In vitro activity, pharmacodynamic profile and dose optimization of biapenem against NDM and OXA-48-like carbapenemase-producing Klebsiella pneumoniae: A multicentre study in Thailand.

BACKGROUND: Biapenem (BIPM) exhibited a less efficient substrate for various metallo-ß-lactamase (MBL) than other carbapenems. OBJECTIVE: We aimed to evaluate in vitro susceptibility data of BIPM and optimal dose based on Monte Carlo simulation to extend treatment options. METHODS: We collected 192 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients among multicentres in Thailand, from June 2019 to March 2023. BIPM disk diffusion and broth-microdilution testing were performed to obtain minimum inhibitory concentration (MIC). Each BIPM 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 among 192 CRKP isolates were blaOXA-48 (62.3%), blaOXA-48+blaNDM (22.6%) and blaNDM (15.1%). BIPM showed 22.4 and 28.6% susceptible rate when interpreted at clinical breakpoints of 1 and 2 mg/L. The MIC50 and MIC90 of BIPM against CRKP were 8 and 32 mg/L. The BIPM dosing regimens of 300 mg q 6 h infused 6 h and 600 mg q 8 h infused 8 h met the PTA target of %fTime >MIC at 50%, 75% and 100% against isolates MICs of ≤2 mg/L. Based on CFR ≥90%, no BIPM regimens were effective against all the studied CRKP isolates. CONCLUSION: BIPM exhibited a partially susceptible rate among the CRKP isolates in Thailand. The current suggested dose of BIPM with prolonged infusion appears appropriate regimen against CRKP MICs of ≤2 mg/L. However, the empirical use of BIPM for severe CRE infection is not recommended unless the susceptibility has been confirmed.

Correction: Nulsopapon et al. The Synergistic Activity and Optimizing Doses of Tigecycline in Combination with Aminoglycosides against Clinical Carbapenem-Resistant Klebsiella pneumoniae Isolates. Antibiotics 2021, 10, 736.

There were errors made in the original article [...].

Optimizing Doses of Ceftolozane/Tazobactam as Monotherapy or in Combination with Amikacin to Treat Carbapenem-Resistant Pseudomonas aeruginosa.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a hospital-acquired pathogen with a high mortality rate and limited treatment options. We investigated the activity of ceftolozane/tazobactam (C/T) and its synergistic effects with amikacin to extend the range of optimal therapeutic choices with appropriate doses. The E-test method is used to determine in vitro activity. The optimal dosing regimens to achieve a probability of target attainment (PTA) and a cumulative fraction of response (CFR) of ≥90% were simulated using the Monte Carlo method. Of the 66 CRPA isolates, the rate of susceptibility to C/T was 86.36%, with an MIC50 and an MIC90 of 0.75 and 24 µg/mL, respectively. Synergistic and additive effects between C/T and amikacin were observed in 24 (40%) and 18 (30%) of 60 CRPA isolates, respectively. The extended infusion of C/T regimens achieved a ≥90% PTA of 75% and a 100% fT > MIC at C/T MICs of 4 and 2 µg/mL, respectively. Only the combination of either a short or prolonged C/T infusion with a loading dose of amikacin of 20−25 mg/kg, followed by 15−20 mg/kg/day amikacin dosage, achieved ≥90% CFR. The C/T infusion, combined with currently recommended amikacin dose regimens, should be considered to manage CRPA infections.

Antimicrobial Activity Profiles and Potential Antimicrobial Regimens against Carbapenem-Resistant Enterobacterales Isolated from Multi-Centers in Western Thailand.

The spread of carbapenem-resistant Enterobacterales (CRE) constitutes a global health burden. Antimicrobial susceptibility and types of carbapenemase differ by geographic region. This study aimed to (1) examine the minimum inhibitory concentrations (MICs) and antibiotic resistance genes and (2) investigate antibiotic dosing regimens against CRE using Monte Carlo simulation. Clinical carbapenem-resistant Klebsiella pneumoniae (CRKP), Escherichia coli (CREC), and Enterobacter cloacae (CREclo) isolates were collected from various hospitals in western Thailand. Broth microdilution was performed, and the types of carbapenemase and mcr-1 genes were detected using polymerase chain reaction (PCR). Monte Carlo simulation was used to establish optimal antimicrobial dosing regimens meeting the criterion of a cumulative fraction of response (CFR) >90%. A total of 150 CRE isolates from 12 hospitals were included. The proportion of CRKP (76%) was greater than that of CREC (22%) and CREclo (2%). Regional hospitals reported higher rates of resistance than general hospitals. Most isolates were resistant to aztreonam and ceftazidime/avibactam, whereas they were highly susceptible to aminoglycosides. Most carbapenemases were NDM (47.33%), OXA-48 (43.33%) and NDM plus OXA-48 (6.67%); five OXA-48 positive isolates carried mcr-1 genes. Currently, high-dose tigecycline is the only optimal regimen against CRE isolates. Further extensive research on antibiotic synergism or new antibiotics should be conducted.

