Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Modelled Target Attainment after Temocillin Treatment in Severe Pneumonia: Systemic and Epithelial Lining Fluid Pharmacokinetics of Continuous versus Intermittent Infusions.

The objective of this article is to describe the population pharmacokinetics (PK) of temocillin administered via continuous infusion (CI) versus intermittent infusion (II) in critically ill patients with pneumonia. Secondary objectives included characterization of epithelial lining fluid (ELF)/plasma penetration ratios and determination of the probability of target attainment (PTA) for a range of MICs. Thirty-two mechanically ventilated patients who were treated for pneumonia with 6 g of temocillin daily for in vitro sensitive pathogens were assigned to either the II (2 g every 8 h over 0.5 h) or the CI (6 g over 24 h after a loading dose of 2 g) group. A population pharmacokinetic model was developed using unbound plasma, and total ELF concentrations of temocillin and related Monte Carlo simulations were performed to assess PTAs. The area under the concentration-time curve from 0 to 24 h (AUC0-24) ELF/plasma penetration ratio was 0.73, at steady state, for both modes of infusion and whatever the level of creatinine clearance. Monte Carlo simulations showed that for the minimal pharmacodynamic (PD) targets of 50% T > 1× MIC (II group) and 100% T > 1× MIC (CI group), PK/PD breakpoints were 4 mg/L in plasma and 2 mg/L in ELF and 4 mg/L in plasma and ELF, respectively. The breakpoint was 8 mg/L in ELF for both modes of infusion in patients with creatinine clearance (CLCR) < 60 mL/min/1.73 m2. While CI provides better PKPD indexes, the latter remain below available recommendations for systemic infections, except in the case of moderate renal impairment, thereby warranting future clinical studies in order to determine the efficacy of temocillin in severe pneumonia.

Iron serum levels and iron homeostasis parameters in patients with nosocomial pneumonia treated with cefiderocol: post hoc analysis of the APEKS-NP study.

Critically ill patients often present with low serum iron levels or anemia. We evaluated the impact of iron levels and iron homeostasis on the efficacy and safety of cefiderocol, an iron-chelator siderophore cephalosporin, in patients with nosocomial pneumonia in a post hoc analysis of the randomized, double-blind, Phase 3 APEKS-NP study (NCT03032380). Patients with Gram-negative nosocomial pneumonia received cefiderocol 2 g, 3-h infusion, q8h, or high-dose, extended-infusion meropenem 2 g, 3-h infusion, q8h, for 7-14 days. Efficacy and safety parameters, including specific iron homeostasis parameters (i.e., hepcidin, iron, total iron binding capacity, transferrin saturation), were analyzed according to baseline iron levels. In the cefiderocol and meropenem arms, 79.1% (117/148) and 83.3% (125/150) randomized patients, respectively, had low baseline serum iron levels. Rates of 14-day (12.3% [14/114] vs 11.6% [14/121]) and 28-day all-cause mortality (20.5% [23/112] vs 19.0% [23/121]), clinical cure (63.2% [72/114] vs 67.2% [82/122]), and microbiological eradication (43.6% [41/94] vs 48.1% [51/106]) at test of cure were similar in cefiderocol vs meropenem arms, respectively. In the overall safety population, rates of anemia-related adverse events were similar (cefiderocol arm 18.2% [27/148], meropenem arm 18.7% [28/150]). Changes from baseline to test of cure in hepcidin, iron, total iron binding capacity, and transferrin saturation were similar between treatment arms. Cefiderocol treatment did not affect iron homeostasis, and its efficacy and safety were not influenced by baseline serum iron levels. Clinicaltrials.gov registration: NCT03032380. Date of registration: 26 January 2017.

Clinical outcomes of ceftazidime-avibactam versus meropenem in Indian patients with nosocomial pneumonia: Subset analysis from the REPROVE study.

The efficacy and safety of Ceftazidime-Avibactam (CAZ-AVI) as compared to meropenem for nosocomial pneumonia was established in a randomized, phase-III, non-inferiority trial REPROVE, which included Indian patients. We determined if the results for the Indian patients were in-line with the results of overall population. Descriptive analysis of efficacy and safety demonstrated ceftazidime-avibactam was comparable to meropenem in the management of nosocomial pneumonia in Indian patients and it may be a useful addition to the armamentarium of antibiotics for management of such infections with Enterobacterales and Pseudomonas.

