Predominance of international clone 2 multidrug-resistant Acinetobacter baumannii clinical isolates in Thailand: a nationwide study.

BACKGROUND: Acinetobacter baumannii has emerged as one of the common multidrug resistance pathogens causing hospital-acquired infections. This study was conducted to elucidate the distribution of antimicrobial resistance genes in the bacterial population in Thailand. Multidrug-resistant A. baumannii (MDR A. baumannii) isolates were characterized phenotypically, and the molecular epidemiology of clinical isolates in 11 tertiary hospitals was investigated at a country-wide level. METHODS: A total of 135 nonrepetitive MDR A. baumannii isolates collected from tertiary care hospitals across 5 regions of Thailand were examined for antibiotic susceptibility, resistance genes, and sequence types. Multilocus sequence typing (MLST) was performed to characterize the spread of regional lineages. RESULTS: ST2 belonging to IC2 was the most dominant sequence type in Thailand (65.19%), and to a lesser extent, there was also evidence of the spread of ST164 (10.37%), ST129 (3.70%), ST16 (2.96%), ST98 (2.96%), ST25 (2.96%), ST215 (2.22%), ST338 (1.48%), and ST745 (1.48%). The novel sequence types ST1551, ST1552, ST1553, and ST1557 were also identified in this study. Among these, the blaoxa-23 gene was by far the most widespread in MDR A. baumannii, while the blaoxa-24/40 and blaoxa-58 genes appeared to be less dominant in this region. The results demonstrated that the predominant class D carbapenemase was blaOXA-23, followed by the class B carbapenemase blaNDM-like, while the mcr-1 gene was not observed in any isolate. Most of the MDR A. baumannii isolates were resistant to ceftazidime (99.23%), gentamicin (91.85%), amikacin (82.96%), and ciprofloxacin (97.78%), while all of them were resistant to carbapenems. The results suggested that colistin could still be effective against MDR A. baumannii in this region. CONCLUSION: This is the first molecular epidemiological analysis of MDR A. baumannii clinical isolates at the national level in Thailand to date. Studies on the clonal relatedness of MDR A. baumannii isolates could generate useful data to understand the local epidemiology and international comparisons of nosocomial outbreaks.

Microbial epidemiology and risk factors for relapse in gram-negative bacteria catheter-related bloodstream infection with a pilot prospective study in patients with catheter removal receiving short-duration of antibiotic therapy.

BACKGROUND: Infectious Diseases Society of America (IDSA) guidelines suggest 7-14 days' duration of antibiotic treatment for uncomplicated Gram-negative bacteria (GNB) catheter-related bloodstream infection (CRBSI). The objectives of this study were to review microbial epidemiology, to determine rate and risk factors for relapse, and to compare clinical outcomes in patients receiving long- versus short-duration antibiotic therapy. METHODS: A retrospective phase 1 study was conducted between January 2010 and October 2016 to review microbial epidemiology and to determine the incidence of and risk factors for relapse in patients with GNB CRBSI, according to the IDSA guidelines diagnostic criteria. In phase 2 of the study, patients without risk factors for relapse between November 2016 and October 2017 were prospectively recruited to receive antibiotic therapy for 7 days after catheter removal. Matched patients from the retrospective phase 1 study who had received antibiotic therapy for ≥14 days were selected as a phase 2 control group to compare outcomes. RESULTS: In phase 1, three most common pathogens identified among 174 cases were Pseudomonas aeruginosa (22.0%), Klebsiella pneumoniae (16.7%), and Stenotrophomonas maltophilia (13.4%). Eighty-nine episodes of infection occurred while patients were receiving antibiotic therapy. Of 140 cases, the relapse rate was 6.4%. Catheter retention was the only risk factor strongly associated with relapse (odds ratio = 145.32; 95% confidence interval 12.66-1667.37, P < 0.001). In phase 2, 11 patients with catheter removal were prospectively recruited to receive short-duration therapy. The number of patients with relapse receiving long- or short-duration therapy was 1 (3%) and 0 (0%), respectively (P = 1.000). CONCLUSIONS: For the management of patients with uncomplicated GNB CRBSI, empiric broad-spectrum antibiotic therapy with adequate coverage of P. aeruginosa should be chosen. Catheter removal should be performed to prevent relapse and shortening the duration of treatment could be considered. TRIAL REGISTRATION: Thai Clinical Trial Registry: TCTR20190914001 . Retrospectively registered on 13 September 2019.

