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.

Does amiodarone impact on apixaban levels? The effect of amiodarone on apixaban level among Thai patients with non-valvular Atrial Fibrillation.

BACKGROUND: Apixaban and amiodarone are drugs used for non-valvular atrial fibrillation (NVAF) in routine practice. The evidence about apixaban plasma levels in patients who receive apixaban with amiodarone, including bleeding outcomes, has been limited. This study aimed to compare the apixaban plasma levels and bleeding outcomes between apixaban monotherapy and apixaban with amiodarone groups. METHODS: This study was a prospective, observational, and single-center research which was conducted from January 2021 to January 2022 in NVAF patients who received apixaban at a tertiary care hospital located in the center of Bangkok, Thailand. RESULTS: Thirty-three patients were measured for their median (5th-95th percentile) apixaban plasma levels. The trough of apixaban plasma level (Ctrough) were 108.49 [78.10-171.52] and 162.05 [87.94-292.88] µg/L in the apixaban monotherapy and apixaban with amiodarone groups, respectively (p = 0.028). Additionally, the peaks of apixaban plasma level (Cpeak) were 175.36 [122.94-332.34] and 191 [116.88-488.21] µg/L in the apixaban monotherapy and apixaban with amiodarone groups, respectively (p = 0.375). There was bleeding that occurred in 7 patients (21.21%); 5 patients in the apixaban monotherapy group and 2 patients in the apixaban with amiodarone group, respectively. CONCLUSIONS: Amiodarone may increase the peaks and troughs of apixaban plasma levels. The co-administration of apixaban with amiodarone is generally well tolerated. However, the careful observation of bleeding symptoms in individual cases is necessary to ensure safety.

The Activities of Antimicrobials Against Stenotrophomonas maltophilia Isolates and Evaluation of Clinical Outcomes Among Treatment Regimens in Patients with Stenotrophomonas maltophilia Infections: A Retrospective Multicenter Cohort Study.

Purpose: Stenotrophomonas maltophilia, a multidrug-resistant pathogen can cause hospital-acquired infections such as pneumonia, or bloodstream infection. S. maltophilia infection is associated with high mortality rates. This retrospective study examined the antimicrobial susceptibility profile of clinical S. maltophilia isolates and evaluated clinical outcomes, treatment regimens, and risk factors associated with 30-day mortality or treatment failure of S. maltophilia infections at three tertiary care hospitals in Central Thailand. Patients and Methods: The characteristics, microbiological data, and clinical treatment outcomes were derived from medical records obtained from three tertiary care hospitals in Central Thailand from January 2017 to October 2022. The primary outcomes were treatment failure and 30-day mortality. The antimicrobial susceptibility rates of trimethoprim-sulfamethoxazole (TMP-SMX), levofloxacin, and ceftazidime were determined by minimum inhibitory concentration (MIC), which were based on broth microdilution and clear zone diameters using the disk diffusion method. However, we also report the susceptibility of minocycline and tigecycline in some clinical S. maltophilia strains (n = 149) and determined by MIC with E-test method. Results: The antimicrobial susceptibility rates to TMP-SMX, levofloxacin, and ceftazidime were 97.1%, 93%, and 55.3%, respectively. The treatment failure rate and 30-day mortality were 66.3% and 49%, respectively. Significant factors associated with treatment failure included APACHE II score ≥15 (OR 3.37, 95% confidence interval (CI) 1.46-7.76), polymicrobial infections (OR 3.20, 95% CI 1.35-7.55). The significant factors associated with reduced treatment failure was treatment with TMP-SMX-based regimen (OR 0.29, 95% CI 0.11-0.76). The 30-day mortality rate was associated with APACHE II score ≥15 (OR 3.27, 95% CI 1.45-7.39) and septic shock (OR 2.53, 95% CI 1.36-4.69). Conclusion: The results indicate a high mortality rate for S. maltophilia infection. The predictive factors for an unfavourable outcome were severity of illness, septic shock, and non-use of TMP-SMX. Therefore, a TMP-SMX-based regimen is recommended for the treatment of S. maltophilia infections.

Telepharmacy during home isolation: drug-related problems and pharmaceutical care in COVID-19 patients receiving antiviral therapy in Thailand.

