Background: This study analyzed the relationship between vancomycin area under the concentration-time curve (AUC) and acute kidney injury (AKI) reported across recent studies.Methods: A systematic review of PubMed, Medline, Scopus, and compiled references was conducted. We included randomized cohort and case-control studies that reported vancomycin AUCs and risk of AKI (from 1990 to 2018). The primary outcome was AKI, defined as an increase in serum creatinine of ≥0.5 mg/L or a 50% increase from baseline on ≥2 consecutive measurements. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Primary analyses compared the impact of AUC cutpoint (greater than ~650 mg × hour/L) and AKI. Additional analysis compared AUC vs trough-guided monitoring on AKI incidence.Results: Eight observational studies met inclusion/exclusion criteria with data for 2491 patients. Five studies reported first-24-hour AUCs (AUC0-24) and AKI, 2 studies reported 24- to 48-hour AUCs (AUC24-48) and AKI, and 2 studies reported AKI associated with AUC- vs trough-guided monitoring. AUC less than approximately 650 mg × hour/L was associated with decreased AKI for AUC0-24 (OR, 0.36 [95% CI, .23–.56]) as well as AUC24-48 (OR, 0.45 [95% CI, .27–.75]). AKI associated with the AUC monitoring strategy was significantly lower than trough-guided monitoring (OR, 0.68 [95% CI, .46–.99]).Conclusions: AUCs measured in the first or second 24 hours and lower than approximately 650 mg × hour/L may result in a decreased risk of AKI. Vancomycin AUC monitoring strategy may result in less vancomycin-associated AKI. Additional investigations are warranted.

Polymyxin B remains an antibiotic of last resort because of its toxicities. Although newer therapies are becoming available, it is anticipated that resistance to these agents will continue to emerge, and understanding the safest and most efficacious manner to deliver polymyxin B will remain highly important. Recent data have demonstrated that polymyxin B may be less nephrotoxic than colistin. Pharmacokinetically, polymyxin B is primarily eliminated via non-renal pathways, and most do not recommend adjusting the dose for renal impairment. However, some recent studies suggest a weak relationship between polymyxin B clearance and patient creatinine clearance. This review article will describe the clinical pharmacokinetics of polymyxin B and address relevant issues in chemistry and assays available.

Objective: Piperacillin-tazobactam is a commonly used antibiotic in critically ill patients; however, controversy exists as to whether mortality in serious infections can be decreased through administration by prolonged infusion compared with intermittent infusion. The purpose of this systematic review and meta-analysis was to describe the impact of prolonged infusion piperacillin-tazobactam schemes on clinical endpoints in severely ill patients. Design: We conducted a systematic literature review and meta-analysis searching MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to April 1, 2017, for studies. Interventions: Mortality rates were compared between severely ill patients receiving piperacillin-tazobactam via prolonged infusion or intermittent infusion. Included studies must have reported severity of illness scores, which were transformed into average study-level mortality probabilities. Measurements and Main Results: Two investigators independently screened titles, abstracts, and full texts of studies meeting inclusion criteria for this systematic review and meta-analysis. Variables included author name, publication year, study design, demographics, total daily dose(s), average estimated creatinine clearance, type of prolonged infusion, prevalence of combination therapy, severity of illness scores, infectious sources, all-cause mortality, clinical cure, microbiological cure, and hospital and ICU length of stay. The review identified 18 studies including 3,401 patients who received piperacillin-tazobactam, 56.7% via prolonged infusion. Across all studies, the majority of patients had an identified primary infectious source. Receipt of prolonged infusion was associated with a 1.46-fold lower odds of mortality (95% CI, 1.20–1.77) in the pooled analysis. Patients receiving prolonged infusion had a 1.77-fold higher odds of clinical cure (95% CI, 1.24–2.54) and a 1.22-fold higher odds of microbiological cure (95% CI, 0.84–1.77). Subanalyses were conducted according to high (≥ 20%) and low (< 20%) average study-level mortality probabilities. In studies reporting higher mortality probabilities, effect sizes were variable but similar to the pooled results. Conclusions: Receipt of prolonged infusion of piperacillin-tazobactam was associated with reduced mortality and improved clinical cure rates across diverse cohorts of severely ill patients.

