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Ertapenem Versus Piperacillin/Tazobactam in the Treatment of Complicated Intraabdominal Infections: Results of a Double-Blind, Randomized Comparative Phase III Trial
Abstract
To examine the clinical efficacy and safety of ertapenem, a novel beta-lactam agent with wide activity against common pathogens encountered in intraabdominal infection.
Ertapenem has a pharmacokinetic profile and antimicrobial spectrum that support the potential for use as a once-a-day agent for the treatment of common mixed aerobic and anaerobic infections. METHODS This prospective, randomized, controlled, and double-blind trial was conducted to compare the safety and efficacy of ertapenem with piperacillin/tazobactam as therapy following adequate surgical management of complicated intraabdominal infections.
Six hundred thirty-three patients were included in the modified intent-to-treat population, with 396 meeting all criteria for the evaluable population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was most common (approximately 60% in microbiologically evaluable population). A prospective, expert panel review was conducted to assess the adequacy of surgical source control in patients who were failures as a component of evaluability. For the modified intent-to-treat groups, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam. One hundred seventy-six of 203 microbiologically evaluable patients treated with ertapenem (86.7%) were cured, as were 157 of the 193 (81.2%) treated with piperacillin/tazobactam.
In this study, the efficacy of ertapenem 1 g once a day was equivalent to piperacillin/tazobactam 3.375 g every 6 hours in the treatment of a range of intraabdominal infections. Ertapenem was generally well tolerated and had a similar safety and tolerability profile to piperacillin/tazobactam. A formal process for review of adequacy of source control was found to be of benefit. The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of intraabdominal infections.
... [163]. Also frequent were the appearance of phlebitis and thrombophlebitis (0.8-12.2%), followed by erythema and pain at the site of the injection [159,165,[166][167][168][169][170][171]. Less frequent were cephaleas (0.4-4.7%) [159,167,168] and candidiasis (1.3-2.9%) ...
... [165,168], amongst others. Alterations were also observed in the enzymes of the liver function, both in transaminases [115,159,165,[166][167][168][169][170][171], as well as in alkaline phosphatase [115,159,[166][167][168][169], and there were alterations in the leukocyte and platelet counts [166][167][168]. ...
... [165,168], amongst others. Alterations were also observed in the enzymes of the liver function, both in transaminases [115,159,165,[166][167][168][169][170][171], as well as in alkaline phosphatase [115,159,[166][167][168][169], and there were alterations in the leukocyte and platelet counts [166][167][168]. ...
... El grupo inicial de once artículos, entre los cuales ocho fueron doble ciego aleatorios, uno multicéntrico aleatorio abierto, uno clínico y otro de revisión. [11][12][13][14][15][16][17][18][19][20] En nueve de los once estudios se reportó la apendicitis aguda como la principal causa de infección intraabdominal. El total de participantes fue de 3.129 pacientes, de los cuales 1.500 individuos presentaron apendicitis aguda como la causa de infección, lo que corresponde al 47.9% (Tabla 1). ...
... Muestra de ello es que de los nueve artículos mencionados en el grupo inicial de infecciones intraabdominales, ocho fueron diseñados con este propósito Cabe mencionar que en la revisión de los artículos en este grupo, la patología con mayor participación de pacientes fue la apendicitis aguda en cualquiera de sus fases clínicas. 11,[13][14][15][16][17][18][19] En el análisis de los resultados concuerdan, a pesar de las diferencias demográficas y temporales, en que el principal germen aislado es E. coli. 11,[13][14][15][16][17]25,28 No se reporta la proporción especifica de aislamientos por patología intraabdominal, ni el porcentaje de cultivos positivos y la proporción de estos con resultados polimicrobianos. ...
... 11,[13][14][15][16][17][18][19] En el análisis de los resultados concuerdan, a pesar de las diferencias demográficas y temporales, en que el principal germen aislado es E. coli. 11,[13][14][15][16][17]25,28 No se reporta la proporción especifica de aislamientos por patología intraabdominal, ni el porcentaje de cultivos positivos y la proporción de estos con resultados polimicrobianos. [16][17][18]20,27 En el ámbito del cuadro clínico de apendicitis aguda las publicaciones tienden a ser antiguas y con un menor número de participantes. ...
La apendicitis aguda es una patología de interés a nivel mundial con una incidencia de 100 por cada 100.000 personas/año, reportada a nivel europeo y norteamericano. La fisiopatología en forma experimental se ha relacionado con un proceso obstructivo, que evoluciona a estado isquémico favoreciendo la translocación bacteriana, por lo cual se han relacionado los distintos microorganismos como factor de importancia en el desarrollo de sus complicaciones. Se realizó una revisión de los estudios publicados en PubMed en los últimos veinte años con términos MeSH appendicitis, bacteria y etiology donde se documento la E. coli como el germen bacteriano más común y B. fragilis como un anaerobio frecuente. No se encontraron estudios que reporten perfiles de sensibilidad a resistencia antibiótica.
... Pastarøjø dviejø bakterijø jautrumui karbapenemams nu-statyti didesnës átakos turi techniniai sunkumai, todël prieðtaringi ávairiø tyrimø rezultatai neatspindi tikro atsparumo ertapenemui lygmens [16]. P. aeruginosa buvo identifikuojama santykinai retai, o enterokokø, vienø daþniausiai iðskiriamø mikroorganizmø, vaidmuo intraabdominaliniø infekcijø patogenezëje nëra iki galo aiðkus [15][16][17]. ...
... Tuomet, kai pagrindinis patogenas bûdavo Pseudomonas aeruginosa, klinikinis atsakas á gydymà ertapenemu buvo 73%, piperacilinu-tazobaktamu 89%, o kai Enterococcusatitinkamai 77% ir 66%. Gautas skirtumas tarp in vitro ir klinikiniø tyrimø negalëjo bûti nulemtas vankomicino vaitojimo, nes vankomicinas kaip papildomas preparatas buvo skiriamas tik 4% ligoniø, gydytø piperacilinu-tazobaktamu ir ertapenemu [17]. Ligoniams, turintiems ðlapimo takø anomalijø didëja Enterobacteriaceae infekcijos rizika. ...
... Nëra sàsajø tarp ertapenemo dozës dydþio ir nepageidaujamø reiðkiniø daþnio, bei nepageidaujamø reiðkiniø pasireiðkimui neturi átakos gretutinëms ligoms gydyti vartojami preparatai, inkstø funkcijos sutrikimai, lytis ir amþius. Visuose tyrimuose registruotø nepageidaujamø reiðkiniø daþnis yra panaðus tiek skiriant ertapenemà, tiek kitus antibiotikus [11,17,26,[28][29][30][31]32]. ...
Albertas Daukša1, Antanas Gulbinas2, Giedrius Barauskas3
1 Kauno medicinos universitetas,
Mickevičiaus g. 9, LT-44307 Kaunas
2 Kauno medicinos universiteto
Biomedicininių tyrimų institutas,
Eivenių g. 4, LT-50009 Kaunas
3 Kauno medicinos universiteto,
Chirurgijos klinika,
Eivenių g. 2, LT-50009 Kaunas
El paštas: a_dauksa@yahoo.com
Ertapenemas – ilgo veikimo karbapenemų grupės antibiotikas, pasižymintis plačiu antibakteriniu poveikiu ir skiriamas vieną kartą per parą. Ertapenemas yra aktyvus prieš daugelį gramteigiamų, gramneigiamų ir anaerobinių bakterijų, išskiriamų sergant įvairiomis infekcijomis (pilvo, odos ir poodžio, mažojo dubens ir šlapimo takų), bet ribotai veikia ligoninės infekcijas sukeliančius patogenus: Pseudomonas aeruginosa, Acinetobacter spp., enterokokus ir meticilinui atsparius stafilokokus. Daugiacentriais, kontroliuojamais, dvigubai aklais atsitiktinių imčių tyrimais nustatyta, kad gydant bakterines infekcijas ertapenemo 1 g dozės efektyvumas nesiskyrė nuo lyginamosiose grupėse vartotų antibakterinių preparatų efektyvumo (piperacilino-tazobaktamo ar ceftriaksono ± metronidazolio). Ertapenemas buvo gerai toleruojamas ligonių, sergančių bakterinėmis infekcijomis, o nepageidaujami reiškiniai buvo lengvi ar vidutinio sunkumo.
Pagrindiniai žodžiai: ertapenemas, karbapenemai, efektyvumas, saugumas
A new carbapenem in the treatment of complicated and polymicrobial infections
Albertas Daukša1, Antanas Gulbinas2, Giedrius Barauskas3
1 Kaunas University of Medicine,
Mickevičiaus str. 9, LT-44307 Kaunas, Lithuania
2 Kaunas University of Medicine,
Insitute for Biomedical Research,
Eivenių g. 4, LT-50009 Kaunas, Lithuania
3 Kaunas University of Medicine,
Department of Surgery,
Eivenių g. 2, LT-50009 Kaunas, Lithuania
E-mail: a_dauksa@yahoo.com
Ertapenem is a long-acting carbapenem antibiotic which has a broad antibacterial spectrum and once-a-day dosing. Ertapenem is active against both Grampositive and Gramnegative bacteria and most species of anaerobic bacteria isolated from a variety of infections (intra-abdominal, skin/soft-tissue, pelvic and urinary tract). It shows restricted activity against nosocomial pathogens such as Pseudomonas aeruginosa, Acinetobacter spp., enterococci and methicillin-resistant staphylococci. Ertapenem 1 g was as effective as comparator antimicrobial agents (piperacillin/tazobactam or ceftriaxone ± metronidazole) in patients with bacterial infections in randomised, double-blind, multicentre clinical trials. Ertapenem was generally well tolerated by patients with bacterial infections, most adverse events being mild to moderate in severity.
Key words: ertapenem, carbapenems, efficacy, safety
... Enterococcus faecalis is isolated in up to 30% of intra-abdominal infections (IAIs) [1][2][3]. However, its pathogenicity in mixed infections remains unclear. ...
... Ertapenem is a broad-spectrum antibiotic with activity against a range of gram-positive, gram-negative, and anaerobic gastrointestinal organisms but with limited activity against E. faecalis [4,5]. Previous studies have shown that ertapenem is equally effective as piperacillin-tazobactam (PTZ) for the treatment of complicated IAIs (cIAIs) [3,[6][7][8], supporting the notion that targeted enterococcal therapy may not be necessary in polymicrobial infections. However, these studies included small numbers of patients with confirmed E. faecalis. ...
... Several randomized controlled trials have concluded that ertapenem is comparable to PTZ for IAIs; however, these studies were not specifically designed to address E. faecalis infections and had limited numbers of patients with culture-confirmed E. faecalis [3,5,7,12] Merck was not involved in the development of the study design, data collection, data analysis, or manuscript preparation. ...
Controversy remains as to whether Enterococcus faecalis recovered from intra-abdominal infections (IAI) requires targeted therapy. In a multicenter study comparing patients with IAIs from which E. faecalis was identified in intra-abdominal cultues, no difference in clinical outcomes was observed between patients receiving ertapenem versus those receiving piperacillin/tazobactam.