An evaluation of meropenem/vaborbactam for the treatment of nosocomial pneumonia.

Introduction: Nosocomial pneumonias are the second most common healthcare-associated infections (HCAIs), often associated with the presence of Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter species, and Enterobacter species. Increasing use of carbapenems has led to an increase in the prevalence of carbapenem-resistant gram-negative organisms, such as carbapenem-resistant Enterobacterales (CRE), P. aeruginosa (CRPA), and Acinetobacter baumannii (CRAB), limiting treatment options for patients at high-risk of multi-drug resistant (MDR) gram-negative pathogens. Areas covered: The purpose of this review is to discuss the role of meropenem/vaborbactam, a beta-lactam combined with a novel non-beta-lactam cyclic boronic acid beta-lactamase inhibitor (BLI), for the treatment of nosocomial pneumonia based on its chemistry, pharmacokinetics/dynamics, microbiological spectrum of activity, mechanisms of resistance, safety, and clinical efficacy. Expert opinion: Currently, any utilization of meropenem/vaborbactam beyond its FDA-approved indication for complicated urinary tract infections is considered off-label use; however, based on the pulmonary penetration of meropenem/vaborbactam, it is highly likely to be a safe and effective alternative to more toxic agents, like aminoglycosides and polymixins, for targeted therapy in pulmonary infections due to CRE. Unfortunately, the multifactorial resistance pattern of CRPA and other non-lactose-fermenting gram-negative bacteria restricts activity against these organisms which are common pathogens implicated in nosocomial pneumonia.

Tailoring Empirical Antimicrobial Therapy in Subjects With Ventilator-Associated Pneumonia With a 10-Hour E-Test Approach.

BACKGROUND: In a previous study of subjects suspected of having ventilator-associated pneumonia, a rapid susceptibility testing approach by using ETEST (BioMérieux) strips directly applied to bronchoalveolar lavage samples provided valuable information at hour 24. The primary objective of this study was to assess a new direct specimen testing by using an even more-rapid E-test approach (at hour 10), which could promote an early de-escalation of the antimicrobial therapy. METHODS: Twenty-eight subjects with ventilator-associated pneumonia admitted to a medical ICU were prospectively included. In parallel with standard routine methods, E-test strips were directly applied onto agar plates seeded with bronchoalveolar lavage samples and were analyzed after 10 h of incubation. E-test results were used to identify potential drug choices by simulating clinical decision making if the microscopy results had been available at the point of care. These choices were analyzed for concordance with the narrowest adequate antimicrobial therapy according to the Minimum Inhibitory Concentrations (MICs) provided by the reference method (ie, the laboratory routine diagnostic). RESULTS: At hour 10, direct specimen testing was readable in 18 of 28 bronchoalveolar lavage samples (64%). Total agreement between the 10-h direct specimen testing approach and the laboratory routine diagnostic approach was 90%, with a sensitivity of 83% and a specificity of 95%, with 8% major errors and 3% very major errors. The concordance between the 2 tests was very good (kappa = 0.79). If the 10-h E-test results were taken into account, then an early de-escalation strategy would have been possible in 10 of 18 cases (55%) at hour 10. CONCLUSIONS: This rapid susceptibility testing approach provided early (10 h) and valuable information that could lead to an early adjustment of empirical antimicrobial treatment in a ventilator-associated pneumonia setting. (ClinicalTrials.gov registration NCT01266863.).

Carbapenems vs. alternative ß-lactams for the treatment of nosocomial pneumonia: A systematic review and meta-analysis.