BACKGROUND: Home isolation has been proposed for coronavirus disease 2019 (COVID-19) patients with mild symptoms to avoid hospital overcrowding. This study aimed to describe the drug-related problems (DRPs) and the pharmaceutical care of home-isolating COVID-19 patients in Thailand. METHODS: Our cross-sectional study was undertaken from July 1 to September 30, 2021, at the King Chulalongkorn Memorial Hospital, Thailand. Patients who were ≥ 18 years old, were diagnosed with mild COVID-19 by real-time polymerase chain reaction (RT-PCR), and were able to isolate at home while receiving an antiviral agent and standard symptomatic treatment were enrolled. Infectious disease pharmacists provided a telepharmacy service on days 1 and 3 after the COVID-19 diagnosis. RESULTS: A total of 197 patients met the study criteria. Their median age was 45 years, and their most common underlying disease was hypertension (44.29%). All patients exhibited excellent anti-COVID-19 drug adherence. We identified 125 DRPs, including adverse reactions (68%), and the unnecessary use of products (62.40%). Moreover, 91 patients (46.19%) reported the use of supplements or herbs, with vitamin C being the main supplement (37.36%). Pharmacists provided 36 recommendations and received 33 questions from COVID-19 patients. CONCLUSIONS: Our study demonstrates that telepharmacy is an essential service for detecting and preventing DRPs in home-isolating COVID-19 patients.

Incidence of urticaria, angioedema, and type I hypersensitivity reactions associated with fibrinolytic agents in Thailand using the database of the health product vigilance center.

BACKGROUND: Besides hemorrhage, allergic reactions have also been observed in several clinical trials of fibrinolytic agents. These reactions might negatively affect patient outcomes, especially life-threatening type I hypersensitivity reactions such as anaphylaxis. However, there are limited data on the incidence of these reactions. OBJECTIVE: The aim of study was to analyze the incidence of urticaria, angioedema, and type I hypersensitivity reactions from fibrinolytic agents for various indications. METHODS: A retrospective analysis of data from the Thai Vigibase database was conducted. All reports of adverse drug reactions from fibrinolytic agents from 1984 to 2017 were identified using the World Health Organization adverse reaction terminology. The proportion of each suspected adverse drug reaction and the cumulative incidence were calculated. RESULTS: A total of 284 reports were identified in the Thai Vigibase database. The overall incidence of urticaria, angioedema, and type I hypersensitivity reactions for the streptokinase group was 52.64/10,000 persons, with individual incidence rates of 9.64/10,000 persons for urticaria, 8.90/10,000 persons for angioedema, and 34.11/10,000 persons for type I hypersensitivity reactions. In the alteplase group, the overall incidence for all suspected reactions was 18.90/10,000 persons, with individual incidence rates of 3.29/10,000 persons for urticaria, 5.75/10,000 persons for angioedema, and 9.86/10,000 persons for type I hypersensitivity reactions. CONCLUSIONS: Type I hypersensitivity reactions were the most common allergic reactions from fibrinolytic agents. It is necessary to take these reactions into consideration when using fibrinolytic therapy.

Characteristics of immediate hypersensitivity reaction to paclitaxel-based chemotherapy in gynecologic cancer patients.

BACKGROUND: Immediate hypersensitivity reactions (IHRs) are commonly found in patients receiving paclitaxel. Effects of paclitaxel vary because of variable co-therapy or re-challenge with paclitaxel. OBJECTIVE: Our objective was to investigate the incidence, patterns, and risk factors for paclitaxel-related IHRs and management of IHRs in gynecologic malignancy patients. METHODS: This retrospective study was performed in gynecologic cancer patients receiving paclitaxel-based regimens at Siriraj hospital from January 2012 to December 2017. RESULTS: 416 subjects were included and received ranitidine 50 mg, dexamethasone 20 mg, ondansetron 16 mg intravenously and diphenhydramine 50 mg orally 30 minutes before starting chemotherapy. The incidence of IHRs was 17.79%. IHRs occurring on first exposure to paclitaxel was 81.1% and occurred within 30 minutes after starting paclitaxel. The most commonly found presentation of IHRs were skin reactions (86.5%). In multivariate analysis, age < 54.5 years, stage of cancer < 2, and leukocyte cell count < 7.735 × 109/L were significantly associated with IHRs. Seventy-two out of 74 patients that recovered from IHRs were reintroduced paclitaxel. Forty-seven patients (97.92%) of 48 patients with mild reactions were successfully reintroduced to paclitaxel after treatment with chlorpheniramine or other interventions. CONCLUSIONS: The incidence of paclitaxel-related IHRs was about one in five. Skin reactions were the most commonly occurring reactions. Younger age, stage of cancer < 2, and leukocytes < 7.735 × 109/L were significant risk factors for IHRs. Patients with IHRs recovered without the use of dexamethasone and antihistamines before the reintroduction of paclitaxel.