... In particular, the isolation of Enterococcus spp. occurs in more than one-third of patients, often as a polymicrobial infection in post-operative infections [3][4][5][6]. Because of the intrinsic resistance of enterococci to many antibiotic agents, it is unclear whether these pathogens warrant an alternative treatment approach with regard to empiric or definitive treatment. ...
... Enterococcus spp. are commonly isolated bacteria from peri-operative cultures, with documented isolation in more than one-third of patients [3][4][5][6]. The incidence of enterococcal isolation increases in post-operative and health-care-associated infections [8,11]. ...
... Despite its association with increased morbidity and mortality in a number of studies, adequate antimicrobial coverage of this organism may not improve outcomes [16] and in one study, was associated with increased mortality [14]; however, post-operative infection rates were reduced with adequate coverage [9]. Large randomized trials that used ertapenem, a carbapenem without Enterococcus activity [17], resulted in similar treatment efficacy for IAIs compared against piperacillin-tazobactam [6,12]. Post hoc analysis of subjects with Enterococcus isolated from three randomized controlled trials showed that treatment failures were predicted by presence of post-operative infection and advanced age, but coverage of Enterococcus did not affect treatment outcomes [12]. ...
Background:
Enterococci are isolated frequently as pathogens in patients with intra-abdominal infections (IAIs) and may predict poor clinical outcomes. It remains controversial whether enterococci warrant an altered treatment approach with regard to antimicrobial treatment.
Patients and methods:
The study population was derived from the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial database. Through post hoc analysis subjects were stratified into two groups based on isolation of Enterococcus. Fifty subjects of the cohort (n = 518) had Enterococcus isolated. Uni-variable and multi-variable analyses were conducted to determine whether isolation of Enterococcus constituted an independent predictor of the pre-defined STOP-IT composite outcome (surgical site infection, recurrent IAI, or death) and the individual components of the composite outcome.
Results:
From the cohort of 50 subjects, we identified 52 isolates of Enterococcus spp. with a predominance of Enterococcus faecalis (40%) followed by other Enterococcus spp. (37%) and Enterococcus faecium (17%). Baseline demographic characteristics were statistically similar between the two groups. Antibiotic utilization distribution remained balanced between the Enterococcus and no Enterococcus groups with the majority receiving piperacillin-tazobactam (62% and 54%, respectively). The groups had comparable infection characteristics including setting of acquisition (>50% community acquired) and origin of infection (predominantly colon or rectum). Individual and composite clinical outcomes were not different statistically between the Enterococcus and no Enterococcus groups: surgical site infection (10% vs. 7.5%; p = 0.53), recurrent IAI (20% vs. 14.1%; p = 0.26), death (2% vs. 1%; p = 0.40), and composite of all three (30% vs. 20.9%; p = 0.14], respectively. Multi-variable analysis revealed that isolation of Enterococcus did not predict independently the incidence of the composite outcome (odds ratio [OR] 1.53 [95% confidence interval {CI} = 0.78-3.01]; p = 0.22; c-statistic = 0.65; goodness of fit, p = 0.71).
Conclusions:
Enterococcus was not a more common pathogen in health-care-associated IAIs and was not an independent risk factor for the composite outcome. The isolation of Enterococcus from IAIs may not warrant an alternative treatment approach but larger studies are needed to validate these findings.
... Nevertheless, only a few case reports or case series discussing the association between ertapenem use and seizures have been published [16][17][18][19][20][21][22][23]. Thus, we designed a case-control study to investigate the factors associated with seizures in those adult patients receiving ertapenem therapy to provide much safer prescription of the antimicrobial agent. ...
... This might be because patients enrolled in our study were older (mean age, 71 vs. <60 years), and old patients at higher risk for ertapenem-associated seizures has been illustrated previously [19,24,26]. In addition, the interval from the administration of ertapenem to the onset of seizures was shorter than that noted in prior clinical trials [16][17][18]. As we understand it, multiple complicated co-morbidities were excluded in previous clinical trials, such as chronic kidney disease [16], thrombocytopenia [16,17], or malignancy [17]; all of these were noted among our studied patients. ...
... In addition, the interval from the administration of ertapenem to the onset of seizures was shorter than that noted in prior clinical trials [16][17][18]. As we understand it, multiple complicated co-morbidities were excluded in previous clinical trials, such as chronic kidney disease [16], thrombocytopenia [16,17], or malignancy [17]; all of these were noted among our studied patients. That might be the reason why earlier development of seizures occurred in our ertapenem-treated patients, but the actual mechanism for latency from symptom onset to diagnosis of seizures should be further surveyed. ...
Objective
The purpose of this study is to compare the characteristics of those ertapenem-treated adult patients with and without development of seizures, and identify the associated factors for the development of seizures.
Methods
This retrospective study was conducted at Chia-Yi Christian Hospital from January 2012 to December 2014. Patients developing seizures during their ertapenem treatment course were identified as case patients. Those without seizures who had received ertapenem for at least five days were considered as the pool of control patients. For each case patient, four matched patients from the control pool were randomly selected as the final control group, based on age, gender, and the date of ertapenem prescription.
Results
A total of 1706 ertapenem-treated patients were identified, 33 (1.9%) individuals developed seizures with the enrollment of 132 matched control patients. Among these 33 patients, the average age was 79.3 ± 7.5 years, and 20 (60.6%) were male. The mean Charlson co-morbidity score was 4.5 ± 2.4, and the first episode of seizure happened 3.3 ± 2.6 days after receiving ertapenem. In multivariate logistic regression analysis, the independent predictors associated with the development of ertapenem-associated seizures were old stroke (OR, 14.36; 95% CI, 4.38–47.02; p < 0.0001), undergoing brain images within one year prior to the admission (OR, 5.73; 95% CI, 1.78–18.43; p = 0.0034), low hemoglobin level (OR, 3.88; 95% CI, 1.28–12.75; p = 0.0165) and low platelet count (OR, 4,94; 95% CI, 1.56–15.68; p = 0.0067) at presentations, and protective factors against the development of seizures were heart failure (OR, 0.04; 95% CI, 0.00–0.63; p = 0.0222), concomitant use of steroids (OR, 0.19; 95% CI, 0.05–0.77; p = 0.0201), or antiplatelet agents (OR, 0.12; 95% CI, 0.02–0.63, p = 0.0123) with ertapenem.
Conclusions
The development of ertapenem-associated seizures may occur more frequently and much earlier due to its widespread use in treating drug-resistant pathogens, especially when these pathogens emerged worldwide.Our study would help physician to estimate the risk of developing seizure among patients receiving ertapenem.
... Six RCTs comparing this agent with other regimens for IAI have been published since 2000 (Supplementary Table G; see online supplementary material at www.liebertpub.com/overview/ surgical-infections/53/) [225][226][227][228][229][230], one of which was reviewed previously [3]. There were no significant differences noted in the clinical success rates between patients receiving piperacillin-tazobactam and those receiving various comparators. ...
... The task force identified nine RCTs published since 2000 evaluating use of this agent as monotherapy for IAI (Supplementary Table I; see online supplementary material at www.liebertpub.com/ overview/surgical-infections/53/) [205,214,220,226,228,230,246,247,284], one of which [226] was reviewed before publication in the previous evidence review [3]. Success rates with ertapenem have been similar to those of comparators except in one trial, in which ertapenem was found to be superior to ampicillin-sulbactam [214]. ...
... The task force identified nine RCTs published since 2000 evaluating use of this agent as monotherapy for IAI (Supplementary Table I; see online supplementary material at www.liebertpub.com/ overview/surgical-infections/53/) [205,214,220,226,228,230,246,247,284], one of which [226] was reviewed before publication in the previous evidence review [3]. Success rates with ertapenem have been similar to those of comparators except in one trial, in which ertapenem was found to be superior to ampicillin-sulbactam [214]. ...
Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations.
Methods: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council.
Results: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included.
Summary: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline.
... Positive blood cultures for the organisms that may do so, including S. aureus, Candida species, and Streptococcus milleri [49], are so rarely reported prior to therapy for these infections that blood cultures are not recommended. [77,165,189]. The frequency of specific Bacteroides species and other anaerobes is provided elsewhere [59]. ...
... The efficacy and cost advantages of generic agents are noted elsewhere [69][70][71][72]. Single agents approved for use include ticarcillin-clavulanate, cefoxitin, moxifloxacin, ertapenem, and tigecycline [73][74][75][76][77][78]. Given the very broad spectrum of tigecycline, including activity against MRSA and a wide variety of other gram-positive and gram-negative organisms not commonly seen in appendix-derived infection, there is concern for its use in mild-to-moderate complicated intra-abdominal infection. ...
BACKGROUND
Antimicrobial resistance and inappropriate antibiotic regimen hamper a favorable outcome in intra-abdominal infections. Clinicians rely on the minimum inhibitory concentration (MIC) value to choose from the susceptible antimicrobials. However, the MIC values cannot be directly compared between the different antibiotics because their breakpoints are different. For that reason, efficacy ratio (ER), a ratio of susceptible MIC breakpoint and MIC of isolate, can be used to choose the most appropriate antimicrobial.
MATERIALS AND METHODS
A prospective, observational study conducted during 2015 and 2016 included 356 Escherichia coli and 158 Klebsiella spp. isolates obtained from the intra-abdominal specimens. MIC was determined by microbroth dilution method, and ER of each antibiotic was calculated for all the isolates.
RESULTS
For both E. coli and Klebsiella spp., ertapenem, amikacin, and piperacillin/tazobactam had the best activities among their respective antibiotic classes.
DISCUSSION
This is the first study calculating ER for deciding empiric treatment choices. ER also has a potential additional value in choosing the use of susceptible drugs as monotherapy or combination therapy. A shift in ERs over a period of time tracks rising MIC values and predicts antimicrobial resistance development.
CONCLUSION
Estimation of ER could be a meaningful addition for the interpretation of an antimicrobial susceptibility report, thus helping the physician to choose the best among susceptible antimicrobials for patient management.
... [8] Recent data suggest that monotherapy with a broad-spectrum antibiotic may be as efficacious as, and potentially less costly than, standard multidrug therapy. [6] Monotherapy with ertapenem (ERT) is recommended for appendicitis [9] in both adult and pediatric patients. Although several randomized clinical trials (RCTs) have been done comparing the efficacy of combined therapy with metronidazole and carbapenem regimen, [10,11] systematic reviews or meta-analyses of these antibiotic therapies are limited. ...
... This enhances the probability that the differences observed between the groups are due to differences in antibiotic efficacy rather than source control. [9,18] In the case of perforated or abscessed appendicitis, important differences between antibiotic regimens might be identified to test the activity of metronidazole and other broad-spectrum agents, such as aminopenicillins with beta-lactam inhibitors or carbapenems and select cephalosporins. ...
The aim of this study was to evaluate the efficacy of combined therapy with metronidazole and broad-spectrum antibiotics for patients with perforated appendicitis who underwent surgical intervention.
Broad-spectrum antibiotic therapy is warranted in the treatment of perforated appendicitis. Metronidazole has been used as anaerobic antimicrobial therapy. However, few studies about the use of metronidazole in perforated appendicitis have been reported.
The medical records of 249 patients treated with metronidazole combined with broad-spectrum antibiotics following perforated appendicitis surgery were reviewed retrospectively and compared with the medical records of 149 patients treated only with broad-spectrum antibiotics. Propensity score matching was performed to adjust for selected baseline variables. Clinical outcomes, including postoperative complications and length of hospital stay, were compared between the 2 groups.
