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High dose vancomycin for osteomyelitis: Continuous vs. intermittent infusion
Journal of Clinical Pharmacy and Therapeutics
Abstract
To compare the efficacy, ease of use and safety of intermittent vancomycin infusion (IVI) and continuous vancomycin infusion (CVI) in high-dose therapy of osteomyelitis. Methods: Forty-four patients with an osteomyelitis requiring vancomycin for more than 4 weeks were prospectively included, 21 receiving IVI and 23, CVI. The target serum concentration of vancomycin was 20-25 mg/L. Pharmacokinetics, adverse effects, and clinical efficacy were recorded.
The mean daily vancomycin dosing was the same in the two groups, but the serum vancomycin concentrations (trough or plateau) were lower in the IVI group than the CVI group (21.7 +/- 9.3 and 26.0 +/- 6.1 mg/L, respectively; P < 0.0001). The target concentrations were achieved quicker with CVI, and daily dosing was changed more frequently in the IVI group. After reaching the target, variability of vancomycin serum concentration (trough or plateau concentrations) was higher in the IVI group than in CVI group (standard deviation 7.9 mg/L vs. 5.6 mg/L, respectively; P = 0.001). CVI did not show clinical superiority, but adverse drug effects were more frequent in the IVI group as compared with the CVI group, 9 (42.9%) and 2 (8.7%), respectively (P = 0.03). Survival multiple regression using Cox's proportional hazard model showed that IVI (RR = 5.9, P = 0.03) and osteomyelitis of the foot (RR = 5.2, P = 0.01) were the only factors associated with adverse drug reactions leading to treatment termination.
CVI is practical and effective, and may be a good alternative for patients requiring prolonged treatment with high vancomycin serum levels.
... 13 patients were less likely to discontinue CI vancomycin because of adverse drug reactions versus intermittent infusion vancomycin (8.7% versus 42.9%). 67 Discontinuations were related largely to adverse drug events, most commonly kidney adverse events. 67 Several retrospective reviews of CI vancomycin in the outpatient setting have demonstrated no difference in clinical failure rates compared with intermittent infusion, despite the potentially improved monitoring capabilities of CI vancomycin. ...
... 67 Discontinuations were related largely to adverse drug events, most commonly kidney adverse events. 67 Several retrospective reviews of CI vancomycin in the outpatient setting have demonstrated no difference in clinical failure rates compared with intermittent infusion, despite the potentially improved monitoring capabilities of CI vancomycin. 68,69 Several studies identified lower incidence and/or slower development of kidney impairment with CI versus intermittent infusion. ...
... 68,69 Several studies identified lower incidence and/or slower development of kidney impairment with CI versus intermittent infusion. 67,68,70 The increased safety and practicality benefits of CI vancomycin should be weighed against the potential work for the patient or caregiver. Patients receiving OPAT vancomycin in one study stated that receipt of vancomycin moderately affected their daily routines, which was not observed with receipt of daptomycin. ...
Outpatient parenteral antimicrobial therapy (OPAT) has been widely used in clinical practice for many decades because of its associated cost savings, reductions in inpatient hospital days, and decreases in hospital-associated infections. Despite this long history, evolving practice patterns and new drug delivery devices continue to present challenges as well as opportunities for clinicians when designing appropriate outpatient antimicrobial regimens. One such change is the increasing use of extended and continuous infusion (CI) of antimicrobials to optimize the achievement of pharmacokinetic and pharmacodynamic targets. Elastomeric devices are also becoming increasingly popular in OPAT, including for the delivery of CI. In this article, we review the clinical evidence for CI in OPAT, as well as practical considerations of patient preferences, cost, and antimicrobial stability.
... Published studies that compared intermittent to continuous administration primarily focused on 2 distinct populations, adult critically ill patients in the ICU with suspected or documented infections and those receiving outpatient antimicrobial therapy (OPAT) for bone and joint infections. [80][81][82][83][84][85][86][87][88][89] Most studies compared CI to II for the risk of AKI and attainment of target serum concentrations; only 4 studies included other outcome endpoints such as treatment failure and mortality. 80,84,87,89 Measures of vancomycin drug exposure reported in clinical trials include trough and average steady-state concentrations and AUC 24 . ...
... [80][81][82][83][84][85][86][87][88][89] Most studies compared CI to II for the risk of AKI and attainment of target serum concentrations; only 4 studies included other outcome endpoints such as treatment failure and mortality. 80,84,87,89 Measures of vancomycin drug exposure reported in clinical trials include trough and average steady-state concentrations and AUC 24 . One challenge when comparing clinical outcomes between CI and II is the lack of consistent reporting of exposure parameters between groups treated using the 2 dosing strategies. ...
... A total of 7 studies compared CI vs II of vancomycin in critically ill patients. [81][82][83][84][85][86][87] Only one study, by Wysocki et al, 80 evaluated both efficacy and safety in a prospective randomized trial comparing vancomycin CI (n = 61) and II (n = 58) in 119 patients. Most patients had pneumonia or bacteremia, mostly due to MRSA. ...
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In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
... Additionally, 3 studies were conducted in orthopedic outpatients. [38][39][40] Notably, these patients demonstrate an increased risk of suboptimal TDM due to inappropriately timed sampling, especially in the case of InI treatment. Vuagnat et al 40 conducted a prospective, comparative investigation in patients with osteomyelitis, striving for higher vancomycin concentrations (trough and steady-state levels of 20-25 mg/L). ...
... The mean RSDs in the vancomycin serum concentration were 46.5% and 32.1% for InI and CoI, respectively, and differed significantly between both treatment groups (P = 0.001) (Fig. 2). The influence of study design and the number of included patients were explored and are presented in Table 2. Eight studies directly compared vancomycin InI and CoI, 8,20,25,29,36,38,40 yielding a median (range) interpatient serum concentration variability of 43.4% in vancomycin InItreated populations (27.6%-70.2%) and 23.5% (11.2%-55.0%) in CoI-treated groups. ...
... Furthermore, the studies that directly compared vancomycin InI with CoI reported a greater interpatient variability in the serum concentrations with InI. 8,20,25,29,36,38,40 Furthermore, these direct comparisons demonstrated a more rapid and higher target attainment with CoI than with InI. 20,25,27,38 In regard to the latter, it should be noted that the definition of target ranges was subjective and also an important variable determining target attainment rates. ...
Background:
Studies comparing the clinical outcomes between vancomycin intermittent infusion (InI) and continuous infusion (CoI) treated patients are generally underpowered. Moreover, due to large differences in the design and efficacy end points in these studies, a meta-analysis of the currently available data is not feasible. Therefore, this systematic review aimed to compare the exposure variability and target attainment with vancomycin during InI and CoI.
Patients and methods:
A literature search was performed, and clinical studies reporting on vancomycin-treated populations were selected. After exclusion of reviews, case reports, and articles not published in the English language, 505 articles were screened for reported data on vancomycin serum concentrations. A total of 34 studies were included in the review. Relative standard deviations reported in the included studies were assessed, and vancomycin serum concentration variability and target attainment were compared between vancomycin InI and CoI.
Results:
The variability in serum concentrations was significantly larger for InI than for CoI (relative standard deviations 46.5% and 32.1%, respectively; P = 0.001). Notably, variability appeared to be independent of the study population or design. Studies directly comparing target attainment between both modes of administration denoted higher and faster target attainment with CoI in all instances.
Conclusions:
In conclusion, CoI was associated with lower variabilities in the serum concentration and favorable target attainment rates compared with InI. These findings are important because vancomycin exposure is considered a major predictor of the patients' clinical outcomes. However, the role of lower serum concentration variability and higher target attainment rates in achieving better clinical outcomes needs to be evaluated in patients treated with vancomycin CoI compared with InI.
... Published studies that compared intermittent to continuous administration primarily focused on 2 distinct populations, adult critically ill patients in the ICU with suspected or documented infections and those receiving outpatient antimicrobial therapy (OPAT) for bone and joint infections. [80][81][82][83][84][85][86][87][88][89] Most studies compared CI to II for the risk of AKI and attainment of target serum concentrations; only 4 studies included other outcome endpoints such as treatment failure and mortality. 80,84,87,89 Measures of vancomycin drug exposure reported in clinical trials include trough and average steady-state concentrations and AUC 24 . ...
... [80][81][82][83][84][85][86][87][88][89] Most studies compared CI to II for the risk of AKI and attainment of target serum concentrations; only 4 studies included other outcome endpoints such as treatment failure and mortality. 80,84,87,89 Measures of vancomycin drug exposure reported in clinical trials include trough and average steady-state concentrations and AUC 24 . One challenge when comparing clinical outcomes between CI and II is the lack of consistent reporting of exposure parameters between groups treated using the 2 dosing strategies. ...
... A total of 7 studies compared CI vs II of vancomycin in critically ill patients. [81][82][83][84][85][86][87] Only one study, by Wysocki et al, 80 evaluated both efficacy and safety in a prospective randomized trial comparing vancomycin CI (n = 61) and II (n = 58) in 119 patients. Most patients had pneumonia or bacteremia, mostly due to MRSA. ...
... The remaining 22 full text articles were assessed for eligibility, in which 7 were excluded, because of no target concentration [19][20][21][22][23][24][25], and 1 study was excluded because of no inclusion data [26]. Eventually 14 articles were included in the study [3,8,[27][28][29][30][31][32][33][34][35][36][37]. ...
... In the included studies, 2 were from France [27,28], 5 were from the United States [30,31,33,35,37], 2 were from Austria [29,32], 2 were from Germany [3,34], 1 was from Singapore [8], 1 was from Poland [36], and 1 was from the Netherland [38]. We did not find related meta-analyses in the Cochrane library. ...
... The RCTs were assessed using the modified Jadad scale; 1 RCT achieved a score of 5 [27,35] and the other RCT achieved a score of 4 [31]. The PrCs and ReCs were assessed using the Newcastle-Ottawa scale; 2 PrCs and 3 ReCs achieved a score of 9 [29,30,32,35,38], 3 PrCs and 2 ReCs achieved a score of 8 [3,28,33,34,36], and 2 ReCs achieved a score of 7 [8,37]. The results of the scales are shown in Table 1. ...
Objective:
The clinical use of intermittent infusion of vancomycin (IIV) and continuous infusion of vancomycin (CIV) is controversial. The aim of this study was to assess the effectiveness and safety of IIV and CIV by using a meta-analysis for cohort studies and randomized controlled trials.
Methods:
We compared the probabilities of target attainment (PTA) for the measured concentration (Cm) ≥the target concentration (Ct), the PTA for the area under the drug concentration curve/minimal inhibitory concentration (AUC/MIC) ≥400, the duration of treatment, nephrotoxicity, and overall mortality after vancomycin treatment as reported in PubMed, Embase, Cochrane, and Web of Science.
Results:
A total of 14 studies with 1640 patients were included in the meta-analysis. For IIV, the PTA of Cm≥Ct (RR=0.72, 95% CI=0.60-0.88), and nephrotoxicity (RR=1.70, 95% CI=1.34-2.14) were significantly different from those of CIV. The treatment duration (SMD=0.08, 95% CI=-0.08-0.25), the PTA of AUC/MIC ≥ 400 (RR=0.84, 95% CI=0.70-1.00) and mortality (RR=0.94, 95% CI=0.72-1.25) were not significantly different from those of CIV.
Conclusions:
The results showed that CIV was easier to achieve Ct and safer than IIV. Additional randomized controlled trials focusing on the concentration of vancomycin are needed for further analysis.
... (1, 3, 15,16,18,19) However, one matched cohort study reported lower mortality rates for critically ill patients with ventilator-associated pneumonia receiving vancomycin in CI (25% vs 55%). Multiple regression analysis of the data confirmed that CI was associated with improved survival. ...
... (12) The latter corresponds to our results which also show improved survival in CI group. Faster achievement of effective VSTC which was seen in our study is similar to the data from other scientists (5, 11,13,14,18), however our results on this do not appear to be statistically significant. As regards CI superiority in terms of lower VSTC variability and its better maintenance within the target range our results match the data of other published studies. ...