Polymyxin B (PB) has reemerged as a common treatment against multidrug-resistant Gram-negative pathogens. However, nephrotoxicity remains a significant dose-limiting side effect, and contemporary pharmacokinetic (PK) data are limited. This study sought to evaluate PB exposure differences in various loading and nonloading strategies according to total body weight (TBW) and adjusted body weight (ABW). Patients treated with PB had plasma samples obtained for clinical care and analyzed using liquid chromatography-tandem mass spectrometry. Compartmental PK models with linear and allometric scaling of TBW were explored. Semiparametric Monte Carlo simulation evaluated the total (i.e., protein bound plus unbound) area under the plasma concentration-time curve (AUC _total ) during the first 24 h of therapy and at 96 h posttherapy for each regimen at the 10th, 50th, and 90th percentiles of TBW and ABW in the derivation cohort. Literature-based values of the 24-h total AUC/MIC ratio (AUC/MIC _total ) of ≥50 defined efficacy, and literature-based values of the 72- to 96-h AUC _total of ≥100 μg · h/ml defined toxicity. Fifty-two patients contributed 156 PB plasma samples. A two-compartment model with allometric scaling of TBW produced a comparable fit (Akaike information criterion [AIC] = 376.7) to that achieved with linear scaling (AIC = 378). The regimen of a loading dose of 2.5 mg/kg of body weight plus a fixed dose of 100 mg every 12 h had the highest probability of achieving a 24-h AUC/MIC _total of ≥50 with the lowest probability of toxicity in all groups at 24 h, aside from those with the lowest 10th percentile of body weight. This is the first study to suggest that a weight-based loading and fixed maintenance (i.e., weight-independent) dosing strategy for polymyxin B may maximize efficacy while balancing toxicity concerns for most patients.

Clinical preference for a semisynthetic penicillin (oxacillin or nafcillin) over cefazolin for deep-seated methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSI) perseveres despite limited data to support this approach. A retrospective cohort study of patients treated for MSSA BSI with either oxacillin or cefazolin was performed across two medical centers in Chicago, IL. The outcome measures included documented in-hospital treatment failure, all-cause in-hospital mortality, duration of MSSA BSI, and incidence of documented adverse events. Of 161 patients with MSSA BSI, 103 (64%) received cefazolin, and 58 (36%) received oxacillin. The identified sources of BSI were central line (37.9%), osteoarticular (18%), and skin and soft tissue (17.4%). Patients with endocarditis (29/52 [44.2%]) and other deep-seated infections (23/52 [55.8%]) were classified under the subset of deep-seated infections (52/161 [32.3%]). Multivariate models found deep-seated infection (adjusted odds ratio [aOR], 4.52; 95% confidence interval [CI], 1.23 to 16.6; P = 0.023), metastatic disease (aOR, 4.21; 95% CI, 1.13 to 15.7; P = 0.033), and intensive care unit (ICU) onset of infection (aOR, 4.80; 95% CI, 1.26 to 18.4; P = 0.022) to be independent risk factors for in-hospital treatment failure. Treatment group was not an independent predictor of failure (aOR, 3.76; 95% CI, 0.98 to 14.4; P = 0.053). The rates of treatment failure were similar among cefazolin-treated (5/32 [15.6%]) and oxacillin-treated (4/20 [20.0%]) patients ( P = 0.72) in the subset of deep-seated infections. Mortality was observed in 1 (1%) and 3 (5.2%) cases of cefazolin- and oxacillin-treated patients, respectively ( P = 0.13). Cefazolin was not associated with higher rates of treatment failure and appears to be an effective alternative to oxacillin for treatment of deep-seated MSSA BSI.