No differences were found between the use of combined therapy with metronidazole and the use of solely broad-spectrum antibiotic agents with regard to postoperative duration of intravenous antibiotic treatment (6.8 ± 1.3 vs 7.9 ± 2.1 days, respectively, P = .18), inflammation variables at POD 5 (white blood cell [WBC] [risk ratio [RR], 1.06; 95% confidence interval [CI], 0.67–1.93, P = .15] and C-reactive protein [CRP] [RR, 1.18; 95% CI, 0.73–2.25, P = .36]) (Table 2), and the mean postoperative length of hospital stay (LOS) (RR, 0.68, 95% CI, 0.41–0.94, P = .41). There were also no differences in the incidence of postoperative complications, including the intra-abdominal or pelvic abscess rate (7[7.1%] vs 9[9.2%], respectively, P = .40), the incidence of wound infection (14[14.3%] vs 15[15.3%], respectively, P = .50), and the 30-day readmission rate (9[9.2%] vs 12[12.2%], respectively, P = .32).
Regarding overall postoperative outcomes and complications, our study demonstrated no beneficial clinical effects of metronidazole administration in patients with perforated appendicitis who underwent surgical intervention. Therefore, metronidazole is not indicated when broad-spectrum antibiotics such as aminopenicillins with β-lactam inhibitors or carbapenems and select cephalosporins are used.
... Neurological adverse effects have been described, both with piperacillin and the piperacillin and tazobactam combination, in 16 patients. These adverse effects include the following [6,24,[114][115][116][117][118][119][120][121][122][123][124]: Patients were aged between 11 and 87 years (median age of 59 years, nine women and seven men), and the time to first symptoms ranged from \24 h to 8 days (median of 4 days, calculated from 11 case reports). The increase in doses led to the onset of symptoms. ...
... A study by Fica and Abusada showed a seizure frequency of 10% (3/30 patients with CNS disorders and stage 3 chronic renal disease) [282]. The neurological symptoms encountered after the literature review (26 patients) included encephalitic signs (26/26, 100%), such as seizures (14/26, 54%), disturbed vigilance (3/26, 12%), visual and auditory hallucinations (12/26, 46%), a confusional state (13/26, 50%), and myosis (2/26, 7.7%); and abnormal movements (4/26, 15%), such as myoclonia (4/ 26, 15%), associated with asterixis (2/26, 7.7%) or nystagmus [25,124,[281][282][283][284][285][286][287][288][289][290][291][292][293][294]. The contributing factors included: ...
β-lactam antibiotics are commonly prescribed antibiotic drugs. To describe the clinical characteristics, risk markers and outcomes of β-lactam antibiotic-induced neurological adverse effects, we performed a general literature review to provide updated clinical data about the most used β-lactam antibiotics. For selected drugs in each class available in France (ticarcillin, piperacillin, temocillin, ceftazidime, cefepime, cefpirome, ceftaroline, ceftobiprole, ceftolozane, ertapenem and aztreonam), a systematic literature review was performed up to April 2016 via an electronic search on PubMed. Articles that reported original data, written in French, Spanish, Portuguese or English, with available individual data for patients with neurological symptoms (such as seizure, disturbed vigilance, confusional state, myoclonia, localising signs, and/or hallucinations) after the introduction of a β-lactam antibiotic were included. The neurological adverse effects of piperacillin and ertapenem are often described as seizures and hallucinations (>50 and 25% of cases, respectively). Antibiotic treatment is often adapted to renal function (>70%), and underlying brain abnormalities are seen in one in four to one in three cases. By contrast, the neurological adverse drug reactions of ceftazidime and cefepime often include abnormal movements but few hallucinations and seizures. These reactions are associated with renal insufficiency (>80%) and doses are rarely adapted to renal function. Otherwise, it appears that monobactams do not have serious neurological adverse drug reactions and that valproic acid and carbapenem combinations should be avoided. The onset of disturbed vigilance, myoclonus, and/or seizure in a patient taking β-lactam antibiotics, especially if associated with renal insufficiency or underlying brain abnormalities, should lead physicians to suspect adverse drug reactions and to consider changes in antibacterial therapy.
... system for a measure of SOI and ROM because pre-treatment measures such as APACHE II were not available. Importantly, we noted substantial differences in the range of diseases treated, demographics, and the outcomes as compared with recently performed randomized registration trials [15][16][17][18][19]. These registration trials included younger patients (mean age <50 y) with complicated appendicitis as the most common infection. ...
... These registration trials included younger patients (mean age <50 y) with complicated appendicitis as the most common infection. In addition, patients were not considered severely ill (APACHE II score predominantly £10) [15][16][17]19]. ...
Background:
Hospital-acquired infections (HAIs) are a persistent concern and include surgical site infections, intravascular line-associated infections, pneumonia, catheter-associated urinary tract infections, and C. difficile infection.
Method:
Review of the pertinent English-language literature.
Results:
Hospital-acquired infections result in significant increases in morbidity, mortality rates, and cost and are a focus of efforts at reduction.
Conclusion:
I discuss efforts specific to each of the most common infections and a philosophical approach to prevention that strives to achieve zero potentially preventable hospital-acquired infections.
... system for a measure of SOI and ROM because pre-treatment measures such as APACHE II were not available. Importantly, we noted substantial differences in the range of diseases treated, demographics, and the outcomes as compared with recently performed randomized registration trials [15][16][17][18][19]. These registration trials included younger patients (mean age <50 y) with complicated appendicitis as the most common infection. ...
... These registration trials included younger patients (mean age <50 y) with complicated appendicitis as the most common infection. In addition, patients were not considered severely ill (APACHE II score predominantly £10) [15][16][17]19]. ...
Background:
The utility of tigecycline as compared with other antibiotic therapies in the treatment of patients with complicated intra-abdominal infection (cIAI) and the short- and long-term outcomes of a large cohort of severely ill patients were examined. We provide the first published data on post-discharge events for these patients.
Methods:
Retrospective data for the cIAI cohort were obtained from a large clinical database. Patients aged ≥18 y were selected for inclusion based on hospitalization with a relevant diagnosis code and procedure code, and guideline-compliant antimicrobial therapy. Propensity scoring was used to reduce treatment-selection bias introduced by the use of observational data. Tigecycline patients were placed into quintiles based on propensity score and were matched 1:3.
Results:
The final model based on propensity score matching included 2,424 patients: Tigecycline (n = 606) and other antibiotic therapy (n = 1,818). Treatment was successful in 426 (70.3%) tigecycline-treated patients and in 1,294 (71.2%) patients receiving other antibiotics. Similar treatment success occurred across all infection sites. Among survivors, treatment failure was associated with a greater need for all-cause re-hospitalization at 30 d and 180 d. No differences in cIAI-related re-hospitalization and discharge status were observed.
Conclusions:
Using propensity scores to match populations, similar outcomes were demonstrated between treatment with tigecycline and other antibiotics as expressed by treatment success, the need for re-admission, similar 30-d discharge status, and the need for re-admission at 180 d.
... Enterococci are found in 20%-30% of ascitic fluid cultures from patients with intra-abdominal infections [3]; they are the most common gram-positive cocci in nosocomial infections [4]. Moreover, intra-abdominal infections, in which enterococci are isolated from ascitic fluid, have a poor prognosis and high mortality rates [5,6]. ...
The clinical significance of enterococci in intra-abdominal infections, particularly those caused by multiple organisms, remains unclear. There are no definitive guidelines regarding the use of empiric therapy with antimicrobial agents targeting enterococci. In this study, we evaluated the impact of the initial antimicrobial therapy administration of anti-enterococcal agents on the treatment of intra-abdominal infections in patients with cancer in whom enterococci were isolated from ascitic fluid cultures. This retrospective study was conducted at Shizuoka Cancer Center between January 1, 2014, and December 31, 2020, on all adult patients with cancer with enterococci in their ascitic fluid cultures. The primary outcome was all-cause mortality, and the secondary outcomes were composite outcomes consisting of three components (mortality, recurrence, and treatment failure) and the risk factors associated with all-cause mortality and composite outcomes. In total, 103 patients were included: 61 received treatment covering enterococci, and 42 did not. The mortality rates did not differ significantly between the treated and untreated groups (treated: 8/61 [13.1%]; untreated: 5/42 [11.9%]; p = 1.00). Additionally, no significant difference was observed between the groups in terms of composite outcomes (treated group: 11/61 [18.0%]; untreated group: 9/42 [21.4%]; p = 0.80). Multivariate analysis showed that performance status (PS2–4; p < 0.0001) was an independent risk factor for mortality. The composite outcome was also significantly higher for PS2–4 (p = 0.007). Anti-enterococcal treatment was not associated with mortality or the composite outcome. In patients with cancer and intra-abdominal infections caused by enterococci, anti-enterococcal therapy was not associated with prognosis, whereas PS2 or higher was associated with prognosis. The results of this study suggest that the initial routine administration of anti-enterococcal agents for intra-abdominal infections may not be essential for all patients with cancer. To substantiate these findings, validation by a prospective randomized trial is warranted.
... However, antimicrobial resistance in key-pathogens isolated in intra-abdominal infection does not seem to be associated with increased virulence, as it occurred at similar rates in infection, sepsis, and septic shock. Overall prevalence of enterococci was 26% and thereby substantially higher as previously reported [19][20][21][22]. This trend can be attributed to the steadily emergence of enterococci in acute care settings or to the particular composition of a cohort of exclusively critically ill patients [23]. ...
Purpose: To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods: We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results: The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicro-bial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation.
... Previous studies on IAI have usually identified polymicrobial infections, and E. coli, Bacteroides, Streptococcus spp., and Enterococcus spp. have been isolated [8][9][10]. In this study, only E. gallinarum was isolated. ...
Intra-abdominal infection (IAI) is a common and important cause of infectious mortality in intensive care units. Adequate source control and appropriate antimicrobial regimens are key in the management of IAI. In community-acquired IAI, guidelines recommend the use of different antimicrobial regimens according to severity. However, the evidence for this is weak. We investigated the effect of enterococcal coverage in antimicrobial regimens in a severe polymicrobial IAI model. We investigated the effects of imipenem/cilastatin (IMP) and ceftriaxone with metronidazole (CTX+M) in a rat model of severe IAI. We observed the survival rate and bacterial clearance rate. We identified the bacteria in blood culture. We measured lactate, alanine aminotransferase (ALT), creatinine, interleukin (IL)-6, IL-10, and reactive oxygen species (ROS) in the blood. Endotoxin tolerance of peripheral blood mononuclear cells (PBMCs) was also estimated to determine the level of immune suppression. In the severe IAI model, IMP improved survival and bacterial clearance compared to CTX+M. Enterococcus spp. were more frequently isolated in the CTX+M group. IMP also decreased plasma lactate, cytokine, and ROS levels. ALT and creatinine levels were lower in IMP group. In the mild-to-moderate IAI model, however, there was no survival difference between the groups. Immune suppression of PBMCs was observed in IAI model, and it was more prominent in the severe IAI model. Compared to CTX+M, IMP improved the outcome of rats in severe IAI model.