Pharmacokinetics and Penetration of Sitafloxacin into Alveolar Epithelial Lining Fluid in Critically Ill Thai Patients with Pneumonia.

Sitafloxacin showed potent activity against various respiratory pathogens. Blood and bronchoalveolar lavage (BAL) fluid samples were obtained from 12 subjects after a single oral dose of sitafloxacin 200 mg. The mean ± SD (median) maximum ratio of epithelial lining fluid (ELF) to unbound plasma concentration was 1.02 ± 0.58 (1.33). The penetration ratios based on the mean and median area under the curve from 0 to 8 h (AUC0-8) were 0.85 and 0.79 µg · h/ml, respectively. Sitafloxacin penetrates well into ELF in critically ill Thai patients with pneumonia. (This study has been registered in the Thai Clinical Trials Registry [TCTR] under registration no. TCTR20170222001.).

Correlation between antimicrobial consumption and the prevalence of carbapenem-resistant Escherichia coli and carbapenem-resistant Klebsiella pneumoniae at a university hospital in Thailand.

WHAT IS KNOWN AND OBJECTIVE: Carbapenem-resistant Enterobacteriaceae (CRE) are virulent gram-negative bacilli and cause urgent healthcare problems worldwide. One of the main factors leading to the emergence of CRE is antimicrobial consumption. The objective of this study was to assess how closely the rate of antimicrobial consumption and the prevalences of carbapenem-resistant Escherichia coli (CR-EC) and carbapenem-resistant Klebsiella pneumoniae (CR-KP) are correlated. METHODS: A retrospective study was performed at a university hospital in Thailand from January 2013 to September 2016. The prevalence of E coli and K pneumoniae was represented as percentages per species per quarter. The antimicrobial consumption rate per quarter was expressed as the defined daily dose (DDD)/1000 patient-days. Evaluation of the relationships between the rate of antimicrobial consumption and the prevalences of CR-EC and CR-KP was conducted via Pearson's or Spearman's correlation analyses. RESULTS AND DISCUSSION: During the study period, the prevalence of CR-EC and CR-KP was less than 6%; however, significantly increasing prevalences were reported for both CR-EC (r = 0.55, P = 0.03) and CR-KP (r = 0.87, P < 0.01). There was a significant increasing trend in the consumption of meropenem (r = 0.65, P = 0.01), levofloxacin (r = 0.63, P = 0.01), ceftriaxone (r = 0.55, P = 0.03), ertapenem (r = 0.52, P = 0.05) and the carbapenem group (r = 0.64, P = 0.01). A significant correlation was observed between CR-KP prevalence and total carbapenem consumption (r = 0.55, P = 0.04). Moreover, levofloxacin consumption had a significant positive relationship with the prevalence of CR-KP (r = 0.65, P = 0.01). No positive correlation was found with the prevalence of CR-EC. WHAT IS NEW AND CONCLUSION: The rate of consumption of levofloxacin and carbapenems was the important key factor correlated with the rate of emergence of CR-KP. This is the first report demonstrating the correlation between levofloxacin consumption and CR-KP prevalence.

Optimization of Intermittent Vancomycin Dosage Regimens for Thai Critically Ill Population Infected by MRSA in the Era of the "MIC Creep" Phenomenon.

BACKGROUND: the shifting of minimum inhibitory concentration (MIC) of methicillin-resistant Staphylocuccus aureus (MRSA) strains to the higher value has emerged to worsen clinical outcome to the patients particularly critically ill population.  The aim of this study was to identify the most appropriate dosage regimen of vancomycin to treat infection caused by MRSA with higher MIC in critically ill Thai population. METHODS: 10,000 replications of intermittent vancomycin dosage regimens were performed using Monte Carlo simulation. Pharmacokinetic parameters were derived from a population pharmacokinetic study conducted specifically in Thai population. The probability of target attainment (PTA) and cumulative fraction of response (CFR) of each dosage regimen were calculated. Risk of nephrotoxicity was also calculated and used as a consideration in determining the most appropriate dosage regimen of vancomycin. RESULTS: in order to achieve desired PTA > 80% vancomycin at higher dosing regimens were needed including 3g/day and 4 g/day for MIC 1.5mg/L and 2.0 mg/L, respectively. Highest CFR of 94.40% and 93.57% were from vancomycin 1 g every 6 h and 2 g every 12h. Standard dose of vancomycin and total dose of vancomycin 3 g/day provided approximately 51% and 73% CFR. Risk of nephrotoxicity afforded by giving 1.5g every 12h and 2g every 12h of vancomycin were 26.59% and 31.20%, respectively. CONCLUSION: the result from this study recommended intermittent dosage regimen 1.5g every 12h and 2g every 12h should be implemented as definite antibiotic treatment when considered infection caused by MRSA with MIC 1.5 and 2.0 mg/L, respectively.