BACKGROUND: Carbapenems have shown efficacy in treating nosocomial pneumonias in clinical trials despite a reported low lung penetration compared with other ß-lactams. Preserving the clinical activity of carbapenems through stewardship efforts is essential. The aim of this review was to identify any differences in outcomes potentially as a function of decreased penetration. METHODS: PubMed and the Cochrane Library were systematically searched for clinical trials comparing carbapenems with other anti-pseudomonal ß-lactams for treatment of nosocomial pneumonia through to end December 2016. Trials reporting clinical and microbiological outcomes associated with treatment were included. Pediatric studies and those with uneven comparators (e.g., carbapenem vs. combination Gram-negative therapy) were excluded. Fixed effects models were used to evaluate the impact of treatment on the odds of clinical failure, death, or microbiological failure. RESULTS: 252 unique articles were identified; five met inclusion criteria and comprised 640 patients in the carbapenem group and 634 patients in the ß-lactam group. No differences in clinical failure (odds ratio [OR] 1.08, 95% confidence interval [CI] [0.81-1.44], I2=16%) or mortality (OR 0.75, CI 0.57-1.11, I2=0%) were noted between groups. Patients infected with P. aeruginosa and treated with imipenem were more likely to experience clinical failure (OR 4.21, CI 1.51-11.12, I2=44%) and to develop resistance to the study carbapenem (OR 2.86, CI 1.08-6.44, I2= 13%) than those treated with alternative ß-lactams. CONCLUSIONS: No differences in clinical outcomes were observed between carbapenems and non-carbapenem ß-lactams in nosocomial pneumonias. Those infected with P. aeruginosa fared worse and were more likely to have resistance develop if they were treated with imipenem. Additional studies are warranted.

Pharmacokinetic/Pharmacodynamic Analysis of Meropenem for the Treatment of Nosocomial Pneumonia in Intracerebral Hemorrhage Patients by Monte Carlo Simulation.

BACKGROUND: Nosocomial pneumonia (NP) is a frequent complication among patients with intracerebral hemorrhage (ICH). However, there are currently no pharmacokinetic (PK) and pharmacodynamic (PD) data to guide meropenem dosing in these patients. OBJECTIVE: To investigate the PK/PD properties of meropenem in these patients and whether the usual dosing regimens of meropenem (2-hour infusion, 1 g, every 8 hours) was suitable. METHODS: A total of 11 patients with a diagnosis of ICH complicated with NP were selected in the emergency internal medicine and treated with a 1-g/2-hours extended infusion model. The plasma concentrations of meropenem were determined by high-performance liquid chromatography. PK parameters were estimated by plasma concentration versus time profile using WinNonlin software. The probability of target attainments (PTAs) of meropenem at different minimum inhibitory concentrations (MICs) based on percentage time that concentrations were above the minimum inhibitory concentration (%T>MIC) value were performed by Monte Carlo simulation. RESULTS: The volume of distribution and total body clearance of meropenem were 55.55 L/kg and 22.89 L/h, respectively. Using 40%T>MIC, PTA was >90% at MICs ≤4 µg/mL. Using 80% or 100%T>MIC, PTA was >90% only at MICs ≤1 µg/mL. CONCLUSIONS: The PK/PD profile of dosing regimens tested will assist in selecting the appropriate meropenem regimens for these patients. At a target of 40%T>MIC, the usual dosing regimens can provide good coverage for pathogens with MICs of ≤4 µg/mL. However, when a higher target (80% or 100%) is desired for difficult-to-treat infections, larger doses, prolonged infusions, shorter intervals, and/or combination therapy may be required.

Linezolid Versus Vancomycin in the Empiric Treatment of Nosocomial Pneumonia: A Cost-Utility Analysis Incorporating Results from the ZEPHyR Trial.

OBJECTIVE: To examine the cost-effectiveness of vancomycin versus linezolid in the empiric treatment of nosocomial pneumonias incorporating results from a recent prospective, double-blind, multicenter, controlled trial in adults with suspected methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. METHODS: A decision-analytic model examining the cost-effectiveness of linezolid versus vancomycin for the empiric treatment of nosocomial pneumonia was created. Publicly available cost, efficacy, and utility data populated relevant model variables. A probabilistic sensitivity analysis varied parameters in 10,000 Monte-Carlo simulations, and univariate sensitivity analyses assessed the impact of model uncertainties and the robustness of our conclusions. RESULTS: Results indicated that the cost per quality-adjusted life-year (QALY) increased 6% ($22,594 vs. $23,860) by using linezolid versus vancomycin for nosocomial pneumonia. The incremental cost per QALY gained by using linezolid over vancomycin was $6,089, and the incremental cost per life saved was $68,615 with the use of linezolid. Vancomycin dominated linezolid in the subset of patients with documented MRSA. The incremental cost per QALY gained using linezolid if no mortality benefit exists between agents or a 60-day time horizon was analyzed was $19,608,688 and $443,662, respectively. CONCLUSIONS: Linezolid may be a cost-effective alternative to vancomycin in the empiric treatment of patients with suspected MRSA nosocomial pneumonia; however, results of our model were highly variable on a number of important variables and assumptions including mortality differences and time frame analyzed.