... As regards CI superiority in terms of lower VSTC variability and its better maintenance within the target range our results match the data of other published studies. (11,13,14,18,19) Our study didn't reveal correlation between CI use and lower incidence of nephrotoxicity. We find this difficult to investigate due to wide ICU patient heterogeneity and specific features, such as variable co-morbidities, hemodynamic instability, 24-hour urine output changes, body fluid compartment volume shifts, and therapeutic use of other potentially nephrotoxic agents, which makes it impossible to attribute serum creatinine changes solely to the effect of vancomycin. ...
Introduction. Vancomycin may be administered by bolus injections (BI) and continuous infusion (CI). Data on BI and CI clinical effectiveness and correlation with mortality, survival and renal injury is variable.
Aim of the study. The aim of the study was to compare the use of vancomycin continuous infusion and bolus administration in intensive care.
Materials and methods. Retrospective analysis of 46 ICU patients (23 patients received vancomycin CI and 23 - BI) was undertaken to compare efficacy and effect on mortality and morbidity of these two administration methods.
Results. The study revealed association of CI administration with more effective (15 - 25 mg/L) serum vancomycin trough concentration maintenance (31.2% vs 25.6% of treatment time, p=0.011) as well as with reduced incidence of subtherapeutic vancomycin levels (34.3% vs 37.2% of treatment time, p=0.015). We also observed better survival times using CI mode.
Conclusions. CI appears to be beneficial in terms of better maintenance of target VSTC and better patient survival. However, its use compared to bolus administration has no statistically significant impact on overall mortality and incidence of nephrotoxicity.
... 3) The PK level to monitor is the plateau level (i.e., steady-state concentration), and the target concentration is 20-25 µg/mL for continuous infusion (III-A). 4) Because no comparative study on efficacy and safety between continuous and intermittent infusion therapy based on AUC-guided dosing is available, vancomycin continuous infusion is not currently recommended [175][176][177][178][179][180][181][182][183] (III-B). ...
... The meta-analysis conducted by Chu et al. [175] also demonstrated a low AKI risk for continuous infusion. Although most continuous infusion studies did not report vasculitis, Vuagnat et al. reported two cases of catheter-associated phlebitis among 23 patients who underwent continuous infusion therapy [182]. ...
Background:
To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM).
Methods:
Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing.
Results:
AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 μg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1-2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI.
Conclusions:
These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects.
... Several studies have evaluated different nomograms or dosing strategies for vancomycin; however, limited data provided an insight into the correlation between time to achieve vancomycin therapeutic levels and signi cant clinical outcomes [12][13][14][15][16]. The median time to reach a therapeutic level for vancomycin in previously reported data was three days, which would be considered late in our study de nition [13][14][15][16] However, a prospective multicenter study that validated the vancomycin consensus guideline nomogram published in 2009 had a median time of two days [17]. ...
... Several studies have evaluated different nomograms or dosing strategies for vancomycin; however, limited data provided an insight into the correlation between time to achieve vancomycin therapeutic levels and signi cant clinical outcomes [12][13][14][15][16]. The median time to reach a therapeutic level for vancomycin in previously reported data was three days, which would be considered late in our study de nition [13][14][15][16] However, a prospective multicenter study that validated the vancomycin consensus guideline nomogram published in 2009 had a median time of two days [17]. Many strategies are suggested to achieve earlier trough levels using continuous vancomycin infusion [18][19][20]. ...
Background: Vancomycin is a commonly used antibiotic in critically ill patients for various indications. Critical illness imposes pharmacokinetic-pharmacodynamics challenges which makes optimizing vancomycin in this population cumbersome. Data are scarce on the clinical impact of time to therapeutic trough levels of vancomycin in critically ill patients. The aim of this study to evaluate the timing to achieve therapeutic trough level vancomycin on 30-day mortality in critically ill patients.
Method: A retrospective cohort study for all adult critically ill patients aged 18 years or older with confirmed Gram-positive infection and received vancomycin between January 1st, 2017 and December 31st, 2018 at a tertiary teaching hospital. We compared early (<48 hours) versus late (≥ 48 hours) attainment of vancomycin therapeutic trough levels. Primary outcome was the 30-day mortality in critically ill patients. Secondary outcomes were development of resistant organisms, eradicating microorganisms within 4-5 days of vancomycin initiation, vancomycin-induced acute kidney injury (AKI), and ICU length of stay (LOS).
Results: Two hundred and nine patients were included. No significant differences between comparative groups in baseline characteristics. Achieving therapeutic levels were associated with better survival at 30 days (OR: 0.48; 95% CI [0.26-0.87]; p<0.01). Additionally, patients who achieved therapeutic levels of vancomycin early were less likely to develop resistant organisms (OR=0.08; 95% CI [0.01-0.59]; p=0.01). The AKI and ICU LOS were not significant between the two groups.
Conclusion: Early attainment of vancomycin therapeutic levels was associated with possible survival benefit.
... Several studies have evaluated different nomograms or dosing strategies for vancomycin; however, limited data provided an insight into the correlation between time to achieve vancomycin therapeutic levels and signi cant clinical outcomes [12][13][14][15][16]. The median time to reach a therapeutic level for vancomycin in previously reported data was three days, which would be considered late in our study de nition [13][14][15][16] However, a prospective multicenter study that validated the vancomycin consensus guideline nomogram published in 2009 had a median time of two days [17]. ...
... Several studies have evaluated different nomograms or dosing strategies for vancomycin; however, limited data provided an insight into the correlation between time to achieve vancomycin therapeutic levels and signi cant clinical outcomes [12][13][14][15][16]. The median time to reach a therapeutic level for vancomycin in previously reported data was three days, which would be considered late in our study de nition [13][14][15][16] However, a prospective multicenter study that validated the vancomycin consensus guideline nomogram published in 2009 had a median time of two days [17]. Many strategies are suggested to achieve earlier trough levels using continuous vancomycin infusion [18][19][20]. ...
Background
Vancomycin is a commonly used antibiotic in critically ill patients for various indications. Critical illness imposes pharmacokinetic-pharmacodynamics challenges which makes optimizing vancomycin in this population cumbersome. Data are scarce on the clinical impact of time to therapeutic trough levels of vancomycin in critically ill patients. Objective (s)The aim of this study to evaluate the timing to achieve therapeutic trough level vancomycin on 30-day mortality in critically ill patients.SettingAdult critically ill patients admitted to intensive care units (ICUs) between January 1st, 2017 and December 31st, 2018 at a tertiary teaching hospital.MethodA retrospective cohort study for all adult critically ill patients aged 18 years or older with confirmed gram-positive infection and received vancomycin. We compared early (<48 hours) versus late (≥ 48 hours) attainment of vancomycin therapeutic trough levels. Main outcomesPrimary outcome was the 30-day mortality in critically ill patients. Secondary outcomes were development of resistant organisms, eradicating microorganisms within 4-5 days of vancomycin initiation, vancomycin-induced acute kidney injury (AKI), and ICU LOS. ResultsTwo hundred and nine patients were included. No significant differences between comparative groups in baseline characteristics. Achieving therapeutic levels were associated with better survival at 30 days (OR: 0.48; 95% CI [0.26-0.87]; p<0.01). Additionally, patients who achieved therapeutic levels of vancomycin early were less likely to develop resistant organisms (OR=0.08; 95% CI [0.01-0.59]; p=0.01). Acute kidney injury (AKI) and ICU length of stay (LOS) were not significant between the two groups.Conclusion
Early attainment of vancomycin therapeutic levels was associated with possible survival benefit.
... Second, it suggests that cure may be more associated with the extent of consistency, sustainability and fluctuations of vancomycin exposure during the course of therapy, rather than a total single exposure estimate. This notion serves as the basis for studies advocating the administration of vancomycin as continuous infusion, rather than intermittent infusion [53][54][55]. Compared to intermittent infusion, continuous infusion resulted in more consistent and sustained exposure at the infection site, despite similar AUCs [54]. ...
... Compared to intermittent infusion, continuous infusion resulted in more consistent and sustained exposure at the infection site, despite similar AUCs [54]. Furthermore, continuous infusion achieved target concentrations faster and was associated with less serum fluctuations [55]. Collectively these studies align with the finding that a minimum cure breakpoint (AUC 24 /MIC > 565) was only detected in the trough-only TDM arm, while peak-trough-based vancomycin dosing was not associated with a minimum threshold. ...
Background
Vancomycin therapeutic drug monitoring (TDM) is based on achieving 24-h area under the concentration–time curve to minimum inhibitory concentration cure breakpoints (AUC24/MIC). Approaches to vancomycin TDM vary, with no head-to-head randomized controlled trial (RCT) comparisons to date.
Objectives
We aimed to compare clinical and pharmacokinetic outcomes between peak–trough-based and trough-only-based vancomycin TDM approaches and to determine the relationship between vancomycin AUC24/MIC and cure rates.
Methods
A multicentered pragmatic parallel-group RCT was conducted in Hamad Medical Corporation hospitals in Qatar. Adult non-dialysis patients initiated on vancomycin were randomized to peak–trough-based or trough-only-based vancomycin TDM. Primary endpoints included vancomycin AUC24/MIC ratio breakpoint for cure and clinical effectiveness (therapeutic cure vs therapeutic failure). Descriptive, inferential, and classification and regression tree (CART) statistical analyses were applied. NONMEM.v.7.3 was used to conduct population pharmacokinetic analyses and AUC24 calculations.
Results
Sixty-five patients were enrolled [trough-only-based-TDM (n = 35) and peak–trough-based-TDM (n = 30)]. Peak–trough-based TDM was significantly associated with higher therapeutic cure rates compared to trough-only-based TDM [76.7% vs 48.6%; p value = 0.02]. No statistically significant differences were observed for all-cause mortality, neutropenia, or nephrotoxicity between the two groups. Compared to trough-only-based TDM, peak–trough-based TDM was associated with less vancomycin total daily doses by 12.05 mg/kg/day (p value = 0.027). CART identified creatinine clearance (CLCR), AUC24/MIC, and TDM approach as significant determinants of therapeutic outcomes. All patients [n = 19,100%] with CLCR ≤ 7.85 L/h, AUC24/MIC ≤ 1256, who received peak–trough-based TDM achieved therapeutic cure. AUC24/MIC > 565 was identified to be correlated with cure in trough-only-based TDM recipients [n = 11,84.6%]. No minimum AUC24/MIC breakpoint was detected by CART in the peak–trough-based group.
Conclusion
Maintenance of target vancomycin exposures and implementation of peak–trough-based vancomycin TDM may improve vancomycin-associated cure rates. Larger scale RCTs are warranted to confirm these findings.
... Until more recently, it was the only available antimicrobial agent that was effective against these organisms despite its known lack of efficacy compared β-lactams when treating susceptible organisms. In a large cohort study of 450 patients with osteomyelitis who were followed for 10 years, vancomycin was associated with 2.5 relative risk of recurrence compared with a penicillinase-resistant penicillin in a univariateanalysis (50).Because of the high failure rate and the increasing minimal inhibitory concentration (MIC) among many Staphylococcusstrains, many experts now advocate the use of higher and continuous dosages of vancomycin, keeping trough levels between 15-and 20µg/ml (50). ...
... Until more recently, it was the only available antimicrobial agent that was effective against these organisms despite its known lack of efficacy compared β-lactams when treating susceptible organisms. In a large cohort study of 450 patients with osteomyelitis who were followed for 10 years, vancomycin was associated with 2.5 relative risk of recurrence compared with a penicillinase-resistant penicillin in a univariateanalysis (50).Because of the high failure rate and the increasing minimal inhibitory concentration (MIC) among many Staphylococcusstrains, many experts now advocate the use of higher and continuous dosages of vancomycin, keeping trough levels between 15-and 20µg/ml (50). ...
Osteomyelitis refers to bone inflammation due to infection. Osteomyelitis is progressive infection (acute, sub-acute, and chronic to persistent) that results in inflammatory destruction, necrosis, and bone deformation secondary to pyogenic bacteria, mycobacteria and fungi. In children, the long bones are usually affected but in the adults, the vertebrae and the pelvis are most commonly involved. Many classification systems are available based on etiology, pathogenesis, and degree of bone involvement, duration, mechanism of infection, and presence of vascular insufficiency as well as age and the immune condition of the patient. Diabetic foot ulcers lead to bony infections resulting into high morbidity & mortality therefore, special attention is required.This paper reviews the microbiologic, clinical and non-surgical therapeutic considerations of osteomyelitis, with brief description of rare osteomyelitis of SAPHOsyndrome.
