Optimal treatment of ceftazidime-avibactam and aztreonam-avibactam against bloodstream infections or lower respiratory tract infections caused by extensively drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa.

Objective: To evaluate the efficacy of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections (BSIs) or lower respiratory tract infections (LRTIs) - caused by extensive drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa. Method: The two-fold dilution method was used to determine the minimum inhibitory concentrations (MICs) of CZA/AZA against XDR/PDR P. aeruginosa. Whole-genome sequencing was used to analyze the resistance determinants of each isolate. Monte Carlo simulations (MCSs) were used to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of each CZA/AZA dosing regimen via traditional infusion (TI)/optimized two-step-administration therapy (OTAT). Results: We found that XDR/PDR P. aeruginosa may carry some rare MBLs (e.g.: IND-6, SLB-1, THIN-B). P. aeruginosa isolates producing IMP-45, VIM-1, or VIM-2 were inhibited by AZA at a concentration of 2 to 8 mg/L. All isolates producing IND-6 plus other serine ß-lactamases were high-level resistant to CZA/AZA (MICs >64 mg/L). All simulated dosing regimens of CZA/AZA against BSIs-causing XDR/PDR P. aeruginosa achieved 100% PTA when the MIC was ≤32 mg/L. Conclusion: AZA has been considered as an option for the treatment of infections caused by XDR/PDR P. aeruginosa producing IMP-45, VIM-1, or VIM-2. OTAT with sufficient pharmacodynamic exposure may be an optimal treatment option for XDR/PDR P. aeruginosa with a high-level MIC of CZA/AZA.

Evaluation of the Efficacy of Optimized Two-Step-Administration Therapy with Ceftazidime/Avibactam for Treating Extensively Drug-Resistant Pseudomonas aeruginosa Pulmonary Infections: a Pharmacokinetic/Pharmacodynamic Analysis.

The objective of this pharmacokinetic (PK)/pharmacodynamic (PD) analysis was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) for the treatment of pulmonary infections by extensively drug-resistant (XDR) Pseudomonas aeruginosa using optimized two-step administration therapy (OTAT) and traditional infusion (TI). We used Monte Carlo simulations (MCS) to integrate PK parameters with PD parameters to assess the adequacy of CZA dosing in critically ill patients with XDR P. aeruginosa pulmonary infections. Dosing models were as follows: 2.5 g q8h, 2.5 g q6h, 4 g q8h, 4 g q6h, 1.25 g q8h, 1.25 g q6h, and 0.94 g q12h. MCS showed that the cumulative fraction of response of all dosing regimens of OTAT was higher than 90%. The probability of target attainment of all dosing regimens of OTAT at MICs (minimal inhibitory concentrations) between 16 mg/L and 32 mg/L was higher than that of TI. Based on these models, PK/PD goals were met with OTAT regimens, even with high MICs (>16 mg/L) compared to traditional infusion (TI) intervals. Thus, this study indicates that OTAT with sufficient PK exposure could improve the efficacy of CZA in critically ill patients with XDR P. aeruginosa pulmonary infections.

Use of Monte Carlo simulation to evaluate the efficacy of tigecycline and minocycline for the treatment of pneumonia due to carbapenemase-producing Klebsiella pneumoniae.

BACKGROUND: Pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-KP) are increasingly encountered in hospitals worldwide, causing high mortality due to lack of treatment options. The goal of this study was to assess the efficacy of tigecycline and minocycline for CP-KP hospital-acquired pneumonia (HAP) by using Monte Carlo simulation. METHODS: A total of 164 non-duplicated CP-KP strains were collected from sputum or blood in patients with HAP. The MICs for antimicrobials were determined by the agar dilution method. A 10,000-patient Monte Carlo Simulation based on a PK/PD model incorporating the MICs and population pharmacokinetic parameters were conducted to calculate probability of target attainment (PTA) at each MIC value and total cumulative fraction of response (CFR). RESULTS: The susceptibility rate of tigecycline and minocycline were 79.9% and 41.5%, respectively. At recommended doses, an optimal PTA of 90% was obtained for treating HAP caused by CP-KP with MICs of tigecycline ≤0.5 mg/L or minocycline ≤4 mg/L. The CFR of tigecycline at the recommended dose and double dose (100 mg q12h) were 71.2% and 90.2%, respectively. The CFR of minocycline at recommended dose and double dose (200 mg q12h) was 53.4% and 77.2%, respectively. CONCLUSIONS: The findings of this study suggest that the recommended dose of tigecycline was not effective in HAP caused by CP-KP, and a higher CFR indicating a better clinical efficacy can be gained by doubling the dose (100 mg q12h). minocycline (200 mg q12h) might be a potential alternative of tigecycline to against strains with MICs ≤ 8 mg/L.