Clinically significant drug interactions among HIV-infected patients receiving antiretroviral therapy.

We conducted a cross sectional study of the outpatient medical records of 1000 HIV-infected patients receiving antiretroviral therapy (ART) in 2011 to determine the incidence of clinically significant drug interactions (CSDI). The severities of the CSDI were graded following the Micromedex" 2.0 database and the Department of Health and Human Services (DHHS) 2012 HIV treatment guidelines. Three hundred thirty-five patients (34%) had 554 episodes of CSDI. Of which 337 episodes (61%), 163 episodes (29%) and 54 episodes (10%) had grades 2, 3 and 4 severity CSDI, respectively. The CSDI were caused by protease inhibitor (PI)-based drug regimens in 79%, by efavirenz-based regimens in 34% and by nevirapine-based regimens in 10% (p<0.001). The three most common grade 4 CSDI were: a PI with simvastatin (n=24), simvastatin with gemfibrozil (n=24) and didanosine with allopurinol (n=2). The three most common grade 3 CSDI were: a PI with a statin drug except simvastatin (n=56), fenofibrate with a statin drug (n=28) and amlodipine with simvastatin (n=14). On multivariate analysis, risk factors associated with CSDI were: receiving a PI-based regimen (OR 14.44; 95% CI: 9.10-22.88), having dyslipidemia (OR 3.94; 95% CI: 1.89-8.21), having >5 items prescribed at a time (OR 1.80; 95% CI: 1.23-2.63), seeing a doctor >4 times a year (OR 1.72; 95% CI: 1.20-2.46), having hypertension (OR 0.60; 95% CI: 0.37-0.98), having a duration of receiving ART of >5 years (OR 0.46; 95% CI: 0.28-0.77) and having a CD4 count of >200 cells/mm3 (OR 0.46; 95%CI: 0.26-0.84). CSDI were common among HIV-infected patients receiving ARV in our outpatient clinic. Patients having a low CD, count, having dyslipidemia, receiving PI-based ART, having a frequent number of visits per year and having a large number of items prescribed at each visit had a greater chance of a CSDI.

Mortality factors and antibiotic options in carbapenem-resistant Enterobacterales bloodstream infections: Insights from a high-prevalence setting with co-occurring NDM-1 and OXA-48.

Bloodstream infections (BSI) caused by carbapenem-resistant Enterobacterales (CRE) are associated with a high mortality rate. This study aimed to investigate factors associated with 14-day mortality and identify a potential treatment option. A retrospective cohort study was conducted on patients with CRE-BSI in Thailand from 2015 to 2020. The multivariate Cox proportional-hazards model was employed to identify factors influencing 14-day mortality. Out of 134 diagnosed cases of CRE-BSI, the all-cause 14-day mortality rate was 35.1%. The most prevalent organism isolated was Klebsiella pneumoniae (85.8%), followed by Escherichia coli (11.9%). Among the 60 isolates tested for carbapenemase genes, the majority exhibited co-occurring blaNDM-1 and blaOXA-48 (51.7%), followed by blaOXA-48 (31.7%) and blaNDM-1 (15.0%). In the multivariate analysis, neutropenia (adjusted hazard ratio [aHR] 2.55; 95% confidence interval [95%CI] 1.28-5.06; p = 0.008), sepsis/septic shock (aHR 3.02; 95%CI 1.33-6.86; p = 0.008), and previous metronidazole exposures (aHR 3.58; 95%CI 1.89-6.71; p < 0.001) were identified as independent factors for 14-day mortality. The fosfomycin-based regimen was found to be protective (aHR 0.37; 95%CI 0.15-0.92; p = 0.032). In patients with CRE-BSI, particularly in regions with a high occurrence of co-occurring blaNDM-1 and blaOXA-48, neutropenia, sepsis/septic shock, and previous metronidazole exposures emerged as independent risk factors for mortality. Moreover, the fosfomycin-based regimen showed an improvement in the survival rate.