... In critically ill patients, more current studies on vancomycin II vs. CI have focused mainly on the comparison in terms of the efficacy and safety of vancomycin (Vuagnat et al., 2004;Hutschala et al., 2009;Akers et al., 2012;Saugel et al., 2013;Schmelzer et al., 2013;Hanrahan et al., 2014;Tafelski et al., 2015;Bissell et al., 2020). However, comparative studies on the outcomes of vancomycin II vs. CI against MRSA isolates with a specific MIC are still scarce. ...
Objective
The study aimed to evaluate and compare the pharmacokinetic/pharmacodynamic (PK/PD) exposure to vancomycin in the novel optimal two-step infusion (OTSI) vs. intermittent infusion (II) vs. continuous infusion (CI) mode, for MRSA bloodstream infections occurring in critical patients.
Methods
With PK/PD modeling and Monte Carlo simulations, the PK/PD exposure of 15 OTSI, 13 II, and 6 CI regimens for vancomycin, at 1, 2, 3, 4, 5, and 6 g daily dose, was evaluated. Using the Monte Carlo simulations, the vancomycin population PK parameters derived from critical patients, the PD parameter for MRSA isolates [i.e., minimum inhibitory concentration (MIC)], and the dosing parameters of these regimens were integrated into a robust mdel of vancomycin PK/PD index, defined as a ratio of the daily area under the curve (AUC0–24) to MIC (i.e., AUC0–24/MIC), to estimate the probability of target attainment (PTA) of these regimens against MRSA isolates with an MIC of 0.5, 1, 2, 4, and 8 mg/L in patients with varying renal function. The PTA at an AUC0–24/MIC ratio of >400, 400–600, and >600 was estimated. A regimen with a PTA of ≥90% at an AUC0–24/MIC ratio of 400–600, which is supposed to maximize both efficacy and safety, was considered optimal.
Results
At the same daily dose, almost only the OTSI regimens showed a PTA of ≥90% at an AUC0–24/MIC ratio of 400–600, and this profile seems evident especially in patients with creatinine clearance (CL cr) of ≥60 ml/min and for isolates with an MIC of ≤2 mg/L. However, for patients with CL cr of <60 ml/min and for isolates with an MIC of ≥4 mg/L, the II regimens often displayed a higher or even ≥90% PTA at an AUC0–24/MIC ratio of >400 and of >600. The CI regimens frequently afforded a reduced PTA at an AUC0–24/MIC ratio of >400 and of >600, regardless of CL cr and MIC.
Conclusions
The data indicated that the OTSI regimens allowed preferred PK/PD exposure in terms of both efficacy and safety, and thus should be focused more on, especially in patients with CL cr of ≥60 ml/min and for isolates with an MIC of ≤2 mg/L.
... The majority of our patients were transitioned to CIV in preparation for OPAT because the once-daily infusion change that occurs with CIV is generally more convenient in the outpatient setting compared with multiple-daily infusions. Continuous-infusion vancomycin for OPAT has been described in the adult literature [7][8][9] with similar outcomes and a trend toward lower rates of nephrotoxicity compared with IIV. Given our small sample size, we were unable to confirm these findings in children. ...
OBJECTIVE
There is minimal published literature regarding the use of continuous-infusion vancomycin (CIV) in children. The objective of this study was to describe the use, dosing requirements, and outcomes of CIV at a free-standing children's hospital.
METHODS
This is a retrospective review of patients who received CIV while admitted to Nationwide Children's Hospital between July 1, 2010, and June 30, 2020. The total daily dose (TDD) of vancomycin required to attain a target serum vancomycin concentration (SVC) was compared between CIV and intermittent-infusion vancomycin (IIV) administration regimens. Safety outcomes and treatment failure were also explored.
RESULTS
Fourteen patients (77% male) with a median age of 7 years (IQR = 1, 10 years) were included. Most patients (71%) were started on CIV in anticipation of outpatient parenteral antimicrobial therapy. The median TDD required to achieve a target SVC was higher with IIV compared with CIV (82.4 mg/kg/day vs 50.5 mg/kg/day; p = 0.02). Despite higher TDD with IIV, median SVC with IIV was similar to SVC with CIV (16.6 mg/L vs 17.6 mg/L; p = 2.00). There were no safety concerns or therapeutic failures identified with CIV.
CONCLUSIONS
Continuous-infusion vancomycin was a well-tolerated and effective alternative to IIV for the patients included in this study. The TDD of vancomycin required to achieve a target SVC was lower in patients receiving CIV compared with those receiving IIV.
... Therefore, keeping the TC above an effective concentration can improve the clinical efficacy. The literature showed that a continuous vancomycin infusion along with an LD increases the clinical efficacy of vancomycin as compared to a normal infusion time [45]. ...
Background:
The clinical significance of utilizing a vancomycin loading dose in critically ill patients remains unclear.
Objective:
The main aim of this systematic review is to evaluate the clinical safety and efficacy of the vancomycin loading dose in critically ill patients.
Methods:
We performed a systematic review using PRISMA guidelines. PubMed, the Web of Science, MEDLINE, Scopus, Google Scholar, the Saudi Digital Library and other databases were searched. Studies that reported clinical outcomes among patients receiving the vancomycin LD were considered eligible. Data for this study were collected using PubMed, the Web of Science, MEDLINE, Scopus, Google Scholar and the Saudi Digital Library using the following terms: "vancomycin", "safety", "efficacy" and "loading dose" combined with the Boolean operator "AND" or "OR".
Results:
A total of 17 articles, including 2 RCTs, 11 retrospective cohorts and 4 other studies, met the inclusion/exclusion criteria out of a total 1189 studies. Patients had different clinical characteristics representing a heterogenous group, including patients in critical condition, with renal impairment, sepsis, MRSA infection and hospitalized patients for hemodialysis or in the emergency department.
Conclusions:
The study shows that the target therapeutic level is achieved more easily among patients receiving a weight-based LD as compared to patients received the usual dose without an increased risk of new-onset adverse drug reactions.
... The significance of this outcome and its application might improve the clinical outcomes in critically ill patients, that has been highlighted in the recent surviving sepsis campaigns guidelines recommendation to improve the patient outcomes with early appropriate antibiotics therapy [34]. The median time for vancomycin to reach a therapeutic level in previously reported data was three days, which is considered late in our study definition [13][14][15][16]. However, a prospective multicenter study that validated the vancomycin consensus guideline nomogram published in 2009 had a median time of two days [17]. ...
Background
Vancomycin is a commonly used antibiotic in critically ill patients for various indications. Critical illness imposes pharmacokinetic-pharmacodynamics challenges, which makes optimizing vancomycin in this population cumbersome. Data are scarce on the clinical impact of time to therapeutic trough levels of vancomycin in critically ill patients. This study aims to evaluate the timing to achieve therapeutic trough level of vancomycin on 30-day mortality in critically ill patients.
Method
A retrospective cohort study was conducted for all adult critically ill patients with confirmed Gram-positive infection who received IV vancomycin between January 1, 2017, and December 31, 2020. We compared early (< 48 h) versus late (≥ 48 h) attainment of vancomycin therapeutic trough levels. The primary outcome was the 30-day mortality in critically ill patients. Secondary outcomes were the development of resistant organisms, microorganisms eradication within 4–5 days of vancomycin initiation, acute kidney injury (AKI), and length of stay (LOS). Propensity score-matched (1:1 ratio) used based on patient’s age, serum creatinine, and albumin values at baseline.
Results
A total of 326 patients were included; 110 patients attained the therapeutic trough levels within 48 h of vancomycin initiation. Late achievement of the therapeutic trough levels was associated with higher 30-day mortality (HR: 2.54; 95% CI [1.24–5.22]; p = 0.01). Additionally, patients who achieved therapeutic trough levels of vancomycin late were more likely to develop AKI (OR = 2.59; 95% CI [1.01–6.65]; p = 0.04). Other outcomes were not statistically significant between the two groups.
Conclusion
Early achievement of vancomycin therapeutic levels in patients with confirmed Gram-positive infection was associated with possible survival benefits.
... In order to achieve these targets, various dosing regimens have been suggested. Adults, in European hospitals often treated by continuous infusion, generally receive a loading dose of 15-25 mg/ kg followed by a maintenance dose of 20-40 mg/kg per 24 h [13][14][15]. In children, empiric dosing of 60-80 mg/kg/ day is common practice, whilst lower initial daily doses of 15-45 mg/kg/day are administered to neonates [16,17]. ...
Background Correct dosing and therapeutic drug monitoring (TDM) practices are essential when aiming for optimal vancomycin treatment. Objective To assess target attainment after initial dosing and dose adjustments, and to determine compliance to dosing and TDM guidelines. Setting Tertiary care university hospital in Belgium. Method A chart review was performed in 150 patients, ranging from preterm infants to adults, treated intravenously with vancomycin. Patient characteristics, dosing and TDM data were compared to evidence-based hospital guidelines. Main outcome measures Target attainment of vancomycin after initial dosing and dose adjustments. Results Subtherapeutic concentrations were measured in 68% of adults, in 76% of children and in 52% of neonates after treatment initiation. Multiple dose adaptations (median 2, Q1 1–Q3 2) were required for target attainment, whilst more than 20% of children and neonates never reached targeted concentrations. Regarding compliance to the hospital guideline, some points of improvement were identified: omitted dose adjustment in adults with decreased renal function (53%), delayed sampling (16% in adults, 31% in children) and redundant sampling (34% of all samples in adults, 12% in children, 13% in neonates). Conclusion Target attainment for vancomycin with current dosing regimens and TDM is poor in all age groups. Besides, human factors should not be ignored when aiming for optimal treatment. This study reflects an ongoing challenge in clinical practice and highlights the need for optimization of vancomycin dosing strategies and improvement of awareness of all health care professionals involved.
... Therefore, we downgraded the certainty of the evidence in our results. Fourth, we defined intermittent infusion time as within 1 h because this cutoff value was used in previous studies [33,34]. In contrast, we defined prolonged infusion time as over 1 h to include all possible studies. ...
Background
The prolonged β-lactam infusion strategy has emerged as the standard treatment for sepsis or septic shock despite its unknown efficacy. This study aimed to assess the efficacy of prolonged versus intermittent β-lactam antibiotics infusion on outcomes in sepsis or septic shock patients by conducting a systematic review and meta-analysis.
Methods
A thorough search was conducted on MEDLINE, the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi databases. Randomized controlled trials (RCTs) comparing mortality between prolonged and intermittent infusion in adult patients with sepsis or septic shock were included. The primary outcome was hospital mortality. The secondary outcomes were the attainment of the target plasma concentration, clinical cure, adverse events, and occurrence of antibiotic-resistant bacteria. We performed a subgroup analysis stratified according to the year of publication before or after 2015 and a trial sequential analysis (TSA). The Der Simonian–Laird random-effects models were subsequently used to report the pooled risk ratios (RR) with confidence intervals (CI).
Results
We identified 2869 studies from the 3 databases, and 13 studies were included in the meta-analysis. Hospital mortality did not decrease (RR 0.69 [95%CI 0.47–1.02]) in the prolonged infusion group. The attainment of the target plasma concentration and clinical cure significantly improved (RR 0.40 [95%CI 0.21–0.75] and RR 0.84 [95%CI 0.73–0.97], respectively) in the prolonged infusion group. There were, however, no significant differences in the adverse events and the occurrence of antibiotic-resistant bacteria between the groups (RR 1.01 (95%CI 0.95–1.06) and RR 0.53 [95%CI 0.10–2.83], respectively). For the subgroup analysis, a significant improvement in hospital mortality or clinical cure was reported in studies published in or after 2015 (RR 0.66 [95%CI 0.44–0.98] and RR 0.67 [95%CI 0.50–0.90], respectively). The results of the TSA indicated an insufficient number of studies for a definitive analysis.
Conclusions
The prolonged infusion of β-lactam antibiotics significantly improved upon attaining the target plasma concentration and clinical cure without increasing the adverse event or the occurrence of antibiotic-resistant bacteria. Prolonged infusion could not improve hospital mortality although an improvement was shown for studies published in or after 2015. Further studies are warranted as suggested by our TSA results.
