of strains closely related to nmMRSA seen in other countries of the southwestern Pacific.
Antibiotics are essential to the treatment of bacterial sepsis as they reduce the bacterial burden. The impact of bacterial resistance has recently been studied and found to be important in a range of conditions. Resistance to antibiotics can be defined genotypically, phenotypically and clinically through pharmacokinetic/pharmacodynamic studies and their correlations with clinical outcomes. Although the kinetics of antibiotics has been shown to be favourably altered in sepsis, a range of studies in sepsis has revealed that for most pathogens resistance contributes to significant increases in mortality. This has been clearly demonstrated in bacteraemia, including community- and hospital-acquired infection, and with bacteraemia caused by vancomycin-resistant enterococci, methicillin-resistant staphylococci and extended-spectrum producing Gram-negative bacteria. Significant mortality increases have also been seen with ventilator-associated pneumonia and serious infections requiring admission to intensive care. Gentotypic and phenotypic resistance in coagulase-negative staphylococci causing bacteraemia, and in invasive pneumococcal disease has not shown differences in mortality. In the latter case, dosage regimens have to date been adequate to overcome laboratory-defined resistance. Early indications are that de-escalating therapy from broad-spectrum initial coverage after results of cultures and susceptibility tests become available does not jeopardize outcomes, and further prospective studies are warranted. There is now convincing evidence that broad-spectrum initial therapy to cover the likely pathogens and their resistances pending culture results is mandatory in sepsis to minimize adverse outcomes.
The aim of the present study was to investigate the epidemiologic evolution of fluoroquinolone resistance of E. coli clinical isolates from patients admitted to a hematology-oncology service where fluoroquinolone prophylaxis during neutropenia was recommended as the standard of care for many years but was then discontinued in a trial conducted in patients with acute leukemia. Fluoroquinolones had been shown to decrease the incidence of gram-negative bacteremia in cancer patients with neutropenia, yet it was thought that the emergence of resistance in Escherichia coli and other gram-negative bacteria may have caused a progressive lack of efficacy of fluoroquinolone prophylaxis. Epidemiologic surveillance of fluoroquinolone resistance of E. coli clinical isolates at our cancer center since 1992 showed a continuing influx of new clones not previously observed in the population of cancer patients, an increase in the number of cancer patients per year colonized and/or infected by fluoroquinolone-resistant E. coli (1992-1994, 10-16 patients; 1995-1997, 24-27 patients), and a resistance rate of >50% among E. coli bloodstream isolates of hematology-oncology patients. A 6-month fluoroquinolone prophylaxis discontinuation intervention trial in 1998 suggested that despite increasing resistance among E. coli isolates, fluoroquinolone prophylaxis in acute leukemia patients was still effective in the prevention of gram-negative bacteremia (incidence rates, 8% during the pre-intervention period vs. 20% after discontinuation; p<0.01). The resumption of fluoroquinolone prophylaxis in acute leukemia patients thereafter decreased the incidence of gram-negative bacteremia to the pre-intervention level (9%; p=0.03), while the proportion of in vitro fluoroquinolone resistance in E. coli bacteremia isolates again increased (from 15% during the intervention period to >50% in the post-intervention period). Relative rates of resistance thus were a poor indicator of the potential clinical benefits associated with fluoroquinolone prophylaxis in cancer patients.
The use of oral prophylactic antibiotics in oncology patients is still a matter of debate. A systematic review was performed to assess the evidence for the effectiveness of oral prophylactic antibiotics to decrease bacteraemia and infection-related mortality in oncology patients during neutropenic episodes. Medline, Embase and the Cochrane register of controlled trials were searched from 1966 until 2002. The main outcome was the number of patients with documented bacteraemia (Gram-negative or Gram-positive bacteraemia) and infection related mortality. Data-extraction and quality assessment were performed independently by two reviewers. A total of 22 trials met the inclusion criteria. Seventeen trials compared prophylaxis (quinolones or Trimethoprim/sulfamethoxazole (TMP/SMZ)) to no prophylaxis. The incidence of Gram-negative bacteraemia decreased significantly (pooled OR 0.39, 95% CI 0.24-0.62) without an increase in Gram-positive bacteraemia. Quinolone-based regimens showed a stronger reduction in Gram-negative bacteraemia while TMP/SMZ based regimens were more effective in Gram-positive bacteraemia. Infection related mortality due to bacterial causes decreased with the use of prophylactic antibiotics (pooled OR 0.49, 95% CI 0.27-0.88). No increase in fungaemia or fungal related mortality was seen with the use of oral prophylaxis. In conclusion, this study has shown that oral prophylactic antibiotics decreased Gram-negative bacteraemia and infection related mortality due to bacterial causes during neutropenic episodes in oncology patients.