Drug-related problems identified by clinical pharmacists in an academic medical centre in Thailand.

Background: Drug-related problems (DRPs) are important issues that interfere with therapeutic outcomes and can cause adverse events. Pharmacists play a vital role in identifying and resolving DRPs. This study aimed to determine the characteristics, and severity of DPRs, including clinical pharmacists' interventions. Method: A retrospective study was conducted at Ramathibodi Hospital, a tertiary university hospital in Thailand. We collected data from the drug-related problem system and the electronic medical record. Descriptive statistics were performed with Statistical Package for Social Sciences (SPSS) software version 18.0. Results: There were 580 patients (20.44%) who had at least one DRP. We classified 1255 DRPs based on Cipolle-Strand-Morley Criteria 2012. The most common DRPs were the need for additional drug therapy (27.09%), followed by dosage too low (26.93%) and dosage too high (22.31%). Anti-infective agents (23.71%) and omeprazole (2.70%) were the most common drug groups and drugs causing DRPs, respectively. The severity of DRPs was mostly categorised to be 'no harm' (95.46%). Almost all of the interventions were completely accepted by physicians (99.12%). Conclusion: The most common DRPs were the need for additional drug therapy and dosage adjustment of antimicrobial agents. The clinical pharmacists on wards are effective in preventing and resolving DRPs.

Molecular investigation of carbapenem resistance among multidrug-resistant Pseudomonas aeruginosa isolated clinically in Thailand.

Carbapenem resistant Pseudomonas aeruginosa were isolated among multidrug-resistant (CR-MDR) organisms from tertiary hospitals in Thailand. Decreased expression of oprD mRNA (93.65%) was predominant followed by increased expression of mexAB-oprM mRNA (92.06%) and mexXY mRNA (63.49%). Interestingly, 23 of 126 (18.25%) isolates were susceptible to imipenem with down-regulated oprD expression and non-up-regulated mexCD-oprJ mRNA expression. Metallo-ß-lactamases production was clearly positive in 24 isolates (18.46%) and weakly positive in 12 isolates (9.23%). Among both of these sets of isolates, imp-1, imp-14 and vim-2 were identified. Hyperproduction of AmpC ß-lactamase had the lowest prevalence rate (3.97%). It was concluded that CR-MDR P. aeruginosa clinical isolates in Thailand possess multifactorial resistance mechanisms.

Comparison of the mathematical equation and trapezoidal approach for 24 h area under the plasma concentration-time curve calculation in patients who received intravenous vancomycin in an acute care setting.

The current recommendation for therapeutic monitoring of vancomycin has recently suggested AUC-guided dosing in patients with serious methicillin-resistant Staphylococcus aureus infections. The study objective was to evaluate mathematical equations and trapezoidal methods for calculating the 24 h area under the plasma vancomycin concentration-time curve (AUC24). The analysis of plasma vancomycin concentrations was performed in 20 adult patients treated with intravenous vancomycin. For each patient, AUC24 was estimated using two methods including, equation and trapezoidal calculation. The AUC24 from two methods was analyzed for correlation. The correlation between the equation and trapezoidal methods was strong. The coefficient of determination (R2 ) values was greater than .99. The two plasma vancomycin concentrations to achieve the highest correlation were concentration at 2.5 to 3 h after starting the infusion and concentration at 1 h before the next dose. Moreover, the AUC24 calculation from trapezoidal and equation methods showed that 19 out of 20 patients (95%) had AUC24 of more than 400 mg·h/L, and more than 50% in this group had AUC24/MIC greater than 600. Of those patients with AUC-trapezoidal >600, 15.38% of patients had trough under 15 mg/L, 15.38% of patients had trough in the range 15 to 20 mg/L and 69.23% of patients had trough more than 20 mg/L. The results of AUC-equation were similar to those of the AUC-trapezoidal method. Our study confirmed that the AUC monitoring is more appropriate than the trough vancomycin concentration. Given these considerations, the AUC-equation method is better and more practical to use in part of a point-of-care treatment, especially in the part of the Bayesian program is not available. The best sampling time point of the peak concentration was 0.5-1 h after 2-h infusion.