... This modality is also associated with less nephrotoxicity and a more rapid time to attainment of a therapeutic concentration in adults. [40][41][42] Continuous infusions do present some limitations in children, however, as reliance on one venous access point for the infusion may impair the ability to administer other medications, particularly those that may interact with vancomycin. Continued study of alternative agents to vancomycin (e.g., those with a more favorable adverse effect profile and no need for serum drug monitoring) should be pursued. ...
OBJECTIVE Subtherapeutic vancomycin trough concentrations are common in children and may be associated with suboptimal therapeutic response. Our objective was to determine if vancomycin loading doses safely increase the frequency of target trough attainment in hospitalized children.
METHODS Patients (≥6 months and <18-years-old) who received a vancomycin loading dose between February 1, 2018, and January 30, 2019, were retrospectively enrolled. These patients were compared to a convenience cohort of patients hospitalized between January 1, 2015, and December 31, 2015, who received vancomycin without a loading dose. Target trough concentrations were defined as >15 mg/dL for invasive infections and >10 mg/dL for non-invasive infections.
RESULTS A total of 151 patients were enrolled, with 77 in the control arm and 74 in the loading dose arm. There was no significant difference in the frequency of comorbidities or need for intensive care unit admission between the two arms. Those receiving a vancomycin loading dose were older (mean age 9.1 vs 5.2 years, p < 0.0001). Patients given a loading dose achieved higher mean initial trough values (13.0 mg/dL vs 9.2 mg/dL, p < 0.0001), were more likely to have an initial trough at or above target (37.0% vs 10.4%, p = 0.0001), were more likely to reach target trough values at any point during therapy (52.1% vs 32.9%, p = 0.0081), and attained a target trough concentration more quickly (mean 41.1 hours vs 58.8 hours, p = 0.0118). There were no significant differences in the frequency of serum creatinine elevation or oliguria at the end of therapy.
CONCLUSIONS Vancomycin loading doses may improve the ability to safely obtain target trough values in hospitalized children.
... 13 One main difference between this study and those previously published was that this study targeted C ss and steady-state troughs of 12-20 mg/L for both CIV and IIV, respectively. Previous studies have targeted higher CIV C ss of 20-25 mg/L 29-32 or wider ranges from 15 to 25 mg/L 10,12 and have predominantly treated MRSA pneumonia 29,31,33,34 or osteomyelitis, 12,32,35 which has limited their generalizability to other pathogens and other foci of infections. ...
Background:
Patients with good renal function receiving intermittent-infusion vancomycin (IIV) may require total daily doses ≥4 g to achieve trough concentrations of 15-20 mg/L, increasing the risk of vancomycin-associated nephrotoxicity. Continuous-infusion vancomycin (CIV) may be associated with a lower risk of vancomycin-associated nephrotoxicity compared with IIV, but studies comparing safety of both dosing strategies are lacking.
Objectives:
To compare the risk of nephrotoxicity with CIV versus IIV when target concentration ranges were the same with both dosing modalities.
Methods:
A retrospective multicentre matched cohort study of admitted patients between 1 January 2010 and 31 December 2016 was completed. Adult patients who received ≥48 h of vancomycin with at least one steady-state vancomycin concentration were eligible. The primary outcome was to compare the rates of nephrotoxic risk and renal injury, defined by the RIFLE criteria, between CIV and IIV.
Results:
Of 2136 patients who received vancomycin during the study period, 146 CIV patients were eligible and matched to 146 IIV patients. After adjustment of potential confounders, CIV was found to have a lower odds of developing nephrotoxic risk (OR 0.42, 95% CI 0.21-0.98, P = 0.025) and renal injury (OR 0.19, 95% CI 0.05-0.59, P = 0.004).
Conclusions:
CIV is associated with a lower odds of nephrotoxicity compared with IIV when targeting the same concentration range and should be an alternative dosing strategy for patients who will receive prolonged therapy or require >4 g/day to achieve therapeutic levels.
... Thus, maintaining an effective trough concentration can improve the bactericidal efficacy. Vuagnat et al [28] conducted a cohort study to compare the efficacy and safety of intermittent vancomycin infusion (IVI) and continuous vancomycin infusion (CVI) in high-dose therapy. With respect to pharmacokinetics, the plateau concentration of vancomycin in CVI group was significantly higher than the mean trough vancomycin concentration in IVI group. ...
Background:
The clinical significance of using vancomycin loading dose remains controversial. A systematic review and meta-analysis were performed to assess the clinical efficacy and safety of vancomycin loading dose in the treatment of infections.
Methods:
The Pubmed, Embase, Web of Science, and Cochrane Library databases were searched from their inception up to 5 May 2019. Randomized controlled trials (RCTs) and other observational studies were included if they provided clinical outcomes or trough concentrations of vancomycin loading dose (20-30 mg/kg) and conventional-dose (10-20 mg/kg) in the treatment of infections. Achievement of therapeutic concentration (serum trough concentrations of vancomycin reached 15-20 mg/L before the second dose), clinical response (clinical improvement or culture-negative), nephrotoxicity (serum creatinine increase ≥0.5 mg/dL or ≥50% increasing from the baseline), other adverse events (including pruritus, flushing, rash, and/or red man syndrome), and mortality were analyzed. Heterogeneity was identified using the Cochrane I statistic, and P-value <.10 or I-values >50% indicated significant heterogeneity. Pooled estimates of the intervention effects were determined by the odds ratios (ORs) and 95% confidence intervals (CIs) in Review Manager program, version 5.3.5.
Results:
Two RCTs and 7 cohort studies including 2816 infected patients were selected for the analysis, in which serum trough concentrations of vancomycin following the use of vancomycin loading dose or other outcomes were available. Loading dose group had a significantly higher compliance rate of serum trough concentration of 15 to 20 mg/L (OR = 3.06; 95% CI = 1.15-8.15; P = .03) and significantly lower incidence of nephrotoxicity (OR = 0.59, 95% CI = 0.40-0.87; P = .008; I = 29%) compared with control group. No significant difference was noted between loading dose group and control group in terms of other adverse events and clinical response (OR = 1.98, 95% CI = 0.80-4.93; P = .14; I = 0%). The use of vancomycin loading doses in patients can indeed increase the achievement of therapeutic concentration.
Conclusion:
Vancomycin loading dose increases the achievement of therapeutic concentration without bringing extra risk of nephrotoxicity. However, well-designed large-scale RCTs remain needed to validate the clinical efficacy of vancomycin loading dose and to further evaluate other adverse reactions and mortality.PROSPERO registration number CRD42018093927.
... La penetración y distribución de vancomicina al tejido óseo es también un factor limitante en el tratamiento de las osteomielitis por microorganismos sensibles al fármaco. Vuagnat et al observaron que la concentración de vancomicina en hueso se sitúa entre el 15 y el 20% de la concentración en suero 18 . Ante esta evidencia, sería muy recomendable mantener concentraciones séricas en valle de 15-20 ug/mL. ...
... Continuous infusion of vancomycin (CIV) decreases the risk of nephrotoxicity and the incidence of infusion-related reactions while also decreasing time to therapeutic concentrations and drug cost compared to IIV in adults [5][6][7]. Although CIV is not recommended in the Infectious Diseases Society of America guidelines for the treatment of MRSA because of the lack of clinical benefit of CIV over IIV in adults [2], CIV is an attractive option in the pediatric population given the aforementioned challenges of IIV therapy. ...
Background:
There is a paucity of data on dosing of continuous infusion of vancomycin (CIV) in pediatric patients, despite it being an attractive treatment option for limiting escalating doses of intermittent infusion of vancomycin. The purpose of this study was to determine the total daily dose of CIV required to attain therapeutic serum vancomycin concentrations (SVCs) in pediatric patients according to age (≥31 days to <2 years, 2 to <8 years, and 8 to <18 years).
Methods:
We retrospectively evaluated patients who were transitioned from intermittent infusion of vancomycin to CIV between January 2013 and December 2016. Demographic data, vancomycin data (indication, dosing, steady-state SVCs, and time to reach goal SVC), and adverse-effect data (infusion reactions and serum creatinine level) were collected.
Results:
Of the 240 patients included, 76 had a goal SVC of 10 to 15 µg/mL and 164 had a goal of 15 to 20 µg/mL. The dose of CIV required to reach an SVC of 10 to 15 µg/mL in the youngest age group was 48.4 mg/kg per day versus 45.6 and 39.4 mg/kg per day in the older age groups (P < .005). The 2 younger age groups of patients with a goal SVC of 15 to 20 µg/mL required 50.2 and 50.6 mg/kg per day, respectively, whereas patients aged ≥8 years required 44.7 mg/kg per day (P = .008). One patient experienced renal injury, and 1 experienced renal failure.
Conclusions:
CIV is an effective method for attaining a therapeutic SVC in pediatric patients. Patients <8 years of age require higher dosing than older pediatric patients to reach the goal SVCs of 10 to 15 and 15 to 20 µg/mL.
... The use of continuous infusion to reach plateau concentrations of 20 to 30 mg/liter has been proposed previously to increase the therapeutic effect of vancomycin and to avoid the risk of nephrotoxicity (6,9,(12)(13)(14). Although differences in effectiveness have not been proven, clinical administration of vancomycin by continuous infusion has been increasing, because this method is easy to handle, costs less than intermittent infusion, and requires less sampling for TDM, with less variability in plasma drug concentrations, allowing the rapid achievement of adequate plasma drug concentrations (12,(15)(16)(17). ...
Pathophysiological changes involved on drug disposition in critically ill patients, should be considered on the dosing optimization of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Vancomycin plasma concentrations from 54 critically ill patients were simultaneously analyzed by population pharmacokinetic approach. A nomogram was developed for dosing recommendations and was internally evaluated throughout stochastic simulations. The vancomycin plasma concentration versus time data were best described by a one-compartment open model with exponential inter-individual variability associated to vancomycin clearance and volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and volume of distribution, respectively. Characterization based on the presence of mechanical ventilation, demonstrated a decreasing value of 20% on vancomycin clearance. External validation (n=18) was performed to evaluate the prediction ability of the model with median bias and precision values of 0.7 mg/L (95%CI -0.4, 1.7) and 5.9 mg/L (95%CI 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion in critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications on dosing rates to reach therapeutic range (20–30 mg/L).
... In order to achieve therapeutic serum concentrations as early as possible a LD should be considered [16][17][18]. An LD of 15-20 mg.kg À1 was used in previous studies [7,19,20]. Nevertheless, LD administration is not common in clinical practice, likely due to the fact that the currently valid summary of product characteristics does not recommend a LD. ...
Background: Delayed achievement of target vancomycin serum concentrations may adversely affect clinical outcomes. The objective of this retrospective study was to compare the prediction accuracy of different body weight descriptors for volume of distribution and to propose an optimal loading dose (LD) for continuous infusion regimens in adults.
Methods: Pharmacokinetic variables were computed using one-compartmental analysis. Simulated LDs of vancomycin were evaluated for each patient.
Results: Volume of distribution, clearance, and half-life median values (interquartile range) for vancomycin in the study population (n = 30) were 0.45 (0.39–0.61) L.kg⁻¹, 0.026 (0.015–0.040) L.h⁻¹.kg⁻¹, and 10.3 (7.7–21.3) h, respectively. The observed volume of distribution was better predicted by total body weight (TBW) than by the ideal body weight or the adjusted body weight.
Conclusions: An LD of 10.7 mg per kg TBW was optimal in our study population. Using this LD, 17.9% of simulated vancomycin serum levels were just below the therapeutic range, only 10.7% concentrations exceeded the target range and no concentration was toxic. The use of a LD would lead to reduced median time to reach target concentrations from 17 to 1 h.
... Because of mediocre bone penetration (estimated around 15%). Residual serum trough levels are considered best in the 15-25 mg/L range 67 . Higher trough levels have not demonstrated better outcomes. ...
Chronic osteomyelitis implies an infection of the bone, which may or may not involve the marrow, cortex, periosteum and surrounding tissue, in sequence or at the same time. This chapter briefly discusses the epidemiology, pathogenesis and diagnosis of chronic osteomyelitis in adults. Regarding microbiology, the vast majority of chronic osteomyelitis is caused by bacterial infections. Of lesser importance are fungi, which are mainly observed in intravenous drug users, in skull-base osteomyelitis, and in the immunocompromised host. The chapter also discusses the treatment options for chronic osteomyelitis in detail. Treatment of chronic osteomyelitis is a real challenge, and requires a multidisciplinary team including orthopedic surgeons, infectious disease specialists, nurses, and physiotherapists, in order to achieve the best possible outcome. Finally, great effort must be invested in multicenter, blinded, large, randomized trials for the study of many unanswered questions in the domain of chronic osteomyelitis.