A Monte Carlo pharmacokinetic/pharmacodynamic simulation to evaluate the efficacy of minocycline, tigecycline, moxifloxacin, and levofloxacin in the treatment of hospital-acquired pneumonia caused by Stenotrophomonas maltophilia.

BACKGROUND: Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen in recent years. Increasing antimicrobial resistance and other contraindications have greatly compromised trimethoprim/sulfamethoxazole (SXT) as the first-line therapeutic option. The objective of this study was to explore other options for treating hospital-acquired pneumonia (HAP) caused by S. maltophilia. METHODS: A total of 102 strains of S. maltophilia were isolated from sputum and bronchoalveolar lavage (BAL) specimens of patients with HAP in our institution. The minimum inhibitory concentration (MIC) values of minocycline, tigecycline, moxifloxacin, and levofloxacin were determined by the agar dilution method. Based on the MICs and the population pharmacokinetic parameters of the investigated antimicrobials, a Monte Carlo simulation was performed to simulate the pharmacokinetic/pharmacodynamic (PK/PD) indices of different regimens. The probability of target attainment (PTA) was estimated at each MIC value and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. RESULTS: The susceptibility rates to minocycline, tigecycline, moxifloxacin, and levofloxacin were 96.1%, 80.4%, 74.5%, and 69.6%, respectively. The estimated CFRs were 96.2% for minocycline 100 mg twice daily; 50.8%/67.1%/75.4% for tigecycline 50/75/100 mg twice daily; 34.3%/48.0%/56.6% for levofloxacin 500/750/1000 mg once daily; and 45.7% for moxifloxacin 400 mg once daily. CONCLUSIONS: The simulation results suggest that minocycline may be a proper choice for treatment of HAP caused by S. maltophilia, while tigecycline, moxifloxacin, and levofloxacin may not be optimal as monotherapy.

A pharmacodynamic simulation to evaluate tigecycline in treatment of nosocomial pneumonia caused by multidrug-resistant Acinetobacter baumannii.

The shortage of effective antibiotics against multidrug-resistant Acinetobacter baumannii (MDR-Ab) has posed great threat to the public health. But the advent of tigecycline gives us new hope. The goal of our research was to assess the clinical efficacy of tigecycline at different doses by using a pharmacokinetic/pharmacodynamic (PK/PD) model which can incorporate pharmacokinetic data of tigecycline from patients with pneumonia and MICs of MDR-Ab from a tertiary hospital. A 10000-patient Monte-Carlo Simulation based on the PK/PD model was conducted to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of tigecycline. 97% isolates displayed susceptibility and 3% were tigecycline-intermediate strains and the values of MIC ranged from 0.125 to 4 µ g/ml. A CFR of 61.62% was predicted for tigecycline at current dosage (50 mg q12h). When the dosage was increased, the predicted CFRs for 75 mg q12h, 100 mg q12h, 125 mg q12h, 150 mg q12h were 81.00%, 89.86%, and 94.57%, 96.77%, respectively. Despite presented higher susceptibility, the CFR obtained was not optimal at current dosage. A higher CFR indicating a better clinical efficacy can be gained by the increased dosage.

Treatment of community-acquired pneumonia with moxifloxacin: a meta-analysis of randomized controlled trials.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality throughout the world. To investigate whether moxifloxacin monotherapy is associated with better clinical outcomes than other antibiotics recommended for CAP among adults with mild-to-moderate or severe CAP, we performed a meta-analysis. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched for randomized control trials (RCTs). The efficacy and safety of moxifloxacin were compared with other antimicrobial agents used to treat CAP. Fourteen RCTs, consisting of 6923 total patients, were included in the meta-analysis. No difference was found regarding the incidence of adverse events and mortality between moxifloxacin and the compared regimens. We found that moxifloxacin is as effective and well-tolerated as other recommended antibiotics for the treatment of CAP and possesses a better pathogen eradication rate than beta-lactam-based therapy.