Pharmacokinetic/pharmacodynamic (PK/PD) simulation for dosage optimization of colistin and sitafloxacin, alone and in combination, against carbapenem-, multidrug-, and colistin-resistant Acinetobacter baumannii.

To the best of our knowledge, to date, no study has investigated the optimal dosage regimens of either colistin or sitafloxacin against drug-resistant Acinetobacter baumannii (A. baumannii) infections by using specific parameters. In the current study, we aimed to explore the optimal dosage regimens of colistin and sitafloxacin, either in monotherapy or in combination therapy, for the treatment of carbapenem-, multidrug-, and colistin-resistant A. baumannii infections. A Monte Carlo simulation was applied to determine the dosage regimen that could achieve the optimal probability of target attainment (PTA) and cumulative fraction of response (CFR) (≥90%) based on the specific parameters of each agent and the minimal inhibitory concentration (MIC) of the clinical isolates. This study explored the dosage regimen of 90, 50, 30, and 10 mL/min for patients with creatinine clearance (CrCL). We also explored the dosage regimen for each patient with CrCL using combination therapy because there is a higher possibility of reaching the desired PTA or CFR. Focusing on the MIC90 of each agent in combination therapy, the dosage regimen for colistin was a loading dose of 300 mg followed by a maintenance dose ranging from 50 mg every 48 h to 225 mg every 12 h and the dosage regimen for sitafloxacin was 325 mg every 48 h to 750 mg every 12 h. We concluded that a lower-than-usual dose of colistin based on specific pharmacokinetic data in combination with a higher-than-usual dose of sitafloxacin could be an option for the treatment of carbapenem-, multidrug-, and colistin-resistant. A. baumannii. The lower dose of colistin might show a low probability of adverse reaction, while the high dose of sitafloxacin should be considered. In the current study, we attempted to find if there is a strong possibility of drug selection against crucial drug-resistant pathogen infections in a situation where there is a lack of new antibiotics. However, further study is needed to confirm the results of this simulation study.

A randomized, controlled trial of prulifloxacin as conversion therapy after intravenous carbapenem in the treatment of acute pyelonephritis caused by third generation cephalosporin resistant pathogens: A pilot study.

The efficacy of converting to oral fluoroquinolones after initial intravenous antibiotics for the treatment of acute pyelonephritis (APN) caused by the third-generation cephalosporin resistant Enterobacteriaceae (3-GCrEC) needs to be investigated. The objective was to compare the clinical and bacteriological outcome of oral prulifloxacin with intravenous ertapenem for the treatment of APN caused by 3-GCrEC. A pilot, randomized controlled trial of patients with APN caused by 3-GCrEC was conducted at two hospitals from August 2015 to December 2020. Any intravenous antimicrobial drug was initially permitted for empirical therapy. On day 4, adult patients (aged >18 years) with either non-bacteremic or bacteremic APN were eligible for the study if their infection was caused by 3-GCrEC susceptible to the study drugs. The patients were randomly assigned to receive either oral prulifloxacin or intravenous ertapenem. The total duration of antimicrobial therapy was 14 days. Of the 21 enrolled patients, 11 were treated with prulifloxacin, and 10 were treated with ertapenem. At the test of cure visit, there was no statistically significant difference between the patients with overall clinical success who were treated with prulifloxacin (90.9%) and those treated with ertapenem (100%, p = 0.999). In addition, there was no statistically significant difference in microbiological eradication between the prulifloxacin and ertapenem groups (100% vs. 100%, p = 0.999). The converting to oral prulifloxacin after intravenous antibiotics therapy appears to be an alternative option for treatment of APN caused by 3-GCrEC. A further large randomized controlled trial should be investigated.

Prevalence and genotypic relatedness of carbapenem resistance among multidrug-resistant P. aeruginosa in tertiary hospitals across Thailand.