... Les études cliniques comparant directement la perfusion intraveineuse continue à la perfusion intermittente de vancomycine sont contradictoires et ne permettent pas de recommander l'utilisation systématique de la perfusion continue [204][205][206][207]. Néanmoins, l'administration en perfusion continue permet d'obtenir plus rapidement les concentrations plasmatiques cibles, de limiter le nombre de dosages sanguins ainsi que le coût de traitement [206,208]. ...
... Des données concordantes d'études in vitro et d'études cli niques récentes montrent qu'un rapport ASC 24h /CMI supé rieur à 400 est prédictif de l'efficacité clinique du traitement par la vancomycine dans les pneumonies et les bactériémies à SARM [170, [201][202][203]. Les études cliniques comparant directement la perfusion intraveineuse continue à la perfu sion intermittente de vancomycine sont contradictoires et ne permettent pas de recommander l'utilisation systématique de la perfusion continue [204][205][206][207]. Néanmoins, l'adminis tration en perfusion continue permet d'obtenir plus rapide ment les concentrations plasmatiques cibles, de limiter le nombre de dosages sanguins ainsi que le coût de traitement [206,208]. ...
This study conducted a quantitative meta-analysis to investigate the association of vancomycin indicators, particularly area under the curve over 24 h (AUC24) and trough concentrations (Ctrough), and their relationship with both nephrotoxicity and efficacy. Literature research was performed in PubMed and Web of Science on vancomycin nephrotoxicity and efficacy in adult inpatients. Vancomycin Ctrough, AUC24, AUC24/minimum inhibitory concentration (MIC), nephrotoxicity evaluation and treatment outcomes were extracted. Logistic regression and Emax models were conducted, stratified by evaluation criterion for nephrotoxicity and primary outcomes for efficacy. Among 100 publications on nephrotoxicity, 29 focused on AUC24 and 97 on Ctrough, while of 74 publications on efficacy, 27 reported AUC24/MIC and 68 reported Ctrough. The logistic regression analysis indicated a significant association between nephrotoxicity and vancomycin Ctrough (odds ratio = 2.193; 95% CI 1.582–3.442, p < 0.001). The receiver operating characteristic curve had an area of 0.90, with a cut-off point of 14.55 mg/L. Additionally, 92.3% of the groups with a mean AUC24 within 400–600 mg·h/L showed a mean Ctrough of 10–20 mg/L. However, a subtle, non-statistically significant association was observed between the AUC24 and nephrotoxicity, as well as between AUC24/MIC and Ctrough concerning treatment outcomes. Our findings suggest that monitoring vancomycin Ctrough remains a beneficial and valuable approach to proactively identifying patients at risk of nephrotoxicity, particularly when Ctrough exceeds 15 mg/L. Ctrough can serve as a surrogate for AUC24 to some extent. However, no definitive cut-off values were identified for AUC24 concerning nephrotoxicity or for Ctrough and AUC24/MIC regarding efficacy.
Background:
Administration of vancomycin as a continuous infusion has been associated with reduced nephrotoxicity. Given limited published experience with continuous infusion vancomycin in outpatient parenteral antimicrobial therapy (OPAT) programs, we reviewed outcomes from our center.
Methods:
This was a retrospective, single-center study of adult patients receiving vancomycin OPAT as continuous or intermittent infusion for an intended treatment duration of at least 7 days. The primary outcome was time to nephrotoxicity with continuous versus intermittent infusion vancomycin while on OPAT; additional outcomes included time to any vancomycin-associated adverse event, time to 60-day death or readmission, and time to 60-day emergency department encounter. Proportional hazards modeling was used to identify variables independently associated with outcomes, as well as assess the strength of association of continuous infusion with each outcome.
Results:
Four-hundred ninety-two patients were included: 118 treated with continuous and 374 with intermittent vancomycin infusion. Continuous infusion was not associated with lower rates of nephrotoxicity compared to intermittent infusion (adjusted hazard ratio (aHR) 0.72, 95% CI: 0.35-1.50). There were no advantages of continuous over intermittent infusion in the rates of any adverse event (aHR 0.93, 95% CI: 0.56-1.53), 60-day death or readmission (aHR 1.04, 95% CI: 0.68-1.61), or 60-day emergency department encounter (aHR 1.17, 95% CI: 0.68-1.99). Vancomycin area under the concentration-time curve (AUC) at discharge was the only modifiable factor identified that was independently associated with patient safety outcomes.
Conclusion:
There was no appreciable benefit of continuous infusion vancomycin on outpatient safety outcomes. AUC-centered dosing approaches warrant further investigation as strategies to improve vancomycin safety in OPAT programs.
Vancomycin and teicoplanin are representative glycopeptide antibiotics with activities against gram-positive cocci. The area under the drug concentration–time curve (AUC)/minimal inhibitory concentration (MIC) has been extensively used as an indicator of the bacteriological response to glycopeptide antibiotics, and the trough concentration has been used as a surrogate marker for the AUC/MIC. However, the guidelines for therapeutic drug monitoring (TDM) are being revised in accordance with increasing pharmacokinetic understanding of glycopeptide antibiotics. This review describes the pharmacokinetic/pharmacodynamic characteristics of glycopeptide antibiotics and discusses their optimal use with appropriate TDM.
Pharmacokinetic (PK) and pharmacodynamic (PD) properties of antibiotics are useful to guide the design of dosing regimens that maximize patient outcomes. This chapter aims to describe the influence of PK/PD properties on the mode of infusional drug delivery regimens and due considerations for the design and optimization of antibiotic infusions in the critically‐ill. Further, it summarizes the clinical benefit of the different modes of antibiotic infusion. Existing evidence suggests that short intermittent infusion can achieve required exposure for antibiotics with a PK/PD dosing target of maximum concentration to minimum inhibitory concentration ( C max /MIC) ratio. For time‐dependent antibiotics, prolonged infusions achieve better exposure in terms of time the free antibiotic concentration remains above MIC ( f T >MIC ). For specific PK/PD targets of area under the concentration–time curve (AUC) to MIC ratio, loading dose may be required with prolonged infusion in patients with increased volume of distribution. PD consideration such as the extent of post antibiotic effect and altered susceptibility profile can influence the need for prolonged infusion administration. Short intermittent infusions or short duration of prolonged infusion may be adequate when significant post‐antibiotic effect exists. Better patient outcomes may be achieved with extended or continuous infusion regimens for time‐dependent antibiotics such as β‐lactams compared to intermittent infusions that are often sub‐optimal in critically‐ill patients. However, although some existing evidence demonstrate better clinical cure rates with continuous infusion regimens, no study has yet shown a mortality benefit. The ongoing effort to address this knowledge gap in a large randomized controlled trial is highly recommended.
Introduction: Treatment of methicillin-resistant (MR) staphylococcal prosthetic joint infections (PJIs) remains a matter of discussion, with vancomycin-rifampin combination therapy being the preferred treatment for DAIR and one-stage exchange arthroplasty strategies. This study analyzes the outcomes of patients with chronic methicillin-resistant coagulase-negative staphylococcal PJIs treated with vancomycin-minocycline combination therapy. Methods: This prospective, single center cohort study included all chronic MR coagulase-negative staphylococcal PJIs (01/2004-12/2014) treated with exchange arthroplasty and at least 4 weeks of minocycline-vancomycin. The following endpoints were considered: reinfection including relapse (same microorganism) and a new infection (different microorganism) and PJI-related deaths. Their outcomes were compared with PJIs treated with rifampin-vancomycin during the same period. Results: Thirty-four patients (median age, 69 years) with 22 hip and 12 knee arthroplasty infections were included. Sixteen (47%) had previously been managed in another center. Median vancomycin MIC of strains was 3 mg/L. Nineteen underwent one-stage, 15 two-stage exchange arthroplasty. After a median [IQR] follow-up of 43 [26-68] months, 2 patients relapsed and 6 developed a new PJI. Compared to 36 rifampin-vancomycin treated PJIs, relapse- or reinfection-free survival rates didn't differ, but more new infections developed in the minocycline group (6 vs 3; P 0.3). Conclusions: Minocycline-vancomycin combination therapy for chronic MR coagulase-negative staphylococcal PJIs seems to be an interesting therapeutic alternative.
Study objective:
To compare rates of nephrotoxicity, time to nephrotoxicity onset, and clinical failure among patients who received continuous infusion (C-I) or intermittent infusion (I-I) vancomycin in an outpatient parenteral antimicrobial therapy (OPAT) program. Nephrotoxicity was defined as an increase in serum creatinine of greater than 0.5 mg/dL or 50% increase from baseline for two consecutive measurements while receiving vancomycin during OPAT. Clinical failure was defined as unplanned readmission, extension of therapy, or change in antibiotics.
Design:
Single-center, propensity score-matched, retrospective cohort study.
Setting:
OPAT clinic affiliated with two nearby hospitals.
Patients:
Three hundred patients who received C-I or I-I vancomycin for at least 1 week in the OPAT program between October 1, 2017, and March 31, 2019 were identified. Propensity score matching based on age, gender, and infection was performed to minimize differences in patient characteristics between groups.
Measurements and main results:
After propensity score matching and exclusion criteria, 74 patients were included in each cohort. C-I vancomycin was associated with a 3.22-fold decrease in nephrotoxicity risk (C-I 6.8% [5/74 patients] vs I-I 18.9% [14/74 patients]; odds ratio [OR] 3.22, 95% confidence interval [CI] 1.10-9.46, p=0.027) and a significantly slower onset to nephrotoxicity compared with I-I (p=0.035). No statistically significant difference in clinical failure rates was observed between the C-I and I-I groups (13.5% [10/74 patients] vs 23.0% [17/74 patients], p=0.147).
Conclusion:
In an OPAT setting, C-I vancomycin was associated with a lower risk of and slower onset to nephrotoxicity than I-I vancomycin; however, no statistically significant difference in clinical failure rates was observed with C-I versus I-I vancomycin.
Vancomycin dosing strategy and methods have evolved to be quite diverse despite therapeutic guidelines jointly issued in 2009 by the American Society of Health-System Pharmacists (ASHP) and the Infectious Diseases Society of America. In those guidelines, information was presented to support a target 24-hour area under the concentration–time curve (AUC) of 400 mg · hr/L for methicillin-resistant Staphylococcus aureus (MRSA) isolates that have a vancomycin minimum inhibitory concentration (MIC) of ≤1 mg/L; however, a trough concentration of 10–20 mg/L (or, for seriously ill patients, 15–20 mg/L) was recommended as a surrogate target to simplify monitoring.¹ More recently, there have been concerns over excessive vancomycin doses and 24-hour AUC values when targeting trough concentrations of 15–20 mg/L.2,–5 These concerns have led to calls to implement AUC-based dosing to minimize the risk of toxicity while ensuring a threshold 24-hour AUC of 400 mg · hr/L.⁶ Planned 2019 draft guidelines are anticipated to propose a paradigm shift to an AUC-targeted strategy that will require more serum concentration measurements and/or Bayesian dosing software. The purpose of this article is to summarize historical influences and reasons for the current diversity in approaches to vancomycin dosing. Another purpose is to highlight factors that promote excessive vancomycin exposure and suggest an alternative to fully implementing AUC-based dosing. The primary reasons to manage vancomycin as a special agent include the drug’s strong dependence on renal function for clearance, the potential for nephrotoxicity,7,8 and the association between therapeutic outcomes and serum 24-hour AUC.9,10
Poor penetration of vancomycin into Central Nervous System (CNS) can lead to treatment failure. The aim of this study was to evaluate and compare CSF concentration and serum pharmacokinetics of high dose vancomycin by continuous infusion vs. intermittent infusion in post neurosurgical meningitis patients. Twenty patients were divided into two groups. Patients in intermittent infusion group received vancomycin as a loading dose of 25 mg/kg over two hours, followed by 25 mg/kg over two hours every 12 h. In the Continuous Infusion group, patients received vancomycin as a loading dose of 25 mg/kg over two hours, followed by 50 mg/kg/day by continuous infusion. In the intermittent infusion group, mean ± SD of serum trough, peak and CSF concentrations were 17.49 ± 2.46 mg/L, 41.33 ± 2.73 mg/L, and 4.83 ± 1.05 mg/L, respectively. Mean of CSF/trough% ratio was 27.39 ± 2.43%. A positive linear correlation was found between the serum trough levels and CSF levels (r = 0.970, P < 0.001). In continuous infusion group, mean ± SD of serum and CSF concentrations were 24.76 ± 2.02 mg/L and 6.20 ± 1.31 mg/L respectively. Mean ± SD of CSF/serum% ratio was 24.84% ± 3.54%. The serum and CSF levels revealed positive linear correlation (r = 0.902, P < 0.001). The mean of CSF concentration in CI group was 6.20 ± 1.31 mg/L which was significantly higher than II group (4.83 ± 1.05 mg/L, P < 0.019). CSF/serum ratio did not show any significant difference between the two groups. Continuous infusion of vancomycin makes it possible to achieve faster and constant target level in serum but did not have any significant effect on the penetration (CSF/Serum ratio) of vancomycin in to the CNS. © 2018, Iranian Journal of Pharmaceutical Research. All rights reserved.