... This section discusses whether patients with mild to moderate CA-IAI, severe CA-IAI, and HA-IAI require empiric anti-enterococcal therapy. A total of 24 RCTs investigated whether enterococci should be treated with empiric anti-infective therapy when the patient has mild to moderate CA-IAI [151,152,156,161,162,171,182,184,186,188,191,196,198,199,203,207,210,219,[251][252][253][254][255][256]]. Using the treatment success rate as the main observation indicator, the results showed that empiric therapies that covered enterococci did not improve patient prognosis compared with empiric therapies in which enterococci were not covered, regardless of whether the population was clinically evaluable (CE), modified intent-to-treat (mITT), or microbiological intent-to-treat (MITT) (CE: RR, 0.99; 95% CI, .97-1.01; mITT: RR, 0.99; 95% CI, .95-1.03; ...
The Chinese guidelines for IAI presented here were developed by a panel that included experts from the fields of surgery, critical care, microbiology, infection control, pharmacology, and evidence-based medicine. All questions were structured in population, intervention, comparison, and outcomes format, and evidence profiles were generated. Recommendations were generated following the principles of the Grading of Recommendations Assessment, Development, and Evaluation system or Best Practice Statement (BPS), when applicable. The final guidelines include 45 graded recommendations and 17 BPSs, including the classification of disease severity, diagnosis, source control, antimicrobial therapy, microbiologic evaluation, nutritional therapy, other supportive therapies, diagnosis and management of specific IAIs, and recognition and management of source control failure. Recommendations on fluid resuscitation and organ support therapy could not be formulated and thus were not included. Accordingly, additional high-quality clinical studies should be performed in the future to address the clinicians’ concerns.
... However, antimicrobial resistance in key-pathogens isolated in intra-abdominal infection does not seem to be associated with increased virulence, as it occurred at similar rates in infection, sepsis, and septic shock. Overall prevalence of enterococci was 26% and thereby substantially higher as previously reported [19][20][21][22]. This trend can be attributed to the steadily emergence of enterococci in acute care settings or to the particular composition of a cohort of exclusively critically ill patients [23]. ...
... However, antimicrobial resistance in key-pathogens isolated in intra-abdominal infection does not seem to be associated with increased virulence, as it occurred at similar rates in infection, sepsis, and septic shock. Overall prevalence of enterococci was 26% and thereby substantially higher as previously reported [19][20][21][22]. This trend can be attributed to the steadily emergence of enterococci in acute care settings or to the particular composition of a cohort of exclusively critically ill patients [23]. ...
Purpose: To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods: We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results: The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicro-bial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation.
... However, antimicrobial resistance in key-pathogens isolated in intra-abdominal infection does not seem to be associated with increased virulence, as it occurred at similar rates in infection, sepsis, and septic shock. Overall prevalence of enterococci was 26% and thereby substantially higher as previously reported [19][20][21][22]. This trend can be attributed to the steadily emergence of enterococci in acute care settings or to the particular composition of a cohort of exclusively critically ill patients [23]. ...
... However, antimicrobial resistance in key-pathogens isolated in intra-abdominal infection does not seem to be associated with increased virulence, as it occurred at similar rates in infection, sepsis, and septic shock. Overall prevalence of enterococci was 26% and thereby substantially higher as previously reported [19][20][21][22]. This trend can be attributed to the steadily emergence of enterococci in acute care settings or to the particular composition of a cohort of exclusively critically ill patients [23]. ...
Purpose
To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock).
Methods
We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis.
Results
The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation.
Conclusion
This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection.
... Indeed, several studies identified age as a predictive factor for poor antibiotic treatment outcome [10,11]. However, the rate of clinical cure or improvement in our study was similar to that observed in ertapenem studies with younger patient population [12][13][14][15]. Moreover, our multivariate analysis did not reveal association between age and rate of treatment failure/relapse. ...
Aim:
To evaluate the effectiveness and safety of ertapenem in patients hospitalized at home.
Patients & methods:
Retrospective analysis of data from Spanish Outpatient Parenteral Antimicrobial Therapy (OPAT) registry.
Results:
Data from 1428 patients (median age 70 years; 5.4% institutionalized) and 1547 infectious processes (24% self-administration) were analyzed. Clinical cure or improvement was achieved in 93.8% of cases. Rate of related readmissions was 4.2%, of clinically important complications -3.9%, and of adverse drug reactions -3.2%. High comorbidity burden, contagion in nursing home and certain types of infection were associated with worse prognosis. Self-administration was effective and safe, except in case of nursing home-acquired infections.
Conclusion:
Ertapenem OPAT was effective and safe. Caregivers in nursing homes should be better trained in OPAT-related procedures.
... Бактериальная резистентность может приводить к не эффективности терапии интраабдоминальных инфекций (ИАИ) в случаях, когда возбудитель инфекции не чувствителен к проводимой терапии [4]. Бактерии рода Enterobacteriaceae являются основными возбудителями ИАИ [5][6][7]. В России в структуре возбудителей осложненных внегоспитальных ИАИ их доля составляет 72,88%, из них большая часть -E.Coli [8]. В последние годы наблюдается рост резистентности как внегоспитальных, так и внутригоспитальных штаммов данных E.Coli к бета-лактам преимущественно за счет синтеза бета-лактамаз расширенного спектра (Extended Spectrum BetaLactamases (ESBL)). ...
Aim: To assess economic efficiency of complicated intra-abdomibal infections treatment in real practice compared to alternative scenario (treatment with carbapenem Ertapanem) taking in to account E. coli resistance. Methods: Cost-effectiveness analysis were performed. Mathematic modelling was done to assess prognosis of bacterial resistance. Results: Cost of 1 case of complicated intra-abdomibal infections in real practice is 83048,08 rub compared to 91706,06 rub according to alternative strategy. Cost-effectiveness analysis revealed that real practice of treatment intra-abdomibal infections dominated alternative scenario: less effectiveness lead to lower cost. Additional effectiveness (1,95%) demand additionally 443316,97 rub. Taking into account dynamic of E. Coli resistance ICER during 2011-2015 period decreased up to 40%. Conclusion: Antimicrobial resistance of bacterial agents is important criteria which should be used to estimate economic effectiveness of any medical strategy.
... The rate of imipenem-related seizures ranges from 0.5% to 3.3% [36]; the range is 0.5e6.0% with regard to meropenem-related seizures [37,38], and 0.4% with regard to ertapenem-related seizures [39,40]. Moreover, the rate of seizures reported to occur because of infections ranges from 22% to 32% [35]. ...
Valproic acid (VPA) is a widely used antiepileptic drug (AED). When carbapenems are concomitantly used with VPA, the serum levels of VPA may decrease and aggravate seizures. The aim of this study was to evaluate the risk factors associated with decreased serum VPA levels and clinical outcome in patients being treated with a combination of carbapenems and VPA. Fifty-four adult patients who were treated with VPA for epileptic seizures concomitant with carbapenems for the treatment of infections were evaluated in this study. Serum VPA levels were measured before and during combination therapy with VPA and carbapenems, and the change in serum VPA levels was calculated. The risk factors related to the decrease in serum VPA levels and clinical outcomes were evaluated. Our results show that VPA concentrations were reduced to subtherapeutic levels after the introduction of carbapenems. The reduction in VPA concentrations was found within 24 hours of the start of treatment with carbapenems. VPA levels continuously declined while the combination of treatments was used, which aggravated epileptic seizures in 48% of the patients. Renal disease and enzyme-inducing AEDs were risk factors that contributed to the severity of reduced serum VPA levels during combined treatment with carbapenems. This study suggests that clinicians need to be aware of the reduction of VPA concentrations to subtherapeutic levels and the aggravation of seizures while patients are treated with a combination of carbapenems and VPA.
... Empirical coverage of Enterococci is not generally recommended for patients with community-acquired IAIs. Studies have demonstrated that coverage against Enterococci offers little therapeutic benefit for patients with community-acquired infections [258,259]. ...
Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high. The 2013 update of the World Society of Emergency Surgery (WSES) guidelines for the management of intra-abdominal infections contains evidence-based recommendations for management of patients with intra-abdominal infections.
Objective:
This study's aim was to compare infectious complications in pancreatoduodenectomy (PD) patients with biliary stents treated with short, medium, or long durations of prophylactic antibiotics.
Summary/background data:
Pre-existing biliary stents have historically been associated with higher infection risk after PD. Patients are administered prophylactic antibiotics, but the optimal duration remains unknown.
Methods:
This single-institution retrospective cohort study included consecutive PD patients from October 2016 to April 2022. Antibiotics were continued past the operative dose per surgeon discretion. Infection rates were compared by short (≤24 h), medium (>24 but ≤96 h) and long (>96 h) duration antibiotics. Multivariable regression analysis was performed to evaluate associations with a primary composite outcome of wound infection, organ-space infection, sepsis, or cholangitis.
Results:
Among 542 PD patients, 310 (57%) had biliary stents. The composite outcome occurred in 28% (34/122) short, 25% (27/108) medium, and 29% (23/80) long duration (P=0.824) antibiotic patients. There were no differences in other infection rates or mortality. On multivariable analysis, antibiotic duration was not associated with infection rate. Only postoperative pancreatic fistula (OR 33.1, P<0.001) and male sex (OR 1.9, P=0.028) were associated with the composite outcome.
Conclusions:
Among 310 PD patients with biliary stents, long duration prophylactic antibiotics were associated with similar composite infection rates to short and medium durations but were used almost twice as often in high-risk patients. These findings may represent an opportunity to de-escalate antibiotic coverage and promote risk-stratified antibiotic stewardship in stented patients by aligning antibiotic duration with risk-stratified pancreatectomy clinical pathways.
Background
The treatment of complicated intra-abdominal infections remains a challenge. Both optimal medical and surgical therapy (i.e., source control) are needed to achieve low mortality and morbidity. The objective of this systematic review and meta-analysis is to determine the impact of carbapenem antibiotic therapy compared to other antibiotics in complicated intra-abdominal infections (secondary peritonitis) with an emphasis on mortality and postoperative complications.
Methods
A systematic literature search from PubMed/Medline and Web of Science databases was carried out. The last search was conducted in August 2022. PRISMA guidelines were followed. Pre-defined outcomes were mortality, treatment success, treatment failure, and adverse events.
Results
Ten randomized controlled trials, published from 1983 to 2013 with a total of 2377 patients (1255 patients in the carbapenem antibiotics group and 1122 in the control group), were identified. A meta-analysis comparing patients undergoing carbapenem antibiotic therapy and patients receiving other antibiotics was performed. No significant difference regarding mortality (OR 1.19, 95% CI [0.79; 1.82], p = 0.40), treatment success (OR 1.17, 95% CI [0.72; 1.91], p = 0.53), and treatment failure (OR 0.84, 95% CI [0.48; 1.45], p = 0.52) was observed. Carbapenem therapy was associated with fewer adverse events compared to therapy with other antibiotics (OR 0.79, 95% CI [0.65; 0.97], p = 0.022).
Conclusion
There is currently no evidence that carbapenem antibiotics are superior in terms of mortality, and success or failure for the treatment of complicated intra-abdominal infections (secondary peritonitis). The rate of adverse events is lower under carbapenem therapy compared to control antibiotics.