Metabolomics profiling of culture medium reveals association of methionine and vitamin B metabolisms with virulent phenotypes of clinical bloodstream-isolated Candida albicans.

Candida albicans is a predominant species causing candidemia in hospitalized patients. This study aimed to investigate the association of culture medium metabolomic profiles with biofilm formation and invasion properties of clinical bloodstream-isolated C. albicans. A total of twelve isolates and two reference strains were identified by virulent phenotypes. Their susceptibility was determined by the microdilution method, following EUCAST guidelines. Biofilm formation was evaluated with metabolic activity, morphology and agglutinin-like sequence 3 (ALS3) mRNA expression. Invasion into the vascular endothelial EA.hy926 cells was determined by lactate dehydrogenase release and internalization assay. Their metabolomic profiles were assessed by high-resolution accurate-mass spectrometry (HRAMS). The results showed four different phenotypes of C. albicans: high-biofilm/invasive (50%), high-biofilm/non-invasive (7%), low-biofilm/invasive (36%) and low-biofilm/non-invasive (7%). The metabolomic profiles of the culture medium determined strong correlation of the virulent phenotypes and the alteration of metabolites in the methionine metabolism pathway, such as homocysteine, 5-methyltetrahydrofolate and S-adenosylmethioninamine. Moreover, thiamine and biotin levels were significantly increased in Isolate03, representative of a high-biofilm/invasive phenotype. These results suggest that methionine and vitamin B metabolism pathways might be influenced by their virulent phenotypes and pathogenic traits. Therefore, their metabolism pathways might be a potential target for reducing virulence of C. albicans bloodstream infections.

Clinical Impact of Vancomycin Treatment in Ampicillin-Susceptible Enterococci Bloodstream Infections.

Enterococci are major causes of bacteremia. Although the mortality rate of ampicillin- susceptible enterococci (ASE) bloodstream infections (BSI) is lower, compared with that of ampicillin-resistant enterococci BSI, the role of treatment regimens in ASE BSI remains to be determined. This retrospective study aimed to evaluate the treatment outcomes and factors associated with mortality among patients with ASE BSI. The charts of 145 enrolled patients with ASE BSI between January 2013 and April 2022 at Phramongkutklao Hospital were reviewed. The 30-day and in-hospital mortality rates were 28.8 and 41.9%, respectively. The 30-day mortality rate was higher in the vancomycin treatment group than in the beta-lactam treatment group (61.5 vs. 26%; p = 0.02). Pitt bacteremia score (OR 1.44, 95% CI 1.20-1.71); age-adjusted Charlson Comorbidity Index (OR 1.34, 95% CI 1.14-1.58); and vancomycin treatment (OR 4.07, 95% CI 1.02-16.22) were independent factors associated with 30-day mortality. The severity of illness, comorbidity and definitive therapy with vancomycin increased the mortality rate of patients with ASE BSI. Anti-enterococcal beta-lactams remain the first line antibiotics for ASE bacteremia.

Combination Therapy versus Monotherapy in the Treatment of Stenotrophomonas maltophilia Infections: A Systematic Review and Meta-Analysis.