BACKGROUND: Increased infection caused by multidrug resistant (MDR) Pseudomonas aeruginosa has raised awareness of the resistance situation worldwide. Carbapenem resistance among MDR (CR-MDR) P. aeruginosa has become a serious life-threatening problem due to the limited therapeutic options. Therefore, the objectives of this study were to determine the prevalence, the antibiotic susceptibility patterns and the relatedness of CR-MDR P. aeruginosa in tertiary hospitals across Thailand. METHODS: MDR P. aeruginosa from eight tertiary hospitals across Thailand were collected from 2007-2009. Susceptibility of P. aeruginosa clinical isolates was determined according to the Clinical and Laboratory Standards Institute guideline. Selected CR-MDR P. aeruginosa isolates were genetically analyzed by pulsed-field gel electrophoresis. RESULTS: About 261 clinical isolates were identified as MDR P. aeruginosa and approximately 71.65% were found to be CR-MDR P. aeruginosa. The result showed that the meropenem resistance rate was the highest reaching over 50% in every hospitals. Additionally, the type of hospitals was a major factor affecting the resistance rate, as demonstrated by significantly higher CR-MDR rates among university and regional hospitals. The fingerprinting map identified 107 clones with at least 95% similarity. Only 4 clones were detected in more than one hospital. CONCLUSIONS: Although the antibiotic resistance rate was high, the spreading of CR-MDR was found locally. Specific strains of CR-MDR did not commonly spread from one hospital to another. Importantly, clonal dissemination ratio indicated limited intra-hospital transmission in Thailand.

Correlation between Carbapenem Consumption and Carbapenems Susceptibility Profiles of Acinetobacter baumannii and Pseudomonas aeruginosa in an Academic Medical Center in Thailand.

The emergent issue of carbapenem-resistant Acinetobacter baumannii (A. baumannii) and Pseudomonas aeruginosa (P. aeruginosa) is a major problem in Thailand. The wide use of carbapenems can increase selective pressure of bacterial resistance. The objective of this study was to determine the relationship between carbapenem consumption and the susceptibility rates of A. baumannii and P. aeruginosa, including multi-drug resistance (MDR) strains. This was a retrospective study. Carbapenem consumption and susceptibility profiles were collected from 2007 to 2013 at the Her Royal Highness Princess Maha Chakri Sirindhorn Medical Center, Thailand. We found that the susceptibility rate of A. baumannii to imipenem and meropenem from the sputum and the bronchoalveolar lavage (BAL) specimens was significantly decreased during the study period, but no significant change was found in the P. aeruginosa data. The relationship between carbapenem consumption and the susceptibility rate of A. baumannii had a clear association with the use of ertapenem. We found a statistically significant negative correlation between ertapenem consumption and the susceptibility rate of A. baumannii to imipenem (r = -0.91; p = 0.004) and meropenem (r = -0.97; p = 0.000) in the data from the non-ICU wards. In addition, imipenem use had a moderate negative correlation with the MDR P. aeruginosa data but no statistical significance (r = -0.714; p > 0.05). In conclusion, our study suggested there is an association between carbapenem use and the susceptibility of A. baumannii and P. aeruginosa. Notwithstanding this, information on ecological factors should be considered for further study. These findings showed the need to optimize the carbapenem prescription policy. Avoiding carbapenem overuse and rethinking the appropriate initial therapy might decrease the rate of resistant organisms.

The Evaluation of Meropenem Dosing Regimens Against ESBL-Producing Escherichia coli in ICU Patients Using Monte Carlo Simulation.

PURPOSE: To evaluate the optimal dosing regimens of meropenem against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL E. coli) in critically ill patients with varying degrees of renal function using Monte Carlo simulation (MCS). METHODS: The MCS was performed using the minimum inhibitory concentration (MIC) data from Right Laboratory and Health Screen in Naypyitaw, Myanmar, as well as reported meropenem pharmacokinetic parameters in the target population and the pharmacokinetic-pharmacodynamic index. For each dosing regimen, 10,000 virtual patients were generated to assess the probability of target attainment (PTA) and the cumulative fraction of response (CFR). The most effective dosage regimens were determined using PTA and a CFR of 90%. RESULTS: ESBL E. coli made up 93 of the 396 clinical E. coli isolates, and they are all multidrug-resistant, with resistance to at least five antibiotic classes. The MIC50 and MIC90 were determined to be 0.25 µg/mL. The PTA was affected by five factors: creatinine clearance (CLcr), vasopressor usage, MIC, infusion time, and dosage fractionation. In patients who did not receive vasopressors, the current regimens (US-FDA and EMA) were ineffective in all renal function for MIC >0.25µg/mL. In the subset group of CLcr >80 mL/min for MIC 2µg/mL, the maximum total daily dose of 6g/day (2g q 8hr; 3hr infusion) was still ineffective, but 4g/day (1g q 6hr; 3hr infusion) achieved 98.96% PTA. Almost majority of the simulated regimens produced >90% PTA in vasopressor-dependent patients with all levels of renal function, resulting in a decreased total daily dose requirement. CONCLUSION: For high MIC (>1µg/mL) patients who do not use vasopressors and have a CLcr >80 mL/min, a combination of dosage fractionation and the extended infusion was considered as an effective technique to maximize target attainment. Neither prolonged infusion nor dosage fractionation should be explored in patients using vasopressors.