Résumé
La vancomycine, découverte en 1953 et largement utilisée de nos jours, a un potentiel néphrotoxique qui a longtemps été débattu. La fréquence de l’atteinte rénale est variable et peut aller de 5 % à 30 % en fonction du terrain et des facteurs de risque concomitants : surdosage, insuffisance rénale préalable, obésité, hypovolémie, et utilisation d’autres néphrotoxiques comme les aminosides. Son association avec la pipéracilline–tazobactam semble aussi augmenter le risque de néphrotoxicité, mais cette hypothèse devrait être confirmée expérimentalement. La toxicité tubulaire directe de la molécule et la précipitation intratubulaire sont les deux mécanismes actuellement décrits et pouvant aboutir à des lésions tubulaires aiguës et au déclin rapide de la fonction rénale. Ces lésions sont souvent réversibles à l’arrêt de la perfusion mais parfois une insuffisance rénale séquellaire peut persister. Du fait de l’utilisation à grande échelle de la vancomycine et de la tendance actuelle à augmenter les taux résiduels visés, il est important d’identifier les situations à risque afin de diminuer les cas de néphrotoxicité.
After more than six decades of its use as the mainstay antibiotic for the treatment of multidrug-resistant Gram-positive bacterial infections, dosing and monitoring of vancomycin therapy have not been optimized. The current vancomycin therapeutic guidelines recommend empiric doses of 15–20 mg/kg administered by intermittent infusion every 8–12 h in patients with normal kidney function. Additionally, the guidelines recommend trough concentration of 15–20 mg/L as a therapeutic goal for adult patients with severe infections. This review critically discusses the current guidelines considering the basic pharmacokinetics and pharmacodynamics of vancomycin and the recent published reports from clinical studies. More in-depth discussion will be focused on (1) providing evidence of advantages of administering vancomycin by continuous infusion compared to intermittent infusion; (2) revising the current practice of trough-only monitoring versus the area under concentration–time curve (AUC); and (3) assessing the current practice of weight-based dosing versus AUC-based dosing. Using the gathered information presented in this paper, two user-friendly and scientifically based dosing strategies are proposed to improve the efficiency of vancomycin dosing while avoiding the risk of nephrotoxicity and minimizing the cost of therapeutic drug monitoring.
Objectives
To compare vancomycin dosage adjustment by evaluating trough concentrations (Ctrough) of vancomycin and its pharmacokinetic/pharmacodynamic (PK/PD) correlation (AUC/MIC ≥400).
Methods
A retrospective study of 52 adult haematological patients and 29 ICU patients was carried out. Dosage adjustment was performed in routine clinical practice with Ctrough and then compared using a PK/PD model. The probability of achieving the PK/PD target associated with the success of antimicrobial therapy was evaluated. When the susceptibility of the organism responsible for infection is not known, Monte Carlo simulation calculates the cumulative fraction of response (CFR) from the distribution of MIC values. Values of CFR >90% represent an optimal achieved regimen against a population of microorganisms.
Results
According to dosage adjustment performed with Ctrough, in haematological patients the dose of vancomycin was increased in 65.4% compared with an increase in 53.8% of patients with the PK/PD model. No dose adjustment was needed in 21.1% of patients using Ctrough compared with 7.7% with the PK/PD model and in 13.5% of patients using Ctrough determination and in 38.5% of patients with the PK/PD model the dose was reduced. For ICU patients the dosage adjustment made with Ctrough resulted in an increased dose of vancomycin in 79.4% of patients compared with 41.4% with the PK/PD model. No dose adjustment was needed in 3.4% of patients using Ctrough in comparison with 13.8% with the PK/PD model, and the dose was reduced in 17.2% of patients using Ctrough determination and in 44.8% with the PK/PD model.
Conclusions
Data for bacterial susceptibility combined with measured data for antibiotic concentrations using a PK/PD model predict and improve the dosage adjustment for individual patients. A larger study with more complete datasets are needed for validation before it can be fully introduced into clinical practice.
The management of some serious infections such as infective endocarditis (IE) and bone and joint infections (BJIs) caused by Gram-positive cocci (GPC) is complex and requires great responsiveness and effective antimicrobials with high bioavailability in heart valves or bone tissues. Treatment of these infections requires the use of a higher dosage that may result in increased toxicity or the use of new promising antimicrobials to control the infection. However, use of these new antimicrobials could still bring about new toxicity and resistance. Another approach may be the 'comeback' of old antimicrobials, which is evaluated in this review in the treatment of IE and BJIs caused by GPC.
In this study, vancomycin loaded alginate-chitosan composite microspheres were developed by emulsion crosslinking method. The in vitro and vivo characterizations were done to evaluate the feasibility of application. Our experimental results showed that the emulsification cross-linking technique appeared to be a feasible method for the preparation of alginate-chitosan composite microspheres. The microspheres were spherical in shape and the mean particle size and drug loading were 25.3 ± 5.4 μm and 18.5% ± 2.3%, respectively. A sustained vancomycin release was realized i.e. the amount of cumulative release increased in a time frame of 24 hours to reach an amount i.e. ~ 68%. The model that fit best for vancomycin released from the microspheres was the Higuchi kinetic model with a correlation coefficient r=0.9996. In vivo results showed that the application of microspheres not only reduced the toxicity, but also maintained effective drug concentration. In addition, no severe signs of epithelial necrosis and sloughing of epithelial cells were detected in histological studies. This article is protected by copyright. All rights reserved.
The increasing number of infections produced by beta-lactam resistant Gram-positive bacteria and their secondary morbidity makes it necessary to optimize the use of vancomycin. In 2009, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Disease Pharmacists published specific guidelines about vancomycin dosage and monitoring. However, these guidelines have not been updated in the last 6 years. This review analyzes the new available information about vancomycin published in recent years, regarding pharmacokinetic and pharmacodynamics, serum concentration monitoring, and optimal vancomycin dosing in special situations (obese people, burn patients, renal replacement therapy, among others). Vancomycin efficacy is linked to a correct dosage which should aim to reach an AUC/MIC ≥400; serum trough levels of 15-20 mg/L are considered a surrogate marker of an AUC/MIC of ≥400 for a MIC ≤1 mg/L. For
S. aureus
strains presenting a MIC over 1 mg/L, an alternative agent should be considered. Vancomycin doses must be adjusted according to body weight and its plasma trough levels. Nephrotoxicity has been associated with the target vancomycin trough levels above 15 mg/L. Continuous infusion is an option, especially for patients at high risk of renal impairment or unstable vancomycin clearance. In such cases, vancomycin plasma steady-state levels and creatinine monitoring are strongly indicated.
La monitorización de niveles plasmáticos de los antimicrobianos utilizados para el tratamiento de infecciones en pacientes críticos es una de las estrategias planteadas para mejorar los resultados clínicos. El objetivo de la monitorización es doble, limitar los efectos adversos y aumentar la efectividad de los antimicrobianos. Su desarrollo clínico se limita prácticamente a la monitorización de vancomicina y aminoglucósidos aunque es deseable su extensión, en el futuro, al resto de los antimicrobianos. La aplicación de esta técnica está sometida a múltiples variaciones entre hospitales, lo que dificulta la interpretación y comparación de resultados. Por este motivo, representantes de diversas sociedades científicas, relacionadas con el área de la farmacocinética, han elaborado un conjunto de recomendaciones para la monitorización plasmática de antimicrobianos utilizando como referencia a vancomicina y a los distintos aminoglucósidos. Las recomendaciones se realizan en torno a 14 preguntas que abarcan todas las etapas de proceso: indicación de la prueba, extracción de la muestra (tiempo de extracción, cantidad de sangre, tubos), traslado al laboratorio, técnicas aplicables, valores de normalidad, ajuste de dosis y comunicación de resultados. El objetivo de las recomendaciones es homogeneizar en la medida de lo posible el proceso de la monitorización de estos antimicrobianos y facilitar con ello la realización de estudios multicéntricos y la comparación e interpretación de los resultados.
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
During the last several years a series of staphylococcal isolates that demonstrated reduced susceptibility to vancomycin or other glycopeptides have been reported. We selected 12 isolates of staphylococci for which the vancomycin MICs were > or =4 microg/ml or for which the teicoplanin MICs were > or =8 microg/ml and 24 control strains for which the vancomycin MICs were < or =2 microg/ml or for which the teicoplanin MICs were < or =4 microg/ml to determine the ability of commercial susceptibility testing procedures and vancomycin agar screening methods to detect isolates with reduced glycopeptide susceptibility. By PCR analysis, none of the isolates with decreased glycopeptide susceptibility contained known vancomycin resistance genes. Broth microdilution tests held a full 24 h were best at detecting strains with reduced glycopeptide susceptibility. Disk diffusion did not differentiate the strains inhibited by 8 microg of vancomycin per ml from more susceptible isolates. Most of the isolates with reduced glycopeptide susceptibility were recognized by MicroScan conventional panels and Etest vancomycin strips. Sensititre panels read visually were more variable, although with some of the panels MICs of 8 microg/ml were noted for these isolates. Vitek results were 4 microg/ml for all strains for which the vancomycin MICs were > or =4 microg/ml. Vancomycin MICs on Rapid MicroScan panels were not predictive, giving MICs of either < or =2 or > or =16 microg/ml for these isolates. Commercial brain heart infusion vancomycin agar screening plates containing 6 microg of vancomycin per ml consistently differentiated those strains inhibited by 8 microg/ml from more susceptible strains. Vancomycin-containing media prepared in-house showed occasional growth of susceptible strains, Staphylococcus aureus ATCC 29213, and on occasion, Enterococcus faecalis ATCC 29212. Thus, strains of staphylococci with reduced susceptibility to glycopeptides, such as vancomycin, are best detected in the laboratory by nonautomated quantitative tests incubated for a full 24 h. Furthermore, it appears that commercial vancomycin agar screening plates can be used to detect these isolates.
A continuous infusion of vancomycin (CIV) may provide an alternative mode of infusion in severe hospital-acquired methicillin-resistant staphylococcal (MRS) infections. A multicenter, prospective, randomized study was designed to compare CIV (targeted plateau drug serum concentrations of 20 to 25 mg/liter) and intermittent infusions of vancomycin (IIV; targeted trough drug serum concentrations of 10 to 15 mg/liter) in 119 critically ill patients with MRS infections (bacteremic infections, 35%; pneumonia, 45%). Microbiological and clinical outcomes, safety, pharmacokinetics, ease of treatment adjustment, and cost were compared. Microbiological and clinical outcomes and safety were similar. CIV patients reached the targeted concentrations faster (36 ± 31 versus 51 ± 39 h, P = 0.029) and fewer samples were required for treatment monitoring than with IIV patients (7.7 ± 2.2 versus 11.8 ± 3.9 per treatment, P < 0.0001). The variability between patients in both the area under the serum concentration-time curve (AUC24h) and the daily dose given over 10 days of treatment was lower with CIV than with IIV (variances, 14,621 versus 53,975 mg2/liter2/h2 [P = 0.026] and 414 versus 818 g2 [P = 0.057], respectively). The 10-day treatment cost per patient was $454 ± 137 in the IIV group and was 23% lower in the CIV group ($321 ± 81: P < 0.0001). In summary, for comparable efficacy and tolerance, CIV may be a cost-effective alternative to IIV.