Trial Registration
PROSPERO 2018 CRD42018108854.
Background:
Piperacillin/tazobactam or meropenem are often used to treat patients with severe bacterial infections. We aimed to compare the desirable and undesirable effects of empirical and/or definitive piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections.
Methods:
We searched PubMed, Embase, CENTRAL, Epistemonikos, and trial registers for randomised clinical trials of empirical and/or definitive piperacillin/tazobactam versus carbapenems in adult patients with severe bacterial infection (i.e., any bacterial infection requiring hospitalisation). The primary outcome was all-cause short-term mortality within 90 days. Secondary outcomes were all-cause long-term mortality, adverse events, quality of life, days alive without or duration of life support, secondary infections, selection of fungi or resistant bacteria, and days alive and out of hospital or hospital length of stay. We calculated relative risks (RRs) using random effects and fixed effect meta-analyses along with trial sequential analyses.
Results:
We included 31 trials (n = 8790 patients) with overall high risk of bias. The RR for all-cause short-term mortality was 1.16 (95% confidence interval (CI) 0.94-1.43, low certainty evidence), for adverse events 1.00 (98% CI 0.96-1.04, moderate certainty evidence), for secondary infections 1.13 (98% CI 0.76-1.68, very low certainty evidence), and for selection of fungi or resistant bacteria 1.61 (98% CI 0.89-2.89, very low certainty evidence). There were no or limited data for the remaining outcomes.
Conclusions:
Based on very low or low certainty evidence, piperacillin/tazobactam may be associated with less favourable outcomes in patients with severe bacterial infections as compared with carbapenems, but the information size for a robust conclusion has not been reached. This article is protected by copyright. All rights reserved.
Background:
Eravacycline is a novel, fully synthetic fluorocycline antibiotic for the treatment of adults with complicated intra-abdominal infections (cIAIs). However, the efficacy and safety of eravacycline compared with current clinically common antibiotics remain unknown.
Objective:
This study aims to compare the efficacy and safety of eravacycline and other clinically common antibiotics in China, including tigecycline, meropenem, ertapenem, ceftazidime/avibactam+metronidazole, piperacillin/tazobactam, imipenem/cilastatin, and ceftriaxone+metronidazole, for the treatment of adults with cIAIs and to provide a reference for clinical choice.
Methods:
The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were electronically searched to collect clinical randomized controlled studies (RCTs) comparing different antibiotics in the treatment of patients with cIAIs from inception to June 1, 2021. Two reviewers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies.
Results:
A total of 4050 articles were initially retrieved, and 25 RCTs were included after screening, involving eight treatment therapies and 9372 patients. The results of network meta-analysis showed that in the intention-to-treat (ITT) population, the clinically evaluable (CE) population, and the microbiologically evaluable (ME) population, the clinical response rate of eravacycline was not significantly different from that of the other 7 therapies (P > 0.05). In terms of microbiological response rate, eravacycline was significantly better than tigecycline [tigecycline vs. eravacycline: RR = 0.82, 95%CI (0.65,0.99)], and there was no significant difference between the other 6 regimens and eravacycline (P > 0.05). In terms of safety, the incidence of serious adverse events, discontinuation rate, and all-cause mortality of eravacycline were not significantly different from those of the other 7 treatment therapies (P > 0.05).
Conclusion:
Based on the evidence generated by the current noninferiority clinical trial design, the efficacy and safety of eravacycline for the treatment of adults with cIAIs are not significantly different from those of the other 7 commonly used clinical antibiotics in China. In terms of microbiological response rate, eravacycline was significantly better than tigecycline. In view of the severe multidrug-resistant situation in China, existing drugs have difficulty meeting the needs of clinical treatment, and the new antibacterial drug eravacycline may be one of the preferred options for the treatment of cIAIs in adults.
The Beta lactam antibiotics are a diverse group of antimicrobial agents used for the management of infections in humans, both community and health care acquired. These antibiotic agents have evolved over the last 70 years and have a mechanism of action on the bacterial cell wall synthesis. There have been variations of the basic beta lactam ring that has produced a variety of agents with different spectra of activity. They have also been responsible for antibiotic misuse and abuse, that has resulted in many mechanisms of resistance with a combination of enzyme mediated hydrolysis, blocked porin water filled channels and active efflux pumps or an altered target. The pharmacokinetics of these agents have been diverse and they all follow the pharmacodynamics property of T > MIC. They have been the targets for many clinical trials for the treatment of serious infections, particularly in patients housed in the ICU.
Complicated intra-abdominal infections are a common pathology encountered by trauma and acute care surgeons. Antibiotic regimens have evolved over time to cover common organisms. The duration of antibiotic therapy has been nebulous and not evidence based. Prolonged therapy can be associated with complications such as resistance, nephrotoxicity, extra-abdominal infections, and Clostridium difficile infection. This review seeks to make evidence based-recommendations on appropriate selection and duration of antibiotics for intra-abdominal infections.
Objective: Through historical comparison with our previous study published 10 years ago, this paper aims to provide latest analysis of local bacteriology of acute complicated appendicitis and evaluate the effects of early escalation of potent antibiotics on course of postoperative recovery.
Methods: A 5-year retrospective review of all children receiving emergency laparoscopic appendicectomies for acute appendicitis from December 2014 to November 2019 was conducted.
Results: 257 cases of acute appendicitis were included, 126 were complicated appendicitis (38 gangrenous, 88 ruptured). 96 had positive peritoneal swab culture, 53 (42.1%) grew resistant bacterial strains, including extended spectrum beta-lactamase producing E. coli (ESBL E. coli), Pseudomonas aeruginosa, against traditional empirical triple antibiotics. The prevalence had significantly increased over the past decade (p = 0.008). In our patients, piperacillin/tazobactam, ertapenem, gentamicin provided coverage of 69.8%, 45.3% and 45.3% respectively. For patients with early escalation of postoperative antibiotics, no statistical significance was identified in terms of postoperative complications (p = 0.883), or duration of antibiotics (p = 0.0615).
Conclusion: Growing prevalence of resistant strains were observed over the decade. Piperacillin/tazobactam provided the best coverage (69.8%) against resistant bacterial strains in our patients. Early escalation of antibiotics failed to reduce postoperative complications and antibiotics duration.
Type of Study: Clinical Research, Retrospective Historical Comparative Study
Level of Evidence: Level III
Background:
Delayed treatment of seriously infected patients results in increased mortality. However, antimicrobial therapy for the initial 24 to 48 hours is mostly empirically provided, without evidence regarding the causative pathogen. Whether empiric anti-enterococcal therapy should be administered to treat intra-abdominal infection (IAI) before obtaining culture results remains unknown. We performed a meta-analysis to explore the effects of empiric enterococci covered antibiotic therapy in IAI and the risk factors for enterococcal infection in IAI.
Methods:
We searched multiple databases systematically and included 23 randomized controlled trials (RCTs) and 13 observational studies. The quality of included studies was assessed, and the reporting bias was evaluated. Meta-analysis was performed using random effects or fixed effects models according to the heterogeneity. The risk ratio (RR), odds ratio (OR), and 95% confidence interval (CI) were calculated.
Results:
Enterococci-covered antibiotic regimens provided no improvement in treatment success compared with control regimens (RR, 0.99; 95% CI, 0.97-1.00; p = 0.15), with similar mortality and adverse effects in both arms. Basic characteristic analysis revealed that most of the enrolled patients with IAI in RCTs were young, lower risk community-acquired intra-abdominal infection (CA-IAI) patients with a relatively low APACHE II score. Interestingly, risk factor screening revealed that malignancy, corticosteroid use, operation, any antibiotic treatment, admission to intensive care unit (ICU), and indwelling urinary catheter could predispose the patients with IAI to a substantially higher risk of enterococcal infection. "Hospital acquired" itself was a risk factor (OR, 2.81; 95% CI, 2.34-3.39; p < 0.001).
Conclusion:
It is unnecessary to use additional agents empirically to specifically provide anti-enterococcal coverage for the management of CA-IAI in lower risk patients without evidence of causative pathogen, and risk factors can increase the risk of enterococcal infection. Thus, there is a rationale for providing empiric anti-enterococcal coverage for severely ill patients with CA-IAI with high risk factors and patients with hospital-acquired intra-abdominal infection (HA-IAI).
The principles of appropriate prophylactic antibiotic use for surgical patients begin with the selection of agents that respond well to microorganisms common in surgical wounds. Antibiotics should be administered within 1 hour prior to surgery. When surgery is expected to be prolonged, the antibiotic half-life should be considered, and a second dose may be required to maintain appropriate tissue levels. Routine prophylactic antibiotic administration after surgery should last for no more than 24 hours.
Antibiotics are among the most commonly prescribed medications worldwide but can lead to numerous cutaneous adverse events. Cutaneous adverse drug reactions can range from a common and low‐risk morbilliform eruption to severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis. In the hospital setting, patients often start a myriad of new drugs and may be on multiple antibiotics when the dermatologist is consulted. With the current lack of commercially available testing for delayed‐type hypersensitivity reactions, etiologic confirmation is challenging. While the Naranjo and other standardized assessment criteria are available, complete scoring is often impossible in hospitalized patients. Further, multiple drugs may have been initiated at the same time point. Therefore, the prevalence of antibiotic‐associated drug eruptions often is required to facilitate causality assessments. This review summarizes the prevalence of morbilliform eruptions for the most frequently prescribed antibiotics based upon systematic reviews, retrospective, and prospective analyses, with case series and reports providing other salient details.
Aim: Recently approved for use in complicated intra-abdominal infection, eravacycline is a novel fluorocycline with broad spectrum of activity against resistant Gram-negative pathogens. This manuscript is a pooled analysis of two Phase III trials. Clinical efficacy: Clinical cure rates were 86.8% for eravacycline versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in the Modified Intent to Treat (MITT) populations. Safety: Eravacycline is well tolerated, with lower rates of nausea, vomiting and diarrhea than other tetracyclines. Conclusion: Eravacycline is an effective new option for use in complicated intra-abdominal infections, and in particular, for the treatment of extended-spectrum β-lactamase- and carbapenem-resistant Enterobacteriaceae-expressing organisms.
Background
Complicated intra-abdominal infections (cIAIs) result in substantial significant morbidity, mortality, and cost. Carbapenem-resistant sepsis has increased dramatically in the last decade, resulting in infections that are difficult to treat and associated with high mortality rates. To prevent further antibacterial resistance, it is necessary to use carbapenem selectively.
Objective
To compare the effectiveness and safety of carbapenems versus alternative β-lactams monotherapy or in combination for the treatment of cIAIs.
Methods
PubMed, Embase, Medline (via Ovid SP) and Cochrane library databases were systematically searched. We included randomized controlled trials (RCTs) comparing carbapenems versus alternative β-lactams monotherapy or in combination for the treatment of cIAIs.
Results
Twenty-two studies involving 7720 participants were included in the analysis. No differences in clinical treatment success, odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.71–1.05, I2 = 35%, microbiological treatment success (OR = 0.88, 95% CI = 0.71–1.09, I2 = 25%), adverse events (AEs) (OR = 0.98, 95% CI = 0.87–1.09, I2 = 17%) and mortality (OR = 0.96, 95% CI = 0.68–1.35, I2 = 7%).
