Preecha Montakantikul

Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: the PASSPORT Program—Asia-Pacific Region

Due to escalating antimicrobial resistance amongst Gram-negative organisms, the choice of effective empirical antimicrobial regimens has become challenging. Monte Carlo simulations were conducted for conventional and prolonged infusion regimens of doripenem, imipenem and meropenem using pharmacokinetic data from adult patients with conserved renal function. Minimum inhibitory concentration data against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii were incorporated from the COMPACT surveillance programme in the Asia-Pacific region of the world. The cumulative fraction of response (CFR) was determined for each regimen against each bacterial population. All simulated carbapenem regimens achieved an optimal CFR against E. coli and K. pneumoniae (94.5-100% CFR). Against P. aeruginosa, doripenem achieved 78.7-92.6% CFR, imipenem achieved 60.4-79.0% CFR and meropenem achieved 73.0-85.1% CFR. The only dosing regimen to achieve ≥ 90% CFR against P. aeruginosa was doripenem 1000 mg and 2000 mg every 8 h (4-h infusion). Carbapenem CFRs against A. baumannii were much lower (29.2-54.4% CFR). CFRs for non-fermenting isolates were ca. 10% lower for isolates collected in the Intensive Care Unit. Carbapenem resistance amongst Enterobacteriaceae remains low in the Asia-Pacific region and thus standard carbapenem dosing regimens had a high likelihood of achieving pharmacodynamic exposures. However, larger doses combined with prolonged infusion will be required to increase the CFR for these carbapenems against resistant non-fermenting Gram-negatives that are common in these countries. The safety and efficacy of these high dosing regimens will need to be confirmed in the clinical setting.

The Safety of Antituberculosis Medications During Breastfeeding

Most antituberculosis drugs appear to be safe for use with breastfeeding. These agents are excreted in breast milk at relatively small concentrations. No adverse effects have been reported to date. The percentages of the therapeutic dose of antituberculosis agents that potentially may be delivered to the nursing infants range from 0.05% to 28%. Currently isoniazid, rifampin, ethambutol, streptomycin (first-line agents), kanamycin and cycloserine (second-line agents) are the only agents considered by the AAP to be compatible with breastfeeding. Unfortunately, there are still no clear data on the safety of pyrazinamide, ethionamide, and capreomycin during breastfeeding. If the mother chooses to breastfeed, it may be prudent to examine the infant for signs and symptoms of toxicity. In infants requiring treatment with antituberculosis agents, it is important to use therapeutic doses since drug concentrations in breast milk are not adequate as effective therapy for treatment or prevention. However, dosing at the lower end of the therapeutic range should be prescribed (i.e., 10 mg/kg/day of isoniazid) to decrease the risk of toxicity.

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‐β‐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 β‐lactamase had the lowest prevalence rate (3.97%). It was concluded that CR‐MDR P. aeruginosa clinical isolates in Thailand possess multifactorial resistance mechanisms.

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

BackgroundIncreased 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.MethodsMDR 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.ResultsAbout 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.ConclusionsAlthough 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.

Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation

OBJECTIVE The purpose of the study was to determine the optimal dosing regimen of intravenous fosfomycin for the treatment of Pseudomonas aeruginosa (PA) based on PK/PD targets. METHOD A total of 120 PA isolates were recovered from various clinical specimens at university hospital in Thailand. Minimum Inhibitory Concentrations (MICs) of all the isolates were determined by the E-test method. PK parameters were obtained from a published study. Monte Carlo simulation was performed to calculate the percentage of target attainment (PTA) and cumulative fraction of response (CFR). RESULTS MIC90 of fosfomycin alone, fosfomycin in combination with carbapenem, carbapenems alone and carbapenems in combination with fosfomycin were >1,024, 1,024, >32 and 32μg/ml, for multidrug resistant (MDR)-PA and 512, 128, 8 and 3μg/ml respectively, for non-MDR PA. Approximately 40% of the non-MDR PA were carbapenem-resistant strains. For non-MDR PA with CRPA, fosfomycin 16g continuous infusion in combination with carbapenems provided %PTA of approximately 80 and %CFR of > 88. While, %PTA and %CFR > 90 were achieved with fosfomycin 24g/day prolonged infusion in combination with carbapenem. CONCLUSIONS Prolonged infusion of fosfomycin 16 - 24g combined with extended carbapenem infusion could be used in non-MDR PA treatment with CRPA.