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
Concentrations of vancomycin in bones of 14 patients undergoing total hip arthroplasty (group 1) and 5 patients with osteomyelitis
(group 2) were studied. Group 1 received vancomycin, 15 mg/kg intravenously, 1 h prior to anesthesia. Group 2 received doses
adjusted to achieve peak levels in serum of 20 to 30 micrograms/ml and trough levels of less than 12 micrograms/ml; bone specimens
were collected during surgical debridement. The specimens were pulverized and eluted into phosphate buffer, and the supernatants
were analyzed for vancomycin content by fluorescence polarization immunoassay. In group 1, vancomycin was detectable in all
cancellous specimens with a mean concentration of 2.3 +/- 4.0 micrograms/g (range, 0.5 to 16 micrograms/g); 10 of 14 cortical
specimens had detectable vancomycin; the mean cortical concentration was 1.1 +/- 0.8 micrograms/g (range, not detectable to
2.6 micrograms/g). In group 2, vancomycin was detectable in only two of five cortical bone specimens (mean concentration,
5.9 +/- 3.5 micrograms/g). Cancellous bone was obtained in one patient; the vancomycin concentration was 3.6 micrograms/g.
In most patients the vancomycin levels in bones were higher than the MIC for susceptible staphylococci following single prophylactic
doses. In the few infected patients studied, penetration was variable and deserves further study.
Over the past two decades, vancomycin has been considered the antibiotic of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections. Indeed, multidrug-resistant clones of MRSA for which the only available effective antibacterial agent is vancomycin have recently been identified. Recent reports describing the therapeutic failure of vancomycin for MRSA infections have aroused considerable concern regarding the emergence of MRSA strains for which there will be no effective therapy.1–3 The mechanism of reduced susceptibility in these staphylococcal strains has not been identified, although data indicate that it is not the same as the vancomycin-resistance mechanism in enterococcal strains.4 We describe here . . .
To investigate persistent carriage of methicillin-resistant Staphylococcus aureus (MRSA), we conducted a prospective 10-month study of MRSA carriage in previous carriers who were readmitted to our hospital.
Four screening specimens, 2 from the skin and 2 from the nares, were obtained within 3 days after admission, in addition to
diagnostic specimens requested by physicians. Of the 78 patients included in our study, 31 (40%) were persistent carriers
of MRSA, with an estimated median time of 8.5 months to MRSA clearance. In the multivariate analysis, the only factor significantly
associated with persistent carriage was the presence of a break in the skin at readmission (odds ratio, 4.34; P=.004); however, a trend was found for admission from a chronic-care institution (odds ratio, 3.65; P=.06). Our data confirm that prolonged carriage of MRSA can occur after hospital discharge, support routine screening for
MRSA at readmission of previously MRSA-positive patients, and suggest that a particularly high index of suspicion for MRSA
carriage should be maintained if these patients have a break in the skin.
During the last several years a series of staphylococcal isolates that demonstrated reduced susceptibility to vancomycin or other glycopeptides have been reported. We selected 12 isolates of staphylococci for which the vancomycin MICs were ≥4 μg/ml or for which the teicoplanin MICs were ≥8 μg/ml and 24 control strains for which the vancomycin MICs were ≤2 μg/ml or for which the teicoplanin MICs were ≤4 μg/ml to determine the ability of commercial susceptibility testing procedures and vancomycin agar screening methods to detect isolates with reduced glycopeptide susceptibility. By PCR analysis, none of the isolates with decreased glycopeptide susceptibility contained known vancomycin resistance genes. Broth microdilution tests held a full 24 h were best at detecting strains with reduced glycopeptide susceptibility. Disk diffusion did not differentiate the strains inhibited by 8 μg of vancomycin per ml from more susceptible isolates. Most of the isolates with reduced glycopeptide susceptibility were recognized by MicroScan conventional panels and Etest vancomycin strips. Sensititre panels read visually were more variable, although with some of the panels MICs of 8 μg/ml were noted for these isolates. Vitek results were 4 μg/ml for all strains for which the vancomycin MICs were ≥4 μg/ml. Vancomycin MICs on Rapid MicroScan panels were not predictive, giving MICs of either ≤2 or ≥16 μg/ml for these isolates. Commercial brain heart infusion vancomycin agar screening plates containing 6 μg of vancomycin per ml consistently differentiated those strains inhibited by 8 μg/ml from more susceptible strains. Vancomycin-containing media prepared in-house showed occasional growth of susceptible strains, Staphylococcus aureus ATCC 29213, and on occasion, Enterococcus faecalis ATCC 29212. Thus, strains of staphylococci with reduced susceptibility to glycopeptides, such as vancomycin, are best detected in the laboratory by nonautomated quantitative tests incubated for a full 24 h. Furthermore, it appears that commercial vancomycin agar screening plates can be used to detect these isolates.
31 patients with severe bone and joint infections due to multi-drug resistant staphylococcal strains (S. aureus = 21 patients, S. epidermidis = 10 patients) received continuous-infusion vancomycin (CIV) therapy in combination with one or two other antibiotics after débridement and removal of all foreign material (osteosynthesis = 8 patients, total joint arthroplasty = 15 patients). Vancomycin and teicoplanin MICs were 2–4 μg/ml et 4–16 μg/ml respectively. The mean duration of CIV was 62 days (range 42–78d) for 28 patients and 3 patients had longer CIV (8, 10 and 14 months) because of duration and severity of infections. CIV therapy consisted of 40 to 100 mg/Kg/d infused over 24 h to obtain serum vancomycin concentrations reaching 40 μg/ml. In 20 patients, vancomycin levels in infected bone and tissues ranged between 30 to 80 μg/g at initiation of therapy; they increased to 50–130 μg/g after 1 month of treatment. 30 out of 31 patients were apparently cured (follow-up at least 2 years) and 13 out of 15 patients underwent total joint replacement. Tolerance of 4 to 6 g per day of CIV was excellent. Neither hematological or cutaneous toxicity nor hearing loss were reported in these carefully monitored patients. Transient renal insufficiency was reported in 2 patients treated with furosemide. CIV was well tolerated and easy to monitor. Its efficiency depends on the quality of the excisional surgery.
Since the discovery of the vancomycin-resistant Staphylococcus aureus (VRSA) strain Mu50 (minimum inhibitory concentration [MIC] 8 mg/L), there has been concern about the potential spread of such strains throughout Japanese hospitals. Two important questions need to be answered: (1) what is the prevalence of VRSA, and (2) by what mechanism does vancomycin resistance occur.
The vancomycin susceptibilities of three methicillin-resistant S aureus (MRSA) strains (Mu50, Mu3, and H1) and the methicillin-susceptible S aureus type strain FDA209P were compared by MIC determinations and population analysis. Mu3 (MIC 3 mg/L) was isolated from the sputum of a patient with pneumonia after surgery who had failed vancomycin therapy. H1 (MIC 2 mg/L), which is a representative vancomycin-susceptible MRSA strain, was isolated from a patient with pneumonia who responded favourably to vancomycin therapy. Subclones of Mu3 with increased resistance against vancomycin were selected with serial concentrations of vancomycin and their MICs were determined. The prevalence of VRSA and Mu3-like strains in Japanese hospitals was estimated by population analysis from 1149 clinical MRSA isolates obtained from 203 hospitals throughout Japan. The genetic traits of the Mu3 and Mu50 strains were compared with clonotypes of MRSA from around the world.
Mu3 and Mu50 had an identical pulsed-field gel electrophoresis banding pattern. When grown in a drug-free medium, Mu3 produced subpopulation of cells with varying degrees of vancomycin resistance, thus demonstrating natural heterogeneity, or variability, in susceptibility to vancomycin. In the presence of vancomycin, Mu3 produced subclones with resistance roughly proportional to the concentrations of vancomycin used. Selection of Mu3 with 8 mg/L or more of vancomycin gave rise to subclones with vancomycin resistance equal to that of Mu50 (MIC 8 mg/L) at a frequency of 1/1,000,000. During screening of Japanese MRSA strains, no strain of VRSA additional to Mu50 was found. The prevalence of MRSA isolates heterogeneously resistant to vancomycin was 20% in Juntendo University Hospital, 9.3% in the other seven university hospitals, and 1.3% in non-university hospitals or clinics.
Heterogeneously resistant VRSA is a preliminary stage that allows development into VRSA upon exposure to vancomycin. Heterogeneously resistant VRSA was found in hospitals throughout Japan. This finding could explain, at least partly, the frequent therapeutic failure of MRSA infection with vancomycin in Japan.
Thirteen cases of meningeal and/or ventricular infection and 1 case of septicaemia, all caused by staphylococci, were treated with continuous intravenous infusions of vancomycin. Repeated measurements of vancomycin plasma and CSF levels by microbiological assay or by high performance liquid chromatography showed that the antibiotic entered the CSF after 48 hours of treatment and that its concentrations in CSF remained stable at 1 to 4 micrograms/ml (mean: 2 micrograms/ml) throughout the 3 weeks' treatment period. After treatment was discontinued, vancomycin became undetectable in CSF within less than 24 hours. All the children were cured.
The bacterial aetiology of osteomyelitis is best determined by bone biopsy under radiographic control. While Staphylococcus aureus is still the most common cause of osteomyelitis, Gram-negative bacteria occur more frequently than they did in the past. The prognosis of antibiotic treatment is made worse by chronic infection and by underlying conditions, such as diabetes mellitus or peripheral vascular disease. Treatment for six weeks with single broad-spectrum antimicrobial agents can give success rates similar to those obtained with combination therapy, including aminoglycosides, and with less toxicity. Newer diagnostic methods (radionuclide scans and radiographic techniques) and treatment options (antibiotic-containing acrylic beads and microvascular grafts) may offer improved management if used discriminatingly.
Twenty-five infants with suspected or confirmed coagulase negative staphylococcal infection were studied. Continuous administration of vancomycin was used because it is usual with infusions prepared daily for catheterized patients, and because continuous infusions are well tolerated and achieve better penetration in tissues and CSF. Vancomycin acts as a time-dependent antibiotic. The aim was to obtain a level of 20-25 mg/l. in serum. Fifteen newborns term 27-35 weeks (m = 30.3) aged 7-30 days (m = 16.1) received 10 to 45 mg/kg/day of vancomycin and were monitored for 2 to 12 days. The sample for assay was taken in a peripheral vein, and the results were the same during the infusion or 15 minutes after its end. The daily dose of vancomycin necessary varied from 25 to 40 mg/kg for newborns with serum creatinine < 70 mmol/l and 10 to 30 mg/kg with serum creatinine > or = 90 mmol/l. Except for a newborn with multiorgan failure, serum creatinine rapidly decreased. Four newborns term 38-40 weeks (m = 39.5) aged 2-12 days (m = 8.3) received 20 to 45 mg/kg/day of vancomycin and were monitored for 2 to 12 days. The daily dose necessary varied from 30 to 40 mg/kg/day with important individual variations, and 20 mg/kg/day in a newborn with a high level of creatinine. In 6 infants aged 2-22 months receiving 22-45 mg/kg/day of vancomycin, a mean daily dosage of 40-45 mg/kg was adequate, with important individual variations.(ABSTRACT TRUNCATED AT 250 WORDS)
Eight adult patients with post-surgery meningitis caused by methicillin-resistant staphylococci were treated with continuous intravenous infusion of vancomycin in mean doses of 50 mg/kg/day. This treatment, which lasted 3 to 6 weeks, was well tolerated by the kidneys and resulted in cure in all cases; its effect on the ear was not evaluated. Stable concentrations of 4 to 7 mg/l in cerebrospinal fluid were obtained after the 48th hour of treatment.