Impact of an infectious diseases pharmacist-led intervention on antimicrobial stewardship program guideline adherence at a Thai medical center.

PURPOSE: To evaluate and compare antimicrobial stewardship program (ASP) guideline adherence (primary outcome) as well as length of stay, 30-day all-cause mortality, clinical cure, antimicrobial consumption, and incidence of multidrug-resistant (MDR) pathogens (secondary outcomes) between an infectious diseases (ID) pharmacist-led intervention group and a standard ASP group. METHODS: A quasi-experimental study was performed at Thammasat University Hospital between August 2019 and April 2020. Data including baseline characteristics and primary and secondary outcomes were collected from the electronic medical record by the ID pharmacist. RESULTS: The ASP guideline adherence in the ID pharmacist-led intervention group was significantly higher than in the standard ASP group (79% vs 56.6%; P < 0.001), especially with regard to appropriate indication (P < 0.001), dosage regimen (P = 0.005), and duration (P = 0.001). The acceptance rate of ID pharmacist recommendations was 81.8% (44/54). The most common key barriers to following recommendations were physician resistance (11/20; 55%) and high severity of disease in the patient (6/20; 30%). Compared to the standard ASP group, there was a trend toward clinical cure in the ID pharmacist-led intervention group (63.6% vs 56.1%; P = 0.127), while 30-day all-cause mortality (15.9% vs 1.5%; P = 0.344) and median length of stay (20 vs 18 days; P = 0.085) were similar in the 2 groups. Carbapenem (P = 0.042) and fosfomycin (P = 0.014) consumption declined in the ID pharmacist-led intervention group. A marginally significant decrease in the overall incidence of MDR pathogens was also observed in the ID pharmacist-led intervention group (coefficient, -5.93; P = 0.049). CONCLUSION: Our study demonstrates that an ID pharmacist-led intervention can improve ASP guideline adherence and may reduce carbapenem consumption.

Efficacy comparison between oral erythromycin versus domperidone for the treatment of feeding intolerance in preterm neonates.

BACKGROUND: Domperidone and erythromycin are commonly used as prokinetic agents for feeding intolerance in preterm neonates; however, no data from a previous study have compared their efficacy. This study aimed to compare the efficacy of orally administered domperidone and erythromycin for the treatment of feeding intolerance in preterm infants. METHODS: This retrospective cohort study included preterm neonates with a birthweight of <1800 g and gestational age <37 weeks. Data were collected from medical records at Queen Sirikit National Institute of Child Health (QSNICH) from 2006 to 2014. The primary outcome was the time to establish full enteral feeding (150 ml/kg/day) after starting oral domperidone or erythromycin for the treatment of feeding intolerance in preterm neonates. The secondary outcome was adverse effects associated with domperidone and erythromycin therapy. RESULTS: Among the 150 preterm neonates enrolled in this study, 66 received domperidone, and 84 received erythromycin. The baseline characteristics and comorbidities were not significantly different between the two groups; however, the gestational age at birth of neonates in the domperidone group was significantly lower than that of those in the erythromycin group. The time to establish full enteral feeding did not differ between the domperidone (11 days, "IQR," [6, 17]) and erythromycin (10 days, IQR [7, 14]) groups (p = 0.622). No major adverse effects were noted. There were only three preterm infants who had elevated liver enzymes in each group, but the difference between groups was not significant. CONCLUSION: From this study, the efficacy of oral domperidone was promising equivalent to oral erythromycin and seems to be one of the treatment options for feeding intolerance in preterm neonates. However, large randomized, controlled trials are needed to confirm the efficacy and safety of domperidone in this population.