Bacterial infections are a major cause of illness and death in patients who are neutropenic after chemotherapy treatment for cancer. Trials have shown the efficacy of antibiotic prophylaxis in decreasing the incidence of bacterial infections but not in reducing mortality rates.
To evaluate whether antibiotic prophylaxis in neutropenic patients reduces mortality and incidence of infection and to assess related adverse events.
The Cochrane Cancer Network register of trials (2004), The Cochrane Library (Issue 4, 2004), EMBASE (1980-2004), MEDLINE (1966-2004), and references of identified studies.
Randomized, controlled trials comparing antibiotic prophylaxis with placebo or no intervention or another antibiotic in afebrile neutropenic patients.
Two reviewers independently appraised the quality of trials and extracted data.
Ninety-five trials performed between 1973 and 2004 met inclusion criteria. Fifty-two trials addressed quinolone prophylaxis. Antibiotic prophylaxis significantly decreased the risk for death when compared with placebo or no treatment (relative risk, 0.67 [95% CI, 0.55 to 0.81]). All prophylactic antibiotics were associated with an increased risk for adverse events (relative risk, 1.69 [CI, 1.14 to 2.50]). Fluoroquinolone prophylaxis reduced the risk for all-cause mortality (relative risk, 0.52 [CI, 0.35 to 0.77]), as well as infection-related mortality, fever, clinically documented infections, and microbiologically documented infections. Fluoroquinolone prophylaxis increased the risk for harboring bacilli resistant to the specific drug after treatment and adverse events, but these results were not statistically significant (relative risks, 1.69 [CI, 0.73 to 3.92]) and 1.30 [CI, 0.61 to 2.76], respectively).
Most trials involved patients with hematologic cancer. Data on all-cause mortality were missing in 10 of 50 trials comparing prophylaxis with no prophylaxis. Effect estimates were larger in trials of unclear methodologic quality compared with trials of adequate methodologic quality.
Antibiotic prophylaxis for neutropenic patients undergoing cytotoxic therapy reduces mortality. Mortality was substantially reduced when analysis was limited to fluoroquinolones. Antibiotic prophylaxis, preferably with a fluoroquinolone, should be considered for neutropenic patients.
background We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluoro- uracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer. methods We randomly assigned 1491 women with axillary node-positive breast cancer to six cy- cles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival. results At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The inci- dence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P
Improved management of infectious complications of cancer has contributed substantially to the success of care over the past several decades. In the 1960s it became clear that neutropenia was highly correlated with the occurrence of rapidly progressive sepsis.1 In the 1970s, strategies for empirical antibacterial therapy were devised to minimize these complications. This therapy was directed primarily against gram-negative rods, especially Pseudomonas aeruginosa, with good results.2 Paradoxically, this strategy has caused gram-positive cocci to become the most frequent cause of bacteremia among patients with cancer. However, the need for empirical treatment of infections with gram-positive cocci is rare because they . . .
The role of prophylactic antibacterial agents after chemotherapy remains controversial.
We conducted a randomized, double-blind, placebo-controlled trial in patients who were receiving cyclic chemotherapy for solid tumors or lymphoma and who were at risk for temporary, severe neutropenia (fewer than 500 neutrophils per cubic millimeter). Patients were randomly assigned to receive either 500 mg of levofloxacin once daily or matching placebo for seven days during the expected neutropenic period. The primary outcome was the incidence of clinically documented febrile episodes (temperature of more than 38 degrees C) attributed to infection. Secondary outcomes included the incidence of all probable infections, severe infections, and hospitalization but did not include a systematic evaluation of antibacterial resistance.
A total of 1565 patients underwent randomization (784 to placebo and 781 to levofloxacin). The tumors included breast cancer (35.4 percent), lung cancer (22.5 percent), testicular cancer (14.4 percent), and lymphoma (12.8 percent). During the first cycle of chemotherapy, 3.5 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 7.9 percent in the placebo group (P<0.001). During the entire chemotherapy course, 10.8 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 15.2 percent of patients in the placebo group (P=0.01); the respective rates of probable infection were 34.2 percent and 41.5 percent (P=0.004). Hospitalization was required for the treatment of infection in 15.7 percent of patients in the levofloxacin group and 21.6 percent of patients in the placebo group (P=0.004). The respective rate of severe infection was 1.0 percent and 2.0 percent (P=0.15), with four infection-related deaths in each group. An organism was isolated in 9.2 percent of probable infections.
Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of levofloxacin reduces the incidence of fever, probable infection, and hospitalization.
The prophylactic use of fluoroquinolones in patients with cancer and neutropenia is controversial and is not a recommended intervention.
We randomly assigned 760 consecutive adult patients with cancer in whom chemotherapy-induced neutropenia (<1000 neutrophils per cubic millimeter) was expected to occur for more than seven days to receive either oral levofloxacin (500 mg daily) or placebo from the start of chemotherapy until the resolution of neutropenia. Patients were stratified according to their underlying disease (acute leukemia vs. solid tumor or lymphoma).