Ten patients were treated with conventional dosing (CD) and continuous-infusion (CI) vancomycin therapy in this prospective, randomized, crossover study. Patients were randomized to receive either CD or CI therapy for 2 consecutive days and then crossed over to receive the opposite regimen for 2 days. CD therapy consisted of 1 g of vancomycin every 12 h. CI therapy consisted of a 500-mg loading dose followed by 2 g infused over 24 h. Ten serum samples were obtained on the second day of each therapy for pharmacokinetic and pharmacodynamic analyses. Two clinical isolates of Staphylococcus aureus, one methicillin sensitive (MSSA 1199) and one methicillin resistant (MRSA 494), were chosen for pharmacodynamic evaluation of both regimens. The patient demographics (means +/- standard deviations [SD]) were as follows: sex, six males, four females; age, 36 +/- 11 years; and serum creatinine, 0.72 +/- 0.18 mg/dl. Mean pharmacokinetic parameters +/- SD for CD therapy were as follows: elimination rate constant, 0.16 +/- 0.07 h-1; half-life, 5.6 +/- 3.5 h; volume of distribution, 33.7 +/- 25 liters, 0.5 +/- 0.2 liters/kg; maximum concentration in serum, 53.4 +/- 19.3 micrograms/ml; and minimum concentration, 8.4 +/- 5.9 micrograms/ml. The steady-state concentration for CI was 20.2 +/- 11.1 micrograms/ml. Overall, both regimens resulted in the MIC being exceeded 100% of the time. The mean CD trough serum bactericidal titer (SBT) was 1:8, and the average CI SBTs were 1:16 for both isolates. Even though there was no statistically significant difference between CD trough and CI SBTs, the CI SBTs remained > 1:8 for 100% of the time versus 60% of the time for CD therapy. During CI therapy, 20 and 40% of the patients maintained SBTs of > 1:32 throughout the dosing interval for MSSA 1199 and MRSA 494, respectively. During CD therapy, however, only 10% of patients maintained SBTs of > 1:32 during the entire dosing interval for both isolates. The mean areas under the bactericidal titer-time curve (AUBC24s) +/- SD for MSSA 1199 were 528 +/- 263 for CD therapy and 547 +/- 390 for CI therapy. The mean AUBC24s +/- SD against MRSA 494 were 531 +/- 247 for CD and 548 +/- 293 for CI therapy. Similar to the AUBC24, the mean area under the concentration-time curve for a 24-h dosing interval divided by the MIC (AUC/MIC24) ratios +/- SD were 550.0 +/- 265.7 for CD and 552.6 +/- 373.4 for CI therapy, respectively. No statistically significant differences were found between any of the pharmacodynamic parameters for CD and CI therapy. In addition, no adverse effects with either CD or CI therapy were observed during the study. We conclude that CI and CD vancomycin therapy demonstrated equivalent pharmacodynamic activities. Although CI therapy was more likely to result in SBTs that remained above 1:8 for the entire regimen, the clinical impact of this result is unknown. Serum drug concentration variability was observed with both treatment regimens but to a lesser extent with CI administration. CI administration of vancomycin should be further evaluated to determine the clinical utility of this method of administration.
Thrombosis is a well-recognized complication following insertion of central venous catheters and is associated with significant morbidity. In an attempt to reduce line-associated thrombosis, 108 consecutive patients with haematological malignancies were commenced on prophylactic 'minidose' warfarin, 1 mg/d, at the time of line insertion. This group of patients were compared with a historic group of 115 consecutive patients who had not received warfarin. Clinically-suspected venous thrombosis was confirmed by Doppler ultrasound or venography. Patients taking prophylactic warfarin had their prothrombin time measured three times per week with the aim of maintaining an INR <1.6. Five (5%) of the 108 patients who received minidose warfarin developed a thrombosis, at a median of 72 d (range 5-166) from the time of catheter insertion. In the 115 patients who were not anticoagulated 15 (13%) developed a catheter-associated thrombosis at a median of 16 d (range 1-35). There was a significant reduction in line-associated thrombosis in patients receiving warfarin (P=0.03). These data suggest that minidose warfarin reduces the incidence of central venous catheter related thrombosis in patients with haematological malignancies.
Teicoplanin and vancomycin are antibiotics widely used in the therapy of bone and joint infections. The aim of this study was to compare bone and serum concentrations of each antibiotic in guinea pigs after administration of 50 mg/kg of teicoplanin or vancomycin by the intravenous route. Serum and bone concentrations were determined immediately before and 0.5, 1, 2, 6, 12 and 24 h after drug administration by means of high performance liquid chromatography. Teicoplanin concentrations were always higher than vancomycin levels. Area under the concentration/time curve was significantly greater for teicoplanin than for vancomycin. In bone, teicoplanin concentration increased up to 6 h, while vancomycin reached its peak after 2 h. Moreover, teicoplanin showed markedly higher levels at 6, 12 and 24 h than vancomycin. In conclusion, the ability of teicoplanin to penetrate bone in greater amount than vancomycin confirms the potential use of teicoplanin in the treatment of bone infections and in the prophylaxis of orthopedic surgery.
Recent case reports of vancomycin treatment failures in the United States, Japan, and France have prompted a retrospective
analysis of 42 cases of septicemia caused by epidemic methicillin-resistant Stapyhlococcus aureus strain 15 (EMRSA-15), which is the most prevalent epidemic strain of methicillin-resistant S. aureus in the United Kingdom; all cases occurred in a teaching hospital in Manchester, United Kingdom, between 1994 and 1998. Mortality
was lowest (4%) in patients with rifampin-susceptible isolates treated with vancomycin and rifampin. It rose to 38% in patients
who were treated with both antibiotics but in whom the organism became resistant to rifampin during therapy, and it reached
78% in patients who had rifampin-resistant isolates or in whom rifampin was contraindicated (P < .0001; Fisher exact test, 2-tailed). All isolates were susceptible to vancomycin by conventional laboratory testing, but susceptibility was lost by growth in vancomycin in vitro, becoming resistant at a minimum inhibitory concentration of
8 mg/L. This was associated with accumulation of cell-wall material. The deoxyribonucleic acid fingerprint remained unchanged.
This study suggests that rifampin played a key role in the prevention of deaths caused by an epidemic strain of methicillin-resistant
S. aureus that readily gave rise to a subpopulation with reduced susceptibility to vancomycin.
The emergence of vancomycin intermediate resistant Staphylococcus aureus (VISA) isolates in Japan, USA, France, Hong Kong and Korea among methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, is of great concern. Vancomycin has been the drug of choice for the treatment of multiresistant MRSA infections in the last three decades, but the management of invasive MRSA infections will become a serious problem if VISA strains become widespread. VISA isolates reported to date have a vancomycin MIC of 8 mg/L, and were isolated from patients with underlying diseases whose long-term vancomycin treatment apparently failed. Since many VISA isolates also have been resistant to teicoplanin, the term glycopeptide-intermediate S. aureus (GISA) is more appropriate. The frequency of GISA isolates appears to be extremely low; to date, only 10 GISA infections have been reported worldwide. However, heterogeneous resistance to glycopeptides (h-GISA) have been reported in Japan, Europe and Thailand. These h-GISA strains showed vancomycin MICs ranging from 1 to 4 mg/L, but had subpopulations that could grow on agar plates containing 4-8 mg/L, which may represent the first step in the development of GISA strains. Although GISA isolates have shown resistance to many antimicrobials, all GISA isolates remain susceptible to co-trimoxazole and some of them to other common antimicrobials. Currently, there are no recommended therapy guidelines for GISA infections, although in recent studies, several new drugs have shown promising activity against GISA strains. In addition, synergy between glycopeptides and beta-lactams against GISA strains was observed in some in vivo and in vitro studies. Specific MRSA/GISA control programs, rational antibiotic policies, including the reduction of glycopeptide use, and rapid laboratory detection of GISA and h-GISA strains are the key measures in preventing the spread of these strains.
To evaluate the feasibility, efficacy, and cost of outpatient parenteral antimicrobial therapy (OPAT) in the treatment of osteomyelitis.
39 patients with an osteomyelitis requiring parenterally administered antibiotics for more than 4 weeks, and able to receive antibiotics at home.
All patients had a totally implanted catheter. Antibiotics were administered by continuous infusion using a portable elastomeric infusion system, which was changed every day by the patient or by the home-care nurse. Laboratory monitoring and surveillance were performed weekly. Clinical efficacy, adverse effects and quality of life were recorded.
The most commonly used antibiotics were vancomycin (51%) and beta-lactam (44%) antibiotics. Thirty patients were available for follow-up for a minimum of 12 months after completion of therapy. Twenty-eight (93%) were considered cured of their infection with a mean of 24 +/- 4 months after completion of antibiotic therapy. Adverse effects among the study patients were rare. The 39 patients in our OPAT programme resulted in a potential saving of US $1 873 885 relative to conventional therapy.
OPAT is practicable and effective and may be the best alternative treatment for patients suffering from osteomyelitis requiring intravenous therapy.
In order to understand the mechanism(s) of the resistance/reduced susceptibility of Staphylococcus aureus to glycopeptide antibiotics, the current data on the modes of action of glycopeptides were reviewed. In addition, the different test systems for detecting vancomycin resistance and the clinical relevance of resistant Staphylococcus aureus were analyzed. Finally, strategies to prevent the nosocomial spread of these bacteria are presented, as are new therapeutic options.
Objective: To evaluate the efficacy and safety of vancomycin constant-rate infusion over 24 h in the treatment of Gram-positive bone infections,
Methods: Vancomycin (40 mg/kg/day) was administered without a loading dose to 15 patients (12 male, three female) aged 23–90 years, weighing 46–85 kg, with postoperative chronic bone and joint infections. The 24-h dose was adjusted to maintain plasma levels between 25 and 35 mg/L. Mean duration of therapy was 6.2 months (4–8.5) via a portable infusion pump. Sites of infection included hip and femur (10), tibia (three), patella (one) and vertebrae (one). Sequestrectomy (two), removal of material (7/8 prosthetic hips, 1/5 metal implants) and debridement (two) were performed at the beginning of the treatment. Involved bacteria included Staphylococcus aureus (eight, six methicillin resistant), S. epidermidis (four methicillin-resistant), Enterococcus faecalis (one), Enterococcus avium (one) and Streptococcus bovis (one).
Results: MIC of vancomycin ranged from 1 to 4 mg/L. The mean vancomycin bone concentration when available was 67.7 ± 38.9 μg/L. Based on a mean post-treatment follow-up of 14±4 months (6–20.6), cure was achieved in 10 patients (66.6%). Failures were related to the inability to remove the infected prosthesis (one) or implants (three) and to the persistence of a deep wound abcess (one). Adverse events included pruritus (four cases), tinnitus (two), mild transient elevation of creatinine level (three) and transient neutropenia (two). Vancomycin was maintained in all the patients.
Conclusions: Prolonged treatment with vancomycin constant-rate infusion is effective and safe for treatment of Gram-positive chronic bone and joint infections, providing that complete surgical débridement and prosthetic material removal are performed.
In treating orthopedic infections, the long-term impact of vancomycin therapy on colonization by methicillin-resistant Staphylococcus aureus (MRSA) and the emergence of vancomycin-intermediate S. aureus is unknown.
Prospective surveillance of the effect of long-term vancomycin therapy on colonization by MRSA and the emergence of vancomycin-intermediate S. aureus.
Thirty-four patients with MRSA osteomyelitis that was microbiologically documented were longitudinally observed for the emergence of vancomycin-intermediate S. aureus at 3 body sites (wound, anterior nares, and groin) during the initial period of vancomycin therapy and at the 2-month follow-up. Twenty patients received the standard dose (20 mg/kg/d) for 34 +/- 6 days and 14 patients received a high dose (40 mg/kg/d) of vancomycin for 37 +/- 9 days.
During vancomycin treatment, global MRSA carriage (all body sites) fell from 100% to 25% in the group of patients receiving the standard dose of vancomycin, and from 100% to 40% in the group receiving the high dose. During the 2-month follow-up period after vancomycin therapy, global MRSA carriage increased from 25% to 55% in the group receiving the standard dose and decreased from 43% to 36% in the group receiving the high dose.
Therapy with a high dose of vancomycin contributes to the sustained eradication of MRSA carriage without promoting the emergence of glycopeptide resistance.
Osteomyelitis Principles and practice of infectious diseases
- J Mader
- Calhoun
Mader J, Calhoun J (1995) Osteomyelitis. In: Mandell G, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases, 4th edn. New York: Churchill Livingstone, 1039–1051.
Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies
- Boraks P J Seale
- Price
Boraks P, Seale J, Price J et al. (1998) Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies. British Journal of Haematology, 101, 483– 486.