Stenotrophomonas maltophilia is a multidrug-resistant bacterium that is difficult to treat in hospitals worldwide, leading to high mortality. Published data describing the use of monotherapy or combination therapy and which one is better is still unclear. We aimed to investigate the efficacy of monotherapy and combination therapy in the treatment of S. maltophilia infections. We performed a systematic review of combination therapy and additionally a systematic review and meta-analysis to determine the effects of monotherapy versus combination therapy on mortality in S. maltophilia infections. Electronic databases: Cochrane Library, PubMed, Embase, ClinicalTrials.gov, Scopus, and OpenGrey were accessed. Of the 5030 articles identified, 17 studies were included for a systematic review of combination therapy, of which 4 cohort studies were finally included for meta-analysis. We found there is a trend of favorable outcomes with respect to mortality in the use of combination therapy to treat complex or severe S. maltopholia infections. A meta-analysis of monotherapy showed a statistical significance in the decreasing rate of mortality in hospital-acquired pneumonia (hazard ratio 1.42; 95% confidence interval, 1.04-1.94) compared to combination therapy, but not significant in bacteremia (hazard ratio 0.76; 95% confidence interval, 0.18-3.18). Further studies should continue to explore this association.

Do Apixaban Plasma Levels Relate to Bleeding? The Clinical Outcomes and Predictive Factors for Bleeding in Patients with Non-Valvular Atrial Fibrillation.

Apixaban can significantly prevent stroke events in patients with non-valvular atrial fibrillation (NVAF), as can be observed from the large, randomized, controlled trial conducted in the present study. However, the real-world evidence of bleeding events related to the apixaban plasma levels in Asian populations is limited. This study aimed to investigate the apixaban plasma levels and clinical outcomes among NVAF patients receiving apixaban, including determining the risk factors associated with bleeding during routine care. Seventy-one patients were included in the study. The median values were 112.79 (5-95th percentiles: 68.69-207.8) µg/L and 185.62 (5-95th percentiles: 124.06-384.34) µg/L for the apixaban trough (Ctrough) and apixaban peak plasma levels (Cpeak), respectively. Stroke and bleeding were found in 8 (11.27%) and 14 patients (19.72%), respectively. There was no statistical significance for Ctrough and Cpeak in the stroke and non-stroke groups, respectively. The median of Ctrough (139.15 µg/L) in patients with bleeding was higher than that in the non-bleeding group (108.14 µg/L), but there was no statistical significance. However, multivariate analyses showed that bleeding history (odds ratio (OR): 17.62; 95% confidence interval (CI): 3.54-176.64; and p-value = 0.002) and Ctrough (OR: 1.01; 95%: CI 1.00-1.03; and p-value = 0.038) were related to bleeding events. Almost all of the patients presented apixaban plasma levels within the expected range. Interestingly, bleeding events were associated with the troughs of the apixaban plasma levels and bleeding history.

Impact of Pharmacist-Led Implementation of a Community Hospital-Based Outpatient Parenteral Antimicrobial Therapy on Clinical Outcomes in Thailand.

Few studies have analyzed community hospital-based parenteral anti-infective therapy (CohPAT). We aimed to assess the clinical impact of a pharmacist-led implementation of a clinical practice guideline (CPG) for CohPAT, and to determine the pharmacist's role in CohPAT medication management. The prospective-period patients (post-implementation group) were compared with the historical control-period patients (pre-implementation group) for receiving a continuous antimicrobial parenteral injection. A CPG was used for laboratory testing for efficacy and safety, the monitoring of adverse drug events during admission, microbiology results coordination, and dosage adjustment. For any antimicrobial drug-related problems, the pharmacist consulted with the clinicians. Over 14 months, 50 participants were included in each group. In the pre-implementation period, 7 (14%) and 4 (8%) out of 50 patients received an inappropriate dosage and nonlaboratory monitoring for dose adjustment, respectively. The patients received the proper dosage of antimicrobial agents, which increased significantly from 78% pre- to 100% post-implementation (p = 0.000). The pharmacist's interventions during the prospective-period were completely accepted by the clinicians, and significantly greater laboratory monitoring complying with CPG was given to the postimplementation group than the pre-implementation group (100% vs. 60%; p = 0.000). Significantly less patients with unfavorable outcomes (failure or in-hospital mortality) were observed in the post-implementation than in the pre-implementation (6% vs. 26%; p = 0.006) group. For the logistic regression analysis, lower respiratory infection (adjusted OR, aOR 3.68; 95%CI 1.13-12.06) and the post-implementation period (aOR 0.21; 95%CI 0.06-0.83) were significant risk factors that were associated with unfavorable outcomes. Given the better clinical outcomes and the improved quality of septic patient care observed after implementation, pharmacist-led implementation should be adopted in healthcare settings.