Colistin plus Sulbactam or Fosfomycin against Carbapenem-Resistant Acinetobacter baumannii: Improved Efficacy or Decreased Risk of Nephrotoxicity?

BACKGROUND: Acinetobacter baumannii has been recognized as a cause of nosocomial infection. To date, polymyxins, the last-resort therapeutic agents for carbapenem-resistant A. baumannii (CRAB). Thus, the small number of effective antibiotic options against CRAB represents a challenge to human health. This study examined the appropriate dosage regimens of colistin alone or in combination with sulbactam or fosfomycin using Monte Carlo simulation with the aims of improving efficacy and reducing the risk of nephrotoxicity. MATERIALS AND METHODS: Clinical CRAB isolates were obtained from patients admitted to Phramongkutklao Hospital in 2014 and 2015. The minimum inhibitory concentration (MIC) of colistin for each CRAB isolate was determined using the broth dilution method, whereas those of sulbactam and fosfomycin were determined using the agar dilution method. 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). Nephrotoxicity based on RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria was indicated by colistin trough concentration exceeding ≥3.3 µg/mL. RESULTS: A total of 50 CRAB isolates were included. The MIC50 and MIC90 were 64 and 128 µg/mL, respectively, for sulbactam, 256 and 2,048 µg/mL, respectively, for fosfomycin, and 1 and 4 µg/mL, respectively, for colistin. In patients with creatinine clearance of 91 - 130 m/min, the dosing regimens of 180 mg every 12 h and 150 mg every 8 h achieved ≥ 90% of target of the area under the free drug plasma concentration-time curve from 0 to 24 hr (fAUC24)/MIC ≥25 against isolates MICs of ≤0.25 and ≤0.5 µg/mL, respectively, and their rates of colistin trough concentration more than ≥3.3 µg/mL were 35 and 54%, respectively. Colistin combined with sulbactam or fosfomycin decreased the colistin MIC of CRAB isolates from 1 - 16 µg/mL to 0.0625 - 1 and 0.0625 - 2 µg/mL, respectively. Based on CFR ≥ 90%, no colistin monotherapy regimens in patients with creatinine clearance of 91 - 130 mL/min were effective against all of the studied CRAB isolates. For improving efficacy and reducing the risk of nephrotoxicity, colistin 150 mg given every 12 h together with sulbactam (≥6 g/day) or fosfomycin (≥18 g/day) was effective in patients with creatinine clearance of 91 - 130 mL/min. Additionally, both colistin combination regimens were effective against five colistin-resistant A. baumannii isolates. CONCLUSION: Colistin monotherapy at the maximum recommended dose might not cover some CRAB isolates. Colistin combination therapy appears appropriate for achieving the pharmacokinetic/pharmacodynamic targets of CRAB treatment.

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 .

The Synergistic Activity and Optimizing Doses of Tigecycline in Combination with Aminoglycosides against Clinical Carbapenem-Resistant Klebsiella pneumoniae Isolates.

Carbapenem-resistant Enterobacteriaceae (CRE), especially carbapenem-resistant Klebsiella pneumoniae (CRKP), are among the largest pathogenic threats to humans. The available antibiotic treatment options for combating CRKP are limited. Colistin-resistant Enterobacteriaceae (CoRE) have also been reported worldwide, including in Thailand. Therefore, this study aimed (1) to determine minimum inhibitory concentrations (MICs) and synergistic activities of antibiotics of CRKP, and (2) to determine the probability target of attainment (PTA) and cumulative fraction of response (CFR) using pharmacokinetic/pharmacodynamic (PK/PD) data. Clinical CRKP isolates were obtained from Phramongkutklao Hospital (June to November 2020). Broth microdilution and checkerboard techniques were used to determine the mono- and synergistic activities of antibiotics. Carbapenemase and mcr-1 genes were also identified by polymerase chain reaction (PCR). The optimal antibiotic regimens were evaluated using Monte Carlo simulations. Forty-nine CRKP isolates were collected, 40 of which were CoRKP strains. The MIC50 and MIC90 of tigecycline, amikacin, and gentamicin were 1 and 2 µg/mL, 4 and 16 µg/mL, and 0.25 and 4 µg/mL, respectively. None of any isolates expressed the mcr-1 gene, whereas blaOXA-48 (53.1%) and blaOXA-48 plus blaNDM (42.9%) were detected. Synergistic activity was observed in 8.2% of isolates for tigecycline combined with amikacin or gentamicin. Additive activity was observed in 75.5% of isolates for tigecycline-amikacin and 69.4% for tigecycline-gentamicin, and no antagonism was observed. High-dose antibiotic regimens achieved the PTA target. The general recommended dose of combination regimens began with 200 mg tigecycline and 25 mg/kg amikacin, or 7 mg/kg gentamicin, followed by 100 mg tigecycline every 12 h and 15 mg/kg amikacin or 5 mg/kg gentamicin every 24 h. In conclusion, tigecycline plus aminoglycosides might be a potential regimen against CRKP and CoRKP. The appropriate combination regimen based on MIC-based dose adjustment can improve optimal antibiotic dosing. Further research via clinical studies will be necessary to confirm these results.