Saelim W, et al. Infect Chemother. 2021 Mar;53:e16. https://doi.org/10.3947/ic.2021.0007

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 bla_OXA-48 (53.1%) and bla_OXA-48 plus bla_NDM (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.

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.

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.

There were errors made in the original article

Warfarin is an oral anticoagulant commonly used to prevent thromboembolism. Its pharmacodynamics can be affected by interactions with other drugs and dietary supplements, although there is only limited information available on these interactions. One dietary supplement that has been associated with increased international normalized ratio (INR) levels, potentially leading to supratherapeutic levels, is fish oil. However, the data available on this interaction are not extensive. This case study focused on a sixty-nine years old Thai female who was prescribed warfarin at a weekly dose of 30 milligrams (maintaining an INR range of 2.5-3.5) to prevent thromboembolism resulting from atrial fibrillation (AF) following a mechanical valve replacement at the mitral position. The patient began taking fish oil supplements for a period of 2 months. After initiating the fish oil supplement in addition to the warfarin, the patient’s INR had increased from 2.94 to 4.13, although no bleeding symptoms were observed. When combining fish oil with warfarin, it is important for medical professionals to exercise caution and to monitor the INR levels in all cases to ensure safety and optimize efficacy. KEYWORDS warfarin, fish oil, dietary supplement