Patients
treated with imipenem were more likely to experience clinical or microbiological failure than those treated with alternative β-lactams monotherapy or in combination.
Conclusions
No differences in clinical outcomes were observed between carbapenems and non-carbapenem β-lactams in cIAIs. Patients treated with imipenem were more likely to experience clinical or microbiological failure than those treated with alternative β-lactams monotherapy or in combination.
Introduction. Primary anastomosis is a feasible technique in the management of severe secondary peritonitis in critically ill patients; however, its use has been limited due to the risk of complications and death. Materials and methods. We selected patients with severe secondary peritonitis that required resection of an intestinal segment and managed with temporary intestinal ligature, open abdomen, elective repeat laparotomies, and ulterior deferred primary anastomosis. Primordial success was labeled in those patients that had primary anastomosis and no leakage or fistulae. Results. Twenty six patients were included in the study, with a mean APACHE II score of 15.3. There were 6 anastomoses in the small bowel, 5 in the large bowel, 4 of the ileum to the large bowel, and in 3 patients an anastomosis could not be performed. A mean of 4 scheduled relaparotomies were registered, starting 24 hours after the anastomosis. Primordial success was achieved in 20 patients (77%), 28-day survival was 88.3%; 23 patients left the hospital alive, and only 3 (11.5%) died in the ICU; these deaths were independent of the procedure. Discussion. Damage control surgery was feasible and secure in patients with severe secondary peritonitis, with a primary success rate of 77%; fistulae developed in 11.5%, and mortality was 11.5%.
Carbapenems are among the most commonly used and the most efficient antibiotics since they are relatively resistant to hydrolysis by most β-lactamases, they target penicillin-binding proteins, and generally have broad-spectrum antibacterial effect. In this review, we described the initial discovery and development of carbapenems, chemical characteristics, in vitro/in vivo activities, resistance studies, and clinical investigations for traditional carbapenem antibiotics in the market; imipenem-cilastatin, meropenem, ertapenem, doripenem, biapenem, panipenem/betamipron in addition to newer carbapenems such as razupenem, tebipenem, tomopenem, and sanfetrinem. We focused on the literature published from 2010 to 2016.
Study objective:
It is unknown if beta-lactam monotherapy is sufficient for complicated intra-abdominal infections or if broader coverage is required, such as with vancomycin. This study sought to determine the clinical outcomes of piperacillin/tazobactam monotherapy compared to combination therapy with vancomycin and piperacillin/tazobactam for complicated intra-abdominal infections among patients within a surgical intensive care unit.
Design:
Retrospective cohort study.
Setting:
Three surgical intensive care units at a tertiary academic medical center.
Patients:
417 patients with a secondary peritonitis identified by International Classification of Diseases 9 codes who received either piperacillin/tazobactam monotherapy (228 patients) or piperacillin/tazobactam and vancomycin combination therapy (189 patients).
Measurements and main results:
The primary outcome was day 28 clinical cure; secondary outcomes included day 7 clinical cure, length of stay (LOS), and mortality. There were no statistically significant differences between the monotherapy and combination therapy groups with respect to day 28 clinical cure (33.9% vs. 25.5%, p=0.064), day 7 clinical cure (23.6% vs. 17.6%, p=0.14), or 28 day mortality (7% vs. 7.9%, p=0.72). LOS in the ICU was significantly shorter in the monotherapy group (6 days) compared with the combination group (7 days; p=0.04); however, hospital LOS was not significantly different.
Conclusions:
No difference was observed in clinical cure rates at day 7 or day 28 between those who received PIP/TAZ monotherapy compared to PIP/TAZ and vancomycin combination therapy. This article is protected by copyright. All rights reserved.
Mobilization of Carbapenemase-Mediated Resistance in Enterobacteriaceae, Page 1 of 2
Abstract
After decades of worry, extreme drug resistance has become an unfortunate reality in many hospitals around the world. Rather than arriving in the form of vancomycin-resistant Staphylococcus aureus or pan-drug-resistant tuberculosis, extreme drug resistance has emerged in enteric Gram-negative bacilli. Essentially unheard of prior to 2003, in 2011 11% of Klebsiella pneumoniae isolates from intensive care units in the United States were resistant to carbapenems, with an attributable mortality rate of 40% from associated invasive infections ( 1 – 3 ). From a recent World Health Organization report, carbapenem resistance in Klebsiella pneumoniae had been seen in almost all countries that had data, and some countries reported carbapenem resistance rates of more than 50% ( 4 ). The Centers for Disease Control and Prevention (CDC) listed carbapenem-resistant Enterobacteriaceae as one of the three most urgent groups of drug-resistant microbes threatening human health in the United States ( 5 ).
The incidence of urinary tract infections caused by extended-spectrum β-lactamase (ESBL)-producing pathogens is increasing. These infections are associated with a long hospital stay in patients undergoing urological procedures. We aimed to demonstrate that significant intraprostatic diffusion of ertapenem is achieved after a single preoperative administration. A referred sample of 19 patients requiring surgery for benign prostatic hyperplasia was prospectively included. Patients received a 1 g intravenous (i.v.) dose of ertapenem 1 h (n = 10, group A) or 12 h (n = 9, group B) before blood and prostatic samples were collected. Plasma and intraprostatic concentrations of ertapenem were measured using LC-MS/MS. Intraprostatic concentrations were considered satisfactory when higher than the MIC90 value of urinary-targeted pathogens perioperatively and for 40% of the dosing interval. The Wilcoxon test and a pharmacokinetic predictive model were used. Median plasma concentrations of ertapenem were 144.3 mg/L (95% CI 126.5–157.9) in group A and 30.7 mg/L (95% CI 22.9–36.4) in group B (P < 0.001); median intraprostatic concentrations were 16.6 mg/L (95% CI 13.3–31.4 mg/L) and 4.2 mg/L (95% CI 3.1–4.9 mg/L), respectively (P < 0.001), which were above the MIC90 values of bacteria, including ESBL-producers, during surgery and for 40% of the dosing interval. The plasma-to-prostate concentration ratio was not significantly different between groups (P = 0.97). Single-dose i.v. ertapenem reached satisfactory intraprostatic concentrations, suggesting that it could be a relevant prophylactic strategy for carriers of ESBL-producing bacteria undergoing prostatic procedures, which needs to be confirmed by further prospective trials.
Antibiotics have been the most important risk factor for Clostridium difficile infection (CDI). However, only data from non-randomised studies have been reviewed. We sought to evaluate the risk for development of CDI associated with the major antibiotic classes by analysing data from randomised controlled trials (RCTs). The PubMed, Cochrane and Scopus databases were searched and the references of selected RCTs were also hand-searched. Eligible studies should have compared only one antibiotic versus another administered systemically. Inclusion of studies comparing combinations of antibiotics was allowed only if the second antibiotic was the same or from the same class or if it was administered in a subset of the enrolled patients who were equally distributed in the two arms. Only a minority of the selected RCTs (79/1332; 5.9%) reported CDI episodes. Carbapenems were associated with more CDI episodes than fluoroquinolones [risk ratio (RR) = 2.44, 95% confidence interval (CI) 1.32–4.49] and cephalosporins (RR = 2.24, 95% CI 1.46–3.42), but not penicillins (RR = 2.53, 95% CI 0.87–7.41). Cephalosporins were associated with more CDIs than penicillins (RR = 2.36, 95% CI 1.32–4.23) and fluoroquinolones (RR = 2.84, 95% CI 1.60–5.06) alone. There was no difference in CDI frequency between fluoroquinolones and penicillins (RR = 1.34, 95% CI 0.55–3.25). Finally, clindamycin was associated with more CDI episodes than cephalosporins and penicillins (RR = 3.92, 95% CI 1.15–13.43). In conclusion, data from RCTs showed that clindamycin and carbapenems were associated with more CDIs than other antibiotics.
Les péritonites sont des infections aiguës de la cavité péritonéale le plus souvent d’origine bactérienne et/ou fongique. Le propos de ce chapitre est de traiter des péritonites non postopératoires en détaillant leurs spécificités étiologiques, diagnostiques et thérapeutiques. La principale classification nosologique utilisée actuellement pour décrire les péritonites est la classification de Hambourg (tableau I) [1].
Intra-abdominal infections are commonly encountered in the general medical/surgical intensive care unit (ICU). Perhaps the largest group of these patients has recently undergone or will shortly undergo some form of interventional procedure. There have been important advances in supportive care, diagnostic tools, anti-infective therapy, and interventional techniques; resulting in both improved care and new controversies in the management of these critically ill patients. Most notable is the role of routine non-invasive imaging for suspected intra-abdominal infections, its use in monitoring success of therapy, and the role of percutaneous or laparoscopic intervention to replace formal laparotomy. The continuing development of antibiotics has provided a novel opportunity for tailoring therapy to the requirements of the individual.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
These guidelines deal with the evaluation of anti-infective drugs for the treatment of intraabdominal infections. The clinical entities consist of infections arising from any part of the gastrointestinal tract, from the distal esophagus to the colon. These include surgical infections of the bowel, biliary tree, liver, spleen, and pancreas. Virtually all intraabdominal infections are due to multiple microorganisms resident in the gastrointestinal tract; these include aerobes and facultative and obligate anaerobes. Infections are classified as complicated (requiring an operative procedure), uncomplicated (managed medically), and postoperative wound (the operative procedure should be curative, but anti-infective drugs are used to prevent further infection at the site). Clinical criteria are paramount for entry into a study and for evaluation of efficacy. For complicated infections an adequate operation is an important determinant of outcome and needs assessment. Cultures of purulent intraabdominal fluid or abscess material are the only valid microbiologic indicators of infection. The acute physiology and chronic health evaluation score is useful in defining the severity of acute illness. The control regimen should consist of effective, established drugs and surgical procedures for the condition. Duration of therapy for complicated infections is usually 5-14 days; for uncomplicated infections, 3- 7 days; and for postoperative wound infection, 2-5 days. Periodic assessment of safety and efficacy must be conducted during therapy. The outcome at final assessment is cure, failure, or indeterminate.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
A prospective observational multicenter study with 18 hospitals was performed to assess preoperative risk, therapeutic management and outcome of patients with peritonitis. Data collection was carried out according to standardized and recommended definitions. Included in the study were 355 patients with macroscopically confirmed peritonitis.
In the univariate analysis, the following factors influenced both the mortality and the incidence of postoperative complications: age, presence of certain concomitant disease, site of origin of peritonitis, type of admission and the ability of the surgeon to eliminate the source of infection. In addition, postoperative infective complications were related to the etiology of peritonitis and the exudate. In the multivariate analysis, APACHE II (P<0.001), successful operation (P<0.001), age (P<0.001), liver disease (P<0.03), malignant disease (P<0.04) and renal disease (P<0.05) turned out to be significant with respect to death. Escherichia coli was the predominant organism (51%), following by enterococci (30%) and bacteroides (25%). There was a significantly higher postoperative infection rate in patients with no adequate treatment of enterococci than patients with adequate treatment or no enterococci (P<0.05).
The study demonstrated the important role of the physiological reserve of the patient and of the surgeon, which is not adequately reflected in existing scoring systems. Further investigations are needed to study the impact of enterococci on the outcome.