A prospective, randomized, double dummy, placebo-controlled trial of oral cefditoren pivoxil 400 mg once daily as switch therapy after intravenous ceftriaxone in the treatment of acute pyelonephritis

OBJECTIVES To compare the clinical and bacteriological effectiveness of intravenous (IV) ceftriaxone followed by oral cefditoren pivoxil or IV ceftriaxone for acute pyelonephritis. METHODS A prospective randomized controlled trial of patients with a presumptive diagnosis of acute pyelonephritis was performed. Daily 2g IV ceftriaxone was initially given to all patients. After day 3, patients who satisfied the criteria for switch therapy were randomized to either group A (IV ceftriaxone) or group B (oral cefditoren pivoxil 400mg once daily). RESULTS Eighty-two patients were enrolled; 41 (50%) patients in group A and 41 (50%) patients in group B were evaluated. There was no statistically significant difference in baseline characteristics between the two groups. Clinical cure was observed in 39 of 41 (95.1%) patients in group A and 41 of 41 (100%) patients in group B (p=0.15, 95% confidence interval (CI) -0.12 to 0.02). Urine bacteriological eradication was found in 63.4% in group A and 60% in group B (p=0.75, 95% CI -0.18 to 0.25). There was no statistically significant difference in adverse effects between the two treatment groups. CONCLUSION These data suggest that IV ceftriaxone followed by oral cefditoren pivoxil is highly effective and well-tolerated for the treatment of acute pyelonephritis, even for uropathogens with a high proportion of quinolone-resistant strains.

Effectiveness of Tobacco Education for Pharmacy Students in Indonesia

BACKGROUND Smoking remains the major preventable cause of death worldwide, especially cancer-related death. Evidence clearly indicates that tobacco-related morbidity and mortality is reduced by smoking cessation. Pharmacists are well-positioned to provide tobacco cessation services an involvement of pharmacists in smoking cessation is encouraged by several organizations. While Indonesias prevalence of smoking is in the first rank in Asian countries, none of the pharmacy schools in Indonesia are currently offering tobacco-related courses in their existing curricula at present. Our study aimed to develop and to evaluate the effectiveness of tobacco education (TE) for pharmacy students in Indonesia. MATERIALS AND METHODS A 6-hour TE was developed and evaluated using pre-test/post-test with control group design. A total of 137 fifth-year pharmacy students at Gadjah Mada University (GMU), Yogyakarta, were chosen as an intervention group while a total of 105 fifth-year students of Islamic University of Indonesia, (UII) served as the control group. Knowledge, perceived-role, self-efficacy, and ability to perform counseling using the 5As framework were evaluated. RESULTS A significant improvement (P < 0.001) in knowledge, perceived-role, and self-efficacy was found in the intervention group but not in the control group. In addition, we revealed that 89.7% of the intervention group were able to perform counseling using 5As. CONCLUSIONS The developed TE significantly improved student knowledge, perceived-rolse, self-efficacy, and created an ability to perform cessation counseling. Integration of TE education in curricula of Indonesian pharmacy schools nation-wide should be encouraged.

In vitro synergistic activity of biapenem combination with sulbactam, colistin, and fosfomycin sodium against multidrug-resistant Acinetobacter baumannii isolates from tertiarycare hospitals in Thailand

Abstract Background Acinetobacter baumannii has become a major cause of nosocomial infections worldwide due to highly resistance to various groups of antibacterial agents. This in vitro study was determine the MICs for sulbactam, colistin, fosfomycin sodium individually and synergistic activity of both in combination with biapenem against multidrug-resistant A. baumannii. Methods The MICs and synergistic interaction of sulbactam, colistin, fosfomycin sodium and biapenem were determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines (2016) by the chequerboard technique. 40 clinical MDR-Acinetobacter baumannii isolates from 13 tertiarycare hospitals in Thailand were tested. The synergistic effect was evaluated by the fractional inhibitory concentration index (FICI). Results The MICs for MDR- Acinetobacter baumannii results of biapenem and other agents are shown in Figure 1. The FICI results showed all 40 strains (100%) had an FICI ≤ 0.5, suggesting a synergistic effect of colistin in combination with biapenem (Table 1). MICs of mostly strains were decreased two to four doubling dilutions for both antibacterial agents. Moreover, 95% of isolates have MICs to colistin and fosfomycin sodium lower than sensitivity breakpoint when combined with biapenem. The result showed no data on the antagonistic effect (FICI ˃4) of all biapenem-based combination. Conclusion The combination of colistin or fosfomycin sodium with biapenem show synergistic pattern and MICs improvement for all strains. For that reason, the use of colistin, fosfomycin sodium combined with biapenem could be a promising treatment option for MDR- Acinetobacter baumannii.FIGURE 1. MIC for multidrug resistant Acinetobacter baumannii biapenem (n = 63), sulbactam (n = 40), colistin (n = 40), and fosfomycin sodium(n = 40).TABLE 1. Synergistic effect of sulbactam, colistin, and fosfomycin sodium with biapenem against MDR A. baumannii (n = 40) by using the checkerboard assay Effect Number of Isolates (%) Sulbactam + Biapenem Colistin + Biapenem Fosfomycin sodium + 
Biapenem Synergy (FICI≤0.5) 30 (75) 40 (100) 33 (82.5) Partial synergy (FICI>0.5-<1) 9 (20) 0 7 (17.5) Additive (FICI=1) 1 (5) 0 0 Indifference (FICI>1-≤4) 0 0 0 Antagonism (FICI>4) 0 0 0 Disclosures J. Houngsaitong, Thai Meiji Co.,Ltd: No relationship, Research grant