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 [...].

Association Between Types of Carbapenemase and Clinical Outcomes of Infection Due to Carbapenem Resistance Enterobacterales.

Purpose: Compared with non-carbapenemase producing carbapenem-resistant Enterobacterales (non-CP-CRE), carbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) are associated with considerable mortality. However, given that the patients are treated with various therapeutic options, it remains unclear whether differences in types of carbapenemase genes yield different mortality rates. Therefore, this study aims to identify carbapenemase genes and identify whether clinical outcomes differ according to the prevalence of genotype and phenotype of carbapenemase among Enterobacterales clinical isolated. Patients and Methods: A retrospective cohort study was performed to determine whether types of carbapenemase genes have an impact on clinical outcomes. Carbapenem-resistant clinical isolates were collected at a tertiary care university hospital in Songkhla, Thailand, between June 2018 and February 2020. Demographic and microbiological data such as antimicrobial susceptibility, carbapenemase genes, and overall mortality were evaluated. Results: A total of 121 Enterobacterales clinical isolated were evaluated. The bla NDM-1 gene was detected in 44% of the isolates, followed by bla OXA-48 (28%) and bla NDM-1/OXA-48 (28%). NDM-1- or NDM-1/OXA-48- producing isolates were more likely to require meropenem MICs of ≥16 mg/L, while OXA-48-producing isolates were more likely to require meropenem MICs of <16 mg/L. The patients with NDM-1 or NDM-1/OXA-48 had a higher 14 days mortality rate than those with OXA-48 after treating with carbapenem-containing regimens (P-value 0.001) or colistin-containing regimens (P-value < 0.001). Conclusion: Our findings suggest that the mortality for CP-CRE infection in patients with NDM-1 or NDM-1/OXA-48 was higher than the mortality in those with OXA-48, which It seems that the type of carbapenemase gene may affect meropenem MIC levels. Hence, in treatment decisions involving the use of either carbapenem-containing regiment or colistin-containing regiment in patients with CP-CRE infection, especially those in the NDM-1 and NDM-1/OXA-48 groups, the patient symptoms should be closely monitored.

Comparison of Race-Based and Non-Race-Based Equations for Kidney Function Estimation in Critically Ill Thai Patients for Vancomycin Dosing.

Empiric antibiotic dosing frequently relies on an estimate of kidney function based on age, serum creatinine, sex, and race (on occasion). New non-race-based estimated glomerular filtration rate (eGFR) equations have been published, but their role in supporting dosing is not known. Here, we report on a population pharmacokinetic model of vancomycin that serves as a useful probe substrate of eGFR in critically ill Thai patients. Data were obtained from medical records during a 10-year period. A nonlinear mixed-effects modeling approach was conducted to estimate vancomycin parameters. Data from 208 critically ill patients (58.2% men and 36.0% septic shock) with 398 vancomycin concentrations were collected. Twenty-three covariates including 12 kidney function estimates were tested and ranked on the basis of the model performance. The median (min, max) age, weight, and serum creatinine was 69 (18, 97) years, 60.0 (27, 120) kg, and 1.53 (0.18, 7.15) mg/dL, respectively. The best base model was a 1-compartment linear elimination with zero-order input and proportional error model. A Thai-specific eGFR equation not indexed to body surface area model best predicted vancomycin clearance (CL). The typical value for volume of distribution and CL was 67.5 L and 1.22 L/h, respectively. A loading dose of 2000 mg followed by maintenance dose regimens based on eGFR is suggested. The Thai GFR not indexed to BSA model best predicts vancomycin CL and dosing in the critically ill Thai population. A 5% to 10% absolute gain in the vancomycin probability of target attainment is expected with the use of this population-specific eGFR equation.

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.

Borneol-based antisolvent-induced in situ forming matrix for crevicular pocket delivery of vancomycin hydrochloride.

