Pharmacokinetic and pharmacodynamic profiling of minocycline for injection following a single infusion in critically ill adults in a phase IV open-label multicenter study (ACUMIN)

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR

Reappraisal of Contemporary Pharmacokinetic and Pharmacodynamic Principles for Informing Aminoglycoside Dosing

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All-cause mortality rates in adults with carbapenem-resistant Gram-negative bacterial infections: a comprehensive review of pathogen-focused, prospective, randomized, interventional clinical studies

Carbapenem resistance; Gram-negative; CefiderocolResistència als carbapenems; Gram-negatius; CefiderocolResistencia a carbapenémicos; Gram-negativo; CefiderocolIntroduction Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections. Areas covered We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM). Expert opinion PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37–118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94–406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR Acinetobacter spp., and 20.0% and 30.8% for CR Pseudomonas aeruginosa. The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials

Clinical Outcomes in Patients with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Bloodstream Infection

The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, a problem complicated by the lack of routine screening procedures; however, limited data suggest that hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure, yet these studies have been confounded by design issues. We conducted this study to compare the characteristics of patients with BSI caused by hVISA with those with vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multicenter matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin-resistant Staphylococcus aureus (MRSA) BSI from 2004 to 2012 were matched to VSSA-MRSA BSI patients. The primary outcome was failure of vancomycin treatment, defined as a composite of persistent bacteremia (≥7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. The overall vancomycin failure rate was 57% (82% hVISA versus 33% VSSA; P \u3c 0.001). The individual components of failure in hVISA versus VSSA were persistent bacteremia, 59% versus 21% (P \u3c 0.001); change in MRSA therapy, 54% versus 25% (P = 0.001); MRSA-related mortality, 21% versus 10% (P = 0.081); and recurrence of BSI, 26% versus 2% (P \u3c 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (adjusted odds ratio [aOR], 11.1; 95% confidence interval [CI], 4.3 to 28.7) and intensive care unit (ICU) admission (aOR, 4.5; 95% CI, 1.8 to 11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure of vancomycin treatment, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity

Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin- Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of the American Society of Health- System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists

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Assessment of Time to Clinical Response, a Proxy for Discharge Readiness, among Hospitalized Patients with Community-Acquired Pneumonia Who Received either Ceftaroline Fosamil or Ceftriaxone in Two Phase III FOCUS Trials

ABSTRACT The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n = 562; ceftriaxone, n = 554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria ( P = 0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P = 0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.

Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35ES0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria

Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN)

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii. Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [fAUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (f(ub)) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with f(ub)). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation

Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults: Dose Modification for Weight Is Not Necessary ▿ †

Obesity is an independent risk factor for mortality in patients infected with pandemic influenza A virus (H1N1). Given the poor outcomes observed among adult obese patients with H1N1, the dosing of antiviral agents in this population has been questioned, and use of twice the standard oseltamivir dose has been suggested. However, studies evaluating the disposition of oseltamivir and oseltamivir carboxylate (the active metabolite) in the obese population are scant. We evaluated the single-dose and steady-state pharmacokinetics of oseltamivir (75 mg by mouth twice daily) in a cohort of 21 healthy adult volunteers with class III obesity (body mass index [BMI], ≥40 kg/m2). The median (minimum, maximum) age, weight, and BMI were 36 (19, 50) years, 122 (106, 159) kg, and 43.7 (40.0, 54.4) kg/m2, respectively. The population pharmacokinetic exposure profiles of oseltamivir carboxylate (the active metabolite) were comparable between class III obese subjects and nonobese adults (healthy and infected). Similar to previous pharmacokinetic analyses in nonobese subjects, the mean (percent covariance [CV]) area under the concentration-time curve for the dosing interval (AUC0–τ) was 2,621 ng·h/ml (17) for oseltamivir carboxylate. Body size was significantly (P < 0.05) associated with oseltamivir and oseltamivir carboxylate apparent clearance, but the correlation coefficient was poor (R2 ≤ 0.3). Creatinine clearance estimated by the Cockcroft-Gault method and lean body weight were also significantly (P < 0.05) but poorly (R2 = 0.17) correlated with oseltamivir carboxylate apparent clearance. Since the systemic exposure of oseltamivir carboxylate is not reduced in class III obese adults with standard doses, a dose increment of oseltamivir is likely to be unnecessary