The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital.

PURPOSE: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options. PATIENTS AND METHODS: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June-October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). RESULTS: The most common genotypes of CRKP were blaOXA-48 (53.1%) and blaOXA-48 +blaNDM (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC50 and MIC90 of CZA against CRKP were 2 and >256 µg/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2-3 h every 8 h achieved ≥90% of the target of free ceftazidime plasma concentration over MIC (%fTime >MIC) ≥50% and 100% against isolates MICs of ≤8 and ≤8 µg/mL, respectively. The avibactam regimens also provided 100%fTime at 0.5 µg/mL. Based on CFR ≥90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48. CONCLUSION: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying blaOXA-48 .

Monte Carlo Simulation Methodologies for ß-Lactam/ß-Lactamase Inhibitor Combinations: Effect on Probability of Target Attainment Assessments.

Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for ß-lactam/ß-lactamase inhibitor combinations (BL-BLICs), methods for linking simulated concentration profiles of the ß-lactam (BL) and ß-lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000-patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L. Method A ignored all covariates and correlations, whereas methods B, C, and D enhanced associations by adding (B) pharmacokinetic parameter correlation within each drug only; (C) pharmacokinetic parameter correlation within each drug and creatinine clearance (CRCL); and (D) pharmacokinetic parameter correlation within each drug, CRCL, and pharmacokinetic parameter correlation between drugs. Method D produced a simulated patient population that best recapitulated the observed relationships between pharmacokinetic parameters in actual patients. Ceftazidime/avibactam PTA at MIC 8 mg/L (the susceptibility break point) and 16 mg/L ranged from 92.4% to 98.3% and 80.2% to 88.4%, respectively. PTA was lowest with method A, whereas PTA estimates were similar for all other methods. Compared with ignoring all pharmacokinetic parameter associations, the inclusion of covariate relationships and parameter correlation between both components of ceftazidime/avibactam leads to fewer patients with discordant pharmacokinetic parameters and results in higher PTA. Consideration of these methodologies should guide future MCS analyses for BL-BLIC.

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

BACKGROUND: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients. PATIENTS AND METHODS: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1 mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA. RESULTS: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R = 0.91) and avibactam (R = 0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.1 ± 3.8 L/h, 35 ± 10.5 L, and 4.8 ± 2.15 h, respectively. For avibactam, these values were 11.1 ± 6.8 L/h, 50.8 ± 14.3 L, and 4.1 ± 2.1 h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16 mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal (≥ 3 log10 CFU/mL reduction) activity against each of the study isolates. CONCLUSION: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates.

Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis.

Objectives: To calculate the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations. Methods: Two groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a standard meal on two separate days 1 week apart. One group (n = 14) received 875/125 mg q12h and 500/125 mg q8h and the other group (n = 15) received 500/125 mg q12h and 250/125 mg q8h. In total, 1479 blood samples were collected until 8-12 h after administration. Concentrations were analysed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods. Results: Median Cmax and AUC0-8 were 2.21 mg/L (0.21-4.35) and 4.99 mg·h/L (0.44-8.31), respectively. In 40/58 daily concentration-time profiles, Cmax and AUC0-8 of the morning dose were higher than with later doses. The final population model included a lag time (0.447 h), first-order absorption (3.99 h-1 at 8:00 h, between-subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between-subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125 mg q12h or q8h, %fT > Ct at 0.5 mg/L was 8.33% (q12h) and 15.2% (q8h), %fT > Ct at 1 mg/L was 0% (q12h + q8h), and fAUC0-24 was 3.61 (q12h) and 5.56 (q8h) mg·h/L. Conclusions: Clavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing.

Impact of high-flux haemodialysis on the probability of target attainment for oral amoxicillin/clavulanic acid combination therapy.

Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic/pharmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT>MIC) was used. For clavulanic acid, the time that the free concentration was >0.1 mg/L of ≥45% of the dosing period (≥45%ƒT>0.1 mg/L) was used. Dialysis clearance reported in low-flux haemodialysis for both compounds was doubled to represent the likely clearance during high-flux haemodialysis. Monte Carlo simulations were performed to produce concentration-time profiles over 10 days in 1000 virtual patients. Seven different regimens commonly seen in clinical practice were explored. When AMC was dosed twice daily, the PTA was mostly ≥90% for both compounds regardless of when haemodialysis commenced. When administered once daily, the PTA was 20-30% for clavulanic acid and ≥90% for amoxicillin. The simulations suggest that once-daily orally administered AMC in patients receiving high-flux haemodialysis may result in insufficient concentrations of clavulanic acid to effectively treat infections, especially on days when haemodialysis occurs.

Piperacillin/tazobactam as an alternative antibiotic therapy to carbapenems in the treatment of urinary tract infections due to extended-spectrum ß-lactamase-producing Enterobacteriaceae: an in silico pharmacokinetic study.

Piperacillin/tazobactam (TZP) as an alternative treatment to carbapenems for infections involving extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE) remains debated. In this study, the probabilities of pharmacodynamic (PD) target attainment with different TZP regimens in ESBL-producing Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp) were evaluated in the context of pyelonephritis. Minimum inhibitory concentrations (MICs) of 144 ESBL-Ec and 111 ESBL-Kp from pyelonephritis were measured, and two previously published population pharmacokinetic models were used to determine by Monte Carlo simulation the probabilities of reaching two PD targets (50%fT>MIC and 100%fT>MIC) with TZP doses of 4 g three times daily and 4.5 g four times daily given as short (1 h) or prolonged (4 h) infusions or as 12-18 g/day continuous infusions. Only MICs of the 133 ESBL-Ec and 74 ESBL-Kp strains susceptible to TZP according to inhibition zone diameter were considered for the simulations. Results were similar with the two models, and only prolonged and continuous infusions allowed to reach 50%fT>MIC with a probability of >90% irrespective of bacterial species. Continuous infusion and prolonged infusion combined with the maximum dosage were the only condition allowing to achieve 100%fT>MIC with a probability of >70% with this population of ESBL-Ec. A probability of >90% to reach 100%fT>MIC with ESBL-Kp could be obtained only with the 18 g/day continuous-infusion regimen. TZP may be used for treatment for mild pyelonephritis involving susceptible ESBL-Ec provided that administration modalities are optimised. Conversely, for ESBL-Kp the risk of treatment failure may be higher, supporting the use of continuous infusion.

Clinical outcomes of extended versus intermittent administration of piperacillin/tazobactam for the treatment of hospital-acquired pneumonia: a randomized controlled trial.

The purpose of this study was to assess the pharmacokinetic (PK) characteristics, clinical efficiency, and pharmacoeconomic parameters of piperacillin/tazobactam administered by extended infusion (EI) or intermittent infusion (II) in the treatment of hospital-acquired pneumonia (HAP) in critically ill patients with low illness severity in China. Fifty patients completed the study, with 25 patients receiving 4/0.5 g piperacillin/tazobactam over 30 min as the II group and 25 patients receiving 4/0.5 g piperacillin/tazobactam over 3 h every 6 h as the EI group. Drug assay was performed using high-performance liquid chromatography (HPLC). The percentage of the dosing interval for which the free piperacillin concentration (%fT) exceeds the minimum inhibitory concentration (MIC) was calculated. The patients' therapy cost, clinical efficiency, and adverse effects were also recorded. %fT>MIC was about 100, 98.73, and 93.04 % in the EI arm versus 81.48, 53.29, and 42.15 % in the II arm, respectively, when the microorganism responsible for HAP had an MIC of 4, 8, and 16 mg/L. The therapy cost in the EI group was lower than that of the II group ($1351.72 ± 120.39 vs. $1782.04 ± 164.51, p = 0.001). However, the clinical success rate, clinical failure rate, and drug-related adverse events did not significantly differ between groups. EI treatment with piperacillin/tazobactam was a cost-effective approach to the management of HAP, being equally clinically effective to conventional II.