Given its safety and apparent low aqueous solubility, borneol may serve as a matrix forming component of anti-solvent based in situ forming matrixes (ISMs) for crevicular pocket targeting. Drug-free and vancomycin hydrochloride-loaded borneol ISMs were evaluated for pH, density, viscosity, contact angle, surface tension, matrix formation, drug release behavior, in vitro degradability and antimicrobial activities. Density and pH values of borneol-based ISMs decreased with increasing borneol concentration. Given their markedly low viscosity could facilitate better injectability. The contact angles of the drug-free and vancomycin HCl-loaded borneol ISMs increased after being in contact with the agarose gel or the bulge tissue of porcine due to phase inversion. A dense borneol crystal matrix formed after using the highly concentrated ISM corresponded to fast matrix formation. The borneol-based ISM exhibited a sustainable drug release longer than 14 days with a diffusion-controlled release mechanism. Moreover, the developed ISM exhibited strong antimicrobial activities against various microbes. Thus, the vancomycin HCl-loaded borneol-based ISM is a potentially effective local anti-solvent-based ISM for periodontitis treatment via crevicular pocket injection.

Urticaria, angioedema, and type I hypersensitivity reactions associated with fibrinolytic agents.

BACKGROUND: Several clinical trials of fibrinolytic agents have reported the occurrence of allergic reactions, in addition to hemorrhage. These reactions might worsen patient outcomes, especially by causing life-threatening type I hypersensitivity reactions, including anaphylaxis; however, there is a scarcity of data in this regard. OBJECTIVE: This study described and characterized patients with urticaria, angioedema and type I hypersensitivity reactions caused by fibrinolytic agents. METHODS: This was a retrospective study in which cases of suspected adverse drug reactions from the use of streptokinase, alteplase, and tenecteplase were evaluated over a period of 10 years at Phramongkutklao and Ratchaburi hospitals in Thailand. In addition, patient characteristics and management were assessed. RESULTS: A total of 824 patients received fibrinolytic agents due to various indications. Of 147 patients who received streptokinase, nine (6.12%) had suspected adverse drug reactions (one case of urticaria, two cases of anaphylactic shock, and six cases of hypotension). The prescription rate of alteplase was the highest, being taken by 547 patients; however, only one patient (0.18%) reported an adverse reaction, angioedema in the face and lips. Similarly, of the 130 patients who received tenecteplase, only one patient (0.77%) developed hypotension. CONCLUSIONS: All fibrinolytic agents, either nonfibrin or fibrin-specific, can cause urticaria, angioedema, and type I hypersensitivity reactions due to their mechanism of action.

Effectiveness of thiamine therapy in mortality rate in patients with septic shock: A systematic review and meta-analysis.

BACKGROUND: Septic shock is a serious condition leading to increased mortality. Despite previous report of no benefit, thiamine has emerged as potential therapy to reduce mortality in septic shock patients. This study aimed to investigate the effect of thiamine in mortality rate in patients with septic shock. METHODS: Eight databases, including MEDLINE, EMBASE, Science Direct, Scopus, Cochrane, CINAHL, Open Grey, and Dart-Europe, were systematically searched from the inception of the database up to August 21, 2020. Studies evaluating the effectiveness of thiamine on mortality rate in septic shock patients compared between thiamine and placebo were included. We used random-effects model to analyze the mortality with risk ratio (RR) and 95% confidence interval (95% CI). The subgroup and sensitivity analysis were performed to examine the influence of variables. Publication bias was considered using funnel plot, Begg's test, and Egger's test. RESULTS: A total of 3,658 studies were retrieved and reviewed. Five studies were included for meta-analysis. In random-effects meta-analysis of the randomized controlled trials, although not statistically significant, there was a trend which suggested that thiamine may reduce mortality rate in septic shock patients (RR, 0.96; 95% CI: 0.72-1.28, P = 0.774). The result of sensitivity and subgroup analyses also supported the suggestion that thiamine may decrease mortality in septic shock patients. The Begg's test (P = 0.624) and Egger's test (P = 0.777) revealed no publication bias. CONCLUSIONS: Although not statistically significant, thiamine may reduce mortality rate in septic shock patients. Further prospective studies with larger sample size are warranted.

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.