By using an agar dilution method, the comparative in vitro activities of ertapenem (MK-0826) were studied against 1,001 anaerobes
isolated from human intra-abdominal infections in 17 countries worldwide. MK-0826 was uniformly active against all isolates,
including all Bacteroides fragilis group species isolates, with the exception of 12 of 61 (20%) strains of Bilophila wadsworthia, 3 strains of lactobacilli, and 1 isolate ofAcidaminococcus fermentans. Geographical variation in activity was not observed.
This study compared the in vitro activities of the new long-half-life carbapenem ertapenem (also known as MK-0826 and L-749,345)
with those of imipenem, amoxicillin-clavulanate, and ciprofloxacin against 5,558 recent clinical isolates from 11 North American
medical centers. We confirmed the greater activity of ertapenem than of imipenem against the Enterobacteriaceae and the greater activity of imipenem against pseudomonads and gram-positive bacteria.
Ertapenem (MK-0826, L-749,345) is a 1-β-methyl carbapenem with a long serum half-life. Its in vitro activity was determined
by broth microdilution against 3,478 bacteria from 12 centers in Europe and Australia, with imipenem, cefepime, ceftriaxone,
and piperacillin-tazobactam used as comparators. Ertapenem was the most active agent tested against members of the familyEnterobacteriaceae, with MICs at which 90% of isolates are inhibited (MIC90s) of ≤1 μg/ml for all species. Ertapenem also was more active than imipenem against fastidious gram-negative bacteria and
Moraxella spp.; on the other hand, ertapenem was slightly less active than imipenem against streptococci, methicillin-susceptible staphylococci,
and anaerobes, but its MIC90s for these groups remained ≤0.5 μg/ml.Acinetobacter spp. and Pseudomonas aeruginosawere also much less susceptible to ertapenem than imipenem, and mostEnterococcus faecalis strains were resistant. Ertapenem resistance, based on a provisional NCCLS MIC breakpoint of ≥16 μg/ml, was seen in only
3 of 1,611 strains of the familyEnterobacteriaceae tested, all of them Enterobacter aerogenes. Resistance was also seen in 2 of 135 anaerobes, comprising 1 Bacteroides fragilis strain and 1Clostridium difficile strain. Ertapenem breakpoints for streptococci have not been established, but an unofficial susceptibility breakpoint of
≤2 μg/ml was adopted for clinical trials to generate corresponding clinical response data for isolates for which MICs were
as high as 2 μg/ml. Of 234 Streptococcus pneumoniae strains tested, 2 required ertapenem MICs of 2 μg/ml and one required an MIC of 4 μg/ml, among 67 non-Streptococcus pyogenes, non-Streptococcus pneumoniae streptococci, single isolates required ertapenem MICs of 2 and 16 μg/ml. These streptococci also had diminished susceptibilities
to other β-lactams, including imipenem as well as ertapenem. The Etest and disk diffusion gave susceptibility test results
in good agreement with those of the broth microdilution method for ertapenem.
This document provides new general guidelines for the design and execution of studies evaluating anti-infective drugs for
the prevention or treatment of infectious diseases. The first step in evaluation is the determination of in vitro microbial
susceptibility. Next, studies are conducted in animals. Several animal models provide information useful in the prediction
of appropriate dosing and activity in humans. If the results of these studies are favorable, staged clinical trials are then
conducted. These guidelines reflect changes in the practice of medicine, dealing with topics such as the switch from parenteral
to oral drug administration during a course of therapy, treatment in settings other than acute-care hospitals, and the use
of alternative comparison drugs for the study of indications or dosing schedules not covered by the product label. Because
further changes in practice are anticipated, the present guidelines will need to be updated and revised periodically.
• Intra-abdominal sepsis that involves multiple aerobic and anaerobic bacteria derived from the colonic flora was studied in Wistar rats to determine the relative roles of various microbial species. The rats challenged with pooled colonic contents showed a biphasic disease. Initially, there was acute peritonitis, Escherichia coli bacteremia, and high mortality. In rats that survived this acute peritonitis stage, intra-abdominal abscesses developed, and anaerobic bacteria were the preponderant organisms. Subsequent experiments showed that antibiotics directed against coliforms prevented mortality, whereas agents active against anaerobes reduced the incidence of abscesses. Challenges with Escherichia coli alone produced bacteremia and death, whereas pure cultures of Bacteroides fragilis caused intra-abdominal abscesses. These observations suggest that both coliforms and anaerobes are important pathogens in intra-abdominal sepsis, although the different types of microbes appear to play distinctive roles in the sequence of pathological events.
(Arch Surg 113:853-857, 1978)
Intra-abdominal sepsis was studied in Wistar rats by using four microbial species: Escherichia coli, enterococci, Bacteroides fragilis, and Fusobacterium varium. These organisms were implanted into the peritoneal cavity singly and in all possible dual combinations. Results were evaluated by mortality rates and the incidence of intra-abdominal abscesses on autopsy following sacrifice after 7 days. Mortality was restricted to recipients of E. coli, thus implicating coliforms in the acute lethality associated with this experimental model. Intra-abdominal abscesses were produced in 61 of 95 (94%) animals that received the combination of an anaerobe and a facultative organism. Abscesses failed to form with any single strain or with E. coli plus enterococci, and they were detected in one 1 of 19 animals receiving B. fragilis plus F. varium. These results suggest that intra-abdominal abscess formation is related to synergy between anaerobes and facultative bacteria.
Intra-abdominal infections are commonly closed space infections, and the primary mode of therapy is surgical drainage and removal of necrotic tissue. However, the importance of appropriate antimicrobial therapy is not to be underemphasized.
This document provides new general guidelines for the design and execution of studies evaluating anti-infective drugs for the prevention or treatment of infectious diseases. The first step in evaluation is the determination of in vitro microbial susceptibility. Next, studies are conducted in animals. Several animal models provide information useful in the prediction of appropriate dosing and activity in humans. If the results of these studies are favorable, staged clinical trials are then conducted. These guidelines reflect changes in the practice of medicine, dealing with topics such as the switch from parenteral to oral drug administration during a course of therapy, treatment in settings other than acute-care hospitals, and the use of alternative comparison drugs for the study of indications or dosing schedules not covered by the product label. Because further changes in practice are anticipated, the present guidelines will need to be updated and revised periodically.
These guidelines deal with the evaluation of anti-infective drugs for the treatment of intraabdominal infections. The clinical entities consist of infections arising from any part of the gastrointestinal tract, from the distal esophagus to the colon. These include surgical infections of the bowel, biliary tree, liver, spleen, and pancreas. Virtually all intraabdominal infections are due to multiple microorganisms resident in the gastrointestinal tract; these include aerobes and facultative and obligate anaerobes. Infections are classified as complicated (requiring an operative procedure), uncomplicated (managed medically), and postoperative wound (the operative procedure should be curative, but anti-infective drugs are used to prevent further infection at the site). Clinical criteria are paramount for entry into a study and for evaluation of efficacy. For complicated infections an adequate operation is an important determinant of outcome and needs assessment. Cultures of purulent intraabdominal fluid or abscess material are the only valid microbiologic indicators of infection. The acute physiology and chronic health evaluation score is useful in defining the severity of acute illness. The control regimen should consist of effective, established drugs and surgical procedures for the condition. Duration of therapy for complicated infections is usually 5-14 days; for uncomplicated infections, 3-7 days; and for postoperative wound infection, 2-5 days. Periodic assessment of safety and efficacy must be conducted during therapy. The outcome at final assessment is cure, failure, or indeterminate.
The frequency of isolation of enterococci from surgical patients has increased significantly during the past decade, although
the role of these organisms as pathogens in mixed infections remains a mystery. Bacteremia and other infections in which enterococci
are the only pathogens frequently result in high morbidity and mortality among patients unless specific antimicrobial therapy
is initiated promptly. Debate continues concerning the necessity for treatment with such agents when this organism is isolated
as a component of a polymicrobial infecting flora. Our recent data indicate that enterococci are rarely isolated in postoperative
infections after penetrating abdominal trauma if no gastrointestinal perforation has occurred. However, they were found in
56% of postoperative infections of patients with gastrointestinal perforation. In contrast, enterococci were isolated in only
9% of cultures of specimens from patients with secondary suppurative peritonitis. The occurrence of superinfection after therapy
with a cephalosporin appears to be an important factor in this finding. Future studies are necessary to evaluate the efficacy
of antibiotic treatment of enterococcal infections and to assess the need for prophylaxis against enterococci.
The charts of 480 patients with secondary bacterial peritonitis were reviewed. The antibiotics used were compared with the culture and sensitivity data obtained at surgery, and the outcomes of patients were evaluated. Patients treated with a single broad-spectrum antibiotic had a better outcome than patients treated with multiple drug treatment. Inadequate empiric antibiotic treatment was associated with poorer outcome than any other type of treatment. The outcome of this inadequate treatment group could not be improved by any antibiotic response to culture and sensitivity information after operation. Those patients treated with antibiotic coverage for anticipated organisms and having no cultures taken did as well as patients having cultures taken. Surgeons typically ignore culture data after operation, and only 8.8% of patients in this study had an appropriate change in antibiotic treatment after operation. A benefit from obtaining operative cultures could not be identified.
We designed a multicenter study to compare tobramycin/clindamycin to imipenem/cilastatin for intra-abdominal infections. We included the Acute Physiology and Chronic Health Evaluation (APACHE II) index of severity and excluded patients without established infection. Two hundred ninety patients were enrolled, of whom 162 were evaluable. Using logistic regression to analyze both outcome at the abdominal site of infection and outcome as mortality, we found a significant correlation for both with APACHE II score (p less than 0.0001 for both). Next we analyzed the residual effect of treatment assignment and found a significant improvement in outcome for imipenem/cilastatin-treated patients (p = 0.043). The differences in outcome were explained by a higher failure rate for patients with gram-negative organisms for tobramycin/clindamycin-treated patients (p = 0.018). This was reflected in a significantly higher incidence of fasciitis requiring reoperation and prosthetic fascial replacement. Maximum peak tobramycin levels were analyzed for 63 tobramycin/clindamycin patients harboring gram-negative organisms. For failures the maximum peak was 6.4 +/- 1.9 micrograms/mL, and time to maximum peak was 4.6 +/- 5.2 days. For successes the maximum peak was 6.1 +/- 1.7 micrograms/mL, occurring at 3.8 +/- 2.6 days. This study supports inclusion of severity scoring in statistical analyses of outcome results and supports the notion that imipenem/cilastatin therapy improves outcome at the intra-abdominal site of infection as compared to a conventionally prescribed amino-glycoside-based regimen.
Fifty-three patients with 71 intraabdominal abscesses identified on computed tomography (CT) and treated with percutaneous abscess drainage were evaluated for the possible predictive value of any particular CT feature in relation to the outcome of percutaneous drainage. Features analyzed included the presence of a "rind," sharp exterior margin, air-fluid level, scattered internal gas bubbles, and internal septations, as well as size, site, and the presence or absence of fistulas as determined by sinography. Statistical analysis revealed that only site has predictive value; liver and subphrenic abscesses were more likely to have a successful outcome than abscesses in other locations (84% vs 47% complete cure). The presence of a long air-fluid level denoted communication with the gastrointestinal tract, which led to significantly longer drainage times and larger drainage volumes. Since there are no CT features that can strongly predict a poor outcome, all intraabdominal abscesses should be considered candidates for percutaneous drainage.