Pharmacist-Driven Antibiotic Stewardship Program in Febrile Neutropenic Patients: A Single Site Prospective Study in Thailand.

The antibiotic stewardship program (ASP) is a necessary part of febrile neutropenia (FN) treatment. Pharmacist-driven ASP is one of the meaningful approaches to improve the appropriateness of antibiotic usage. Our study aimed to determine role of the pharmacist in ASPs for FN patients. We prospectively studied at Thammasat University Hospital between August 2019 and April 2020. Our primary outcome was to compare the appropriate use of target antibiotics between the pharmacist-driven ASP group and the control group. The results showed 90 FN events in 66 patients. The choice of an appropriate antibiotic was significantly higher in the pharmacist-driven ASP group than the control group (88.9% vs. 51.1%, p < 0.001). Furthermore, there was greater appropriateness of the dosage regimen chosen as empirical therapy in the pharmacist-driven ASP group than in the control group (97.8% vs. 88.7%, p = 0.049) and proper duration of target antibiotics in documentation therapy (91.1% vs. 75.6%, p = 0.039). The multivariate analysis showed a pharmacist-driven ASP and infectious diseases consultation had a favorable impact on 30-day infectious diseases-related mortality in chemotherapy-induced FN patients (OR 0.058, 95%CI:0.005-0.655, p = 0.021). Our study demonstrated that pharmacist-driven ASPs could be a great opportunity to improve antibiotic appropriateness in FN patients.

Colistin Dosing Regimens against Pseudomonas aeruginosa in Critically Ill Patients: An Application of Monte Carlo Simulation.

Our aims are to assess various colistin dosing regimens against Pseudomonas aeruginosa (P. aeruginosa) infection in critically ill patients and to propose an appropriate regimen based on microbiological data. A Monte Carlo simulation was performed using the published colistin's pharmacokinetic parameters of critically ill patients, the published pharmacodynamic target from a mouse thigh infection model, and the minimum inhibitory concentration (MIC) results from a Vietnamese hospital. The probability of target attainment (PTA) of 80% and cumulative fraction of response (CFR) of 90% were used to evaluate the efficacy of each regimen. Of 121 P. aeruginosa laboratory datasets, the carbapenem-resistant P. aeruginosa (CRPA) and the colistin-resistant P. aeruginosa rates were 29.8% and 0.8%, respectively. MIC50,90 were both 0.5 mg/L. The simulated results showed that at MIC of 2 mg/L, most regimens could not reach the PTA target, particularly in patients with normal renal function (Creatinine clearance (CrCl) ≥ 80 mL/min). At MIC of 0.5 mg/L and 1 mg/L, current recommendations still worked well. On the basis of these results, aside from lung infection, our study recommends three regimens against P. aeruginosa infection at MIC of 0.5 mg/L, 1 mg/L, and 2 mg/L. In conclusion, higher total daily doses and fractionated colistin dosing regimens could be the strategy for difficult-to-acquire PTA cases, while a less aggressive dose might be appropriate for empirical treatment in settings with low MIC50/90.

In Vitro Activities of Colistin and Sitafloxacin Combinations against Multidrug-, Carbapenem-, and Colistin-Resistant Acinetobacter baumannii Using the Broth Microdilution Checkerboard and Time-Kill Methods.

Drug-resistant Acinetobacter baumannii (A. baumannii) infections are a critical global problem, with limited treatment choices. This study aims to determine the in vitro activities of colistin-sitafloxacin combinations against multidrug-, carbapenem- and colistin-resistant A. baumannii (MDR-AB, CRAB, CoR-AB, respectively) clinical isolates from tertiary care hospitals. We used the broth microdilution checkerboard and time-kill methods in this study. Synergy was found using both methods. The colistin-sitafloxacin combination showed synergy in MDR-AB, CRAB, and CoR-AB isolates (3.4%, 3.1%, and 20.9%, respectively). No antagonism was found in any type of drug-resistant isolate. The majority of CoR-AB isolates became susceptible to colistin (95.4%). The time-kill method also showed that this combination could suppress regrowth back to the initial inocula of all representative isolates. Our results demonstrated that the colistin-sitafloxacin combination might be an interesting option for the treatment of drug-resistant A. baumannii. However, further in vivo and clinical studies are required.