An intention-to-treat analysis showed that fever was present for the duration of neutropenia in 65 percent of patients who received levofloxacin prophylaxis, as compared with 85 percent of those receiving placebo (243 of 375 vs. 308 of 363; relative risk, 0.76; absolute difference in risk, -20 percent; 95 percent confidence interval, -26 to -14 percent; P=0.001). The levofloxacin group had a lower rate of microbiologically documented infections (absolute difference in risk, -17 percent; 95 percent confidence interval, -24 to -10 percent; P<0.001), bacteremias (difference in risk, -16 percent; 95 percent confidence interval, -22 to -9 percent; P<0.001), and single-agent gram-negative bacteremias (difference in risk, -7 percent; 95 percent confidence interval, -10 to -2 percent; P<0.01) than did the placebo group. Mortality and tolerability were similar in the two groups. The effects of prophylaxis were also similar between patients with acute leukemia and those with solid tumors or lymphoma.
Prophylactic treatment with levofloxacin is an effective and well-tolerated way of preventing febrile episodes and other relevant infection-related outcomes in patients with cancer and profound and protracted neutropenia. The long-term effect of this intervention on microbial resistance in the community is not known.
Recently, two Dutch hospitals reported outbreaks of Clostridium difficile ribotype 027, toxinotype III. This strain, which was seen earlier in the United States, Canada and the United Kingdom, produces large amounts of toxins due to a defect in the toxin-regulating gene and causes severe diarrhoea. Antibiotic use, especially use of fluoroquinolones, is a risk factor. Control of outbreaks is hampered by the fact that Clostridium forms spores that can survive for a very long time in the environment and are resistant to the usual surface disinfectants. Protocols for diagnostic investigations, prevention and control of outbreaks are available.
Recent reports suggest that the rate and severity of Clostridium difficile-associated disease in the United States are increasing and that the increase may be associated with the emergence of a new strain of C. difficile with increased virulence, resistance, or both.
A total of 187 C. difficile isolates were collected from eight health care facilities in six states (Georgia, Illinois, Maine, New Jersey, Oregon, and Pennsylvania) in which outbreaks of C. difficile-associated disease had occurred between 2000 and 2003. The isolates were characterized by restriction-endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), and toxinotyping, and the results were compared with those from a database of more than 6000 isolates obtained before 2001. The polymerase chain reaction was used to detect the recently described binary toxin CDT and a deletion in the pathogenicity locus gene, tcdC, that might result in increased production of toxins A and B.
Isolates that belonged to one REA group (BI) and had the same PFGE type (NAP1) were identified in specimens collected from patients at all eight facilities and accounted for at least half of the isolates from five facilities. REA group BI, which was first identified in 1984, was uncommon among isolates from the historic database (14 cases). Both historic and current (obtained since 2001) BI/NAP1 isolates were of toxinotype III, were positive for the binary toxin CDT, and contained an 18-bp tcdC deletion. Resistance to gatifloxacin and moxifloxacin was more common in current BI/NAP1 isolates than in non-BI/NAP1 isolates (100 percent vs. 42 percent, P<0.001), whereas the rate of resistance to clindamycin was the same in the two groups (79 percent). All of the current but none of the historic BI/NAP1 isolates were resistant to gatifloxacin and moxifloxacin (P<0.001).
A previously uncommon strain of C. difficile with variations in toxin genes has become more resistant to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of C. difficile-associated disease.
In neutropenic patients receiving quinolone prophylaxis, bacteremia with viridans group streptococci resistant to quinolones is a known complication. The frequency of occurrence of quinolone-resistant organisms colonizing the oropharynx during antibacterial prophylaxis with a quinolone is not well defined. In 48 patients undergoing hematopoietic stem cell transplantation, the prevalence of quinolone resistance in viridans group streptococci colonizing the oropharynx before and during antibacterial prophylaxis with gatifloxacin or moxifloxacin (most with concomitant penicillin) was determined. For quinolone-resistant isolates, mutations in the genes gyrA and parC, which confer resistance to quinolones, were analyzed. Seventy-four isolates before and 27 isolates during quinolone use were recovered from patients' oropharynxes. The numbers of susceptible isolates recovered before versus during quinolone use were as follows: 52 (70%) versus three (11%) for ciprofloxacin, 66 (89%) versus eight (30%) for levofloxacin, 66 (89%) versus ten (37%) for gatifloxacin, and 67 (91%) versus 11 (41%) for moxifloxacin (p<0.0001). Mutations in gyrA and/or parC were detected in quinolone-resistant isolates. Quinolone-resistant viridans group streptococci are frequently found in the oropharynx of neutropenic patients after a brief (median, 8 days) exposure to gatifloxacin or moxifloxacin.