A prospective, randomized, double-blinded comparison of Sulbactam and ampicillin and clindamycin and gentamicin is described. The combination of ampicillin and Sulbactam was not as effective in the management of perforated appendicitis and gangrenous appendicitis as was clindamycin and gentamicin. While both combinations of antibiotics had good anaerobic activity and failures were not associated with the recovery of Bacteroides fragilis group organisms, infectious complications were seen in patients from whom Pseudomonas were isolated. These pseudomonads were not nosocomially acquired and were found especially in patients with perforated appendicitis. We concluded that the combination of clindamycin and gentamicin, although less convenient to administer to the patient, remains the adjunctive antibiotic management of choice for perforated or gangrenous appendicitis. The epidemiologic factors of Pseudomonas species as a primary pathogen in peritonitis deserves further attention.
Outcome in patients with abdominal abscesses treated at the University of Pennsylvania, Philadelphia, between 1973 and 1978 (group 1) was compared with that in patients treated between 1981 and 1986 (group 2). Mortality was less in group 2 patients (21% vs 39% in group 1). The decrease in mortality in group 2 was accompanied by a greater percentage of successful predrainage localization (74% vs 55% in group 1), successful initial drainage (76% vs 55% in group 1), and decreased predrainage organ failure (23% vs 52% in group 1). Because failure of initial drainage and predrainage organ failure were associated with increased mortality, improvement in both of these criteria contributed substantially to the lower mortality in group 2 patients. There were no differences in mortality, in initial success in drainage, or in length of hospital stay when 29 group 2 patients who underwent percutaneous drainage were compared with 37 patients who underwent surgical drainage. Mortality (22% vs 21%) and initial success (78% vs 72%) were similar for patients who underwent surgical and percutaneous drainage, respectively. We conclude that initial success in localization and drainage of the abscess is more important than whether drainage is surgical or percutaneous.
A matched case-control study of the efficacy of gentamicin dosage adjustment through the use of pharmacokinetic analysis of serum drug concentrations in patients treated by appendectomy for perforated or gangrenous appendicitis was performed. Two groups of patients were compared. In one group gentamicin was initiated preoperatively at 1.5 mg/kg Intravenous Piggy Back (IVPB) every 8 h. Postoperatively, serum levels were obtained to maintain peak concentrations within a range of 6-8 micrograms/ml. The comparison group was given gentamicin without measurement of drug levels. Both groups received clindamycin 600 mg IVPB every six h. Matched cases and control subjects were compared, controlling for pathologic state of the appendicitis, age, and sex. The patients were predominantly young men with normal renal function. More patients in the nonadjusted group had infectious complications than in the dose-adjusted group. There were seven failures (11.3%) in the nonadjusted group compared with only one failure (1.6%) in the dose-adjusted group, a significant difference (p = 0.03). Among the nonadjusted group, the complications were four abdominal abscesses, two wound infections, and one persistent high fever. There was no evidence of nephrotoxicity in either group. Our recommendations are that patients who are to undergo appendectomy for perforated/gangrenous appendicitis should be treated with clindamycin and gentamicin at a dose of 1.5 mg/kg. With normal renal function, an interval of 8 h is appropriate. Serum gentamicin levels should be obtained and the dose adjusted to maintain peak concentrations of 6-8 micrograms/ml.
A study of 130 adult patients with surgically treated gangrenous or perforated appendicitis was undertaken to evaluate the efficacy of three antibiotic regimens. Forty-eight patients received cefamandole, 40 were given the combination of clindamycin and gentamicin, and 42 were treated with cefoperazone. Side effects from these antibiotics were infrequent and mild. When all cases were compared for infectious failure, clindamycin-gentamicin showed a clear advantage over cefamandole. Because of the heterogeneity of the total study population, patients with perforation and peritonitis were compared separately. This analysis confirmed the advantage of clindamycin-gentamicin over cefamandole. In addition, it appears that clindamycin-gentamicin is more efficacious than cefoperazone.
The relationships between resistant pathogens, serum levels of gentamicin, and the outcomes of gangrenous or perforated appendicitis
were analyzed in 147 patients. Failure to cure the infection occurred significantly more frequently among patients treated
with cefoperazone or cefamandole than among those treated with clindamycin and gentamicin in combination. The failures were
associated with recovery of resistant Bacteroides fragilis from intraoperative cultures. Pseudomonas species were also associated with failures, their in vitro susceptibility not correlating with clinical cure. Patients with
gentamicin peak serum levels of <6 µg/ml in the first three days were not more likely to be associated with failure than were
patients with higher levels. These clinical observations indicate that antibiotic therapy of intra-abdominal sepsis should
include antibiotics with in vitro activity against B fragilis and that precise adjustments of gentamicin levels may not improve outcome. In addition, Pseudomonas species may playa significant role in some of these infections.
The role of enterococcus in intraabdominal infection is controversial. This study examines the contribution of enterococcus to adverse outcome in a large intraabdominal infection trial.
A randomized prospective double-blind trial was performed to compare two different antimicrobial regimens in combination with surgical or percutaneous drainage in the treatment of complicated intraabdominal infections. A total of 330 valid patients was enrolled from 22 centers in North America.
In 330 valid patients, 71 had enterococcus isolated from the initial drainage of an intraabdominal focus of infection. This finding was associated with a significantly higher treatment failure rate than that of patients without enterococcus (28% versus 14%, p < 0.01). In addition, only Acute Physiology and Chronic Health Evaluation II score and presence of enterococcus were significant independent predictors of treatment failure when stepwise logistic regression was performed (p < 0.01 and < 0.03). Risk factors for the presence of enterococcus include age, Acute Physiology and Chronic Health Evaluation II, preinfection hospital length of stay, postoperative infections, and anatomic source of infection. There was no difference between the clinical trial treatment regimens with regard to overall failure, failure associated with enterococcus, or frequency of enterococcal isolation.
This study is the first to report enterococcus as a predictor of treatment failure in complicated intraabdominal infections. This trial also identifies several significant risk factors for the presence of enterococcus in such infections.
The clinical results with the beta-lactam/beta-lactamase inhibitor class of antimicrobials in the treatment of intra-abdominal infections are reviewed. The three agents now in clinical use--ampicillin/sulbactam, ticarcillin/clavulanate, and piperacillin/tazobactam--are effective against a broad variety of gram-positive and gram-negative organisms. The beta-lactamase inhibitor is an irreversible inactivator of beta-lactamase enzymes, which are produced by many gram-negative and gram-positive organisms. Randomized, prospective, clinical trials of each agent indicate clinical cure rates > 85% that are not significantly different from those obtained with second-generation cephalosporin or aminoglycoside plus antianaerobic comparators, with the exception of one study. Piperacillin/tazobactam has also been compared with imipenem, with equivalent or superior outcomes, depending on the dose of the imipenem comparator. Side effects in the non-penicillin-allergic patient are few. The incidence of abnormal renal function tests are generally lower than that obtained with aminoglycoside plus antianaerobic therapy. Introduction of this new beta-lactam antimicrobial group provides another important strategy for the adjunctive management of surgically treated, community-acquired, intra-abdominal infection.
L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.
MK-826 (formerly L-749,345), is a potent 1-beta-methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other beta-lactam agents in two in vivo murine infection models. The distribution in tissue and pharmacokinetic properties of MK-826 and ceftriaxone (CTRX) were also evaluated in CD-1 mice following a single intraperitoneal dose (10 mg/kg of body weight). In addition, concentrations in plasma as well as biliary and urinary recovery of MK-826 were compared to that of CTRX in a cannulated rat model. In a localized murine thigh infection model, MK-826 and IPM were superior to a variety of beta-lactam antibiotics in reduction of Staphylococcus aureus CFU compared with results from nontreated controls (eliminating >/=4 log10 CFU). Similar activities of IPM and MK-826 were observed in a gram-positive bacterial murine systemic infection model. While IPM demonstrated greater efficacy than MK-826 against Enterobacter cloacae (50% effective doses [ED50s] of 0.062 and 0.227 mg/kg, respectively) and Pseudomonas aeruginosa (ED50s of 0.142 and 3.0 mg/kg, respectively) systemic infections, MK-826 was 8- to 350-fold more efficacious than IPM against all other gram-negative organisms in this infection model. In mice, MK-826 demonstrated a higher peak concentration in serum (62.8 versus 42.6 microg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 microg . hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 microg/ml remaining, respectively, at 6 h posttreatment. The rat pharmacokinetic model showed the average AUC of MK-826 to be greater than that of CTRX (284 versus 142 microg . hr/ml) following a single 10-mg/kg dose. Also, a half-life of MK-826 longer than that of CTRX (3.2 versus 2.3 h) was observed in this species. The total amount of drug excreted in the bile in 8 h was greater for CTRX (55 to 64% of the dose) than for MK-826 (6 to 12.5% of the dose). Urinary recovery was similar for both antibiotics, with 16 to 18% of the dose recovered over an 8-h period. This excellent broad-spectrum in vivo efficacy of MK-826, together with advantageous pharmacokinetics, supports the argument for its further clinical development.
In May 1997, a panel of surgeon-investigators met to discuss the clinical importance and research implications of controlling the source of abdominal infections. It was concluded that source control is critical to therapeutic success and that antimicrobial therapy and other adjunctive interventions will fail if the source of infection is not controlled by resection, exteriorization or other means. The panelists presented different definitions of source control, depending on the scientific purpose of the definition. All participants agreed that failure to consider the adequacy of source control of infection has limited the value of most clinical trials of therapeutic anti-infective agents. Besides recognizing source control as an essential goal of patient care, the panelists emphasized the need for further investigative work to define, record and stratify the adequacy of source control in clinical trials of therapeutic agents for abdominal infections.
Clinafloxacin is a novel quinolone with wide activity against the plethora of microorganisms encountered in intraabdominal infections. This trial was performed to examine its clinical efficacy.
Clinafloxacin is representative of a new class of quinolones with considerable antimicrobial activity resulting from their mechanisms of action and pharmacodynamics. There is, however, concern about specific potential toxicities, including photosensitivity.
This prospective, randomized, double-blind trial was conducted to compare clinafloxacin with imipenem/cilastatin as adjuncts in the management of complicated intraabdominal infections.
Five hundred twenty-nine patients were included in the intent-to-treat population, with 312 meeting all criteria for the valid population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was the most common (approximately 50%). One hundred twenty-three of the 150 valid patients treated with clinafloxacin (82%) had successful outcomes, as did 130 of the 162 (80%) treated with imipenem. For the intent-to-treat groups, 219 of 259 patients treated with clinafloxacin (85%) had successful outcomes, as did 219 of 270 patients treated with imipenem/cilastatin (81%). Treatment failure occurred in 39 patients who underwent drainage. There were substantially more gram-negative organisms recovered from the patients with treatment failure who were initially treated with imipenem/cilastatin.
The results of this study clearly demonstrate the safety and efficacy of clinafloxacin in the treatment of a range of intraabdominal infections, and in patients with a broad range of physiologic disturbances.