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.

A Randomized Controlled Trial of Colistin Combined with Sulbactam: 9 g per Day versus 12 g per Day in the Treatment of Extensively Drug-Resistant Acinetobacter baumannii Pneumonia: An Interim Analysis.

Extensively drug-resistant A. baumannii (XDRAB) pneumonia has a high mortality rate in hospitalized patients. One of the recommended treatments is colistin combined with sulbactam; however, the optimal dosage of sulbactam is unclear. In an open-label, superiority, randomized controlled trial, patients diagnosed with XDRAB pneumonia were randomly assigned (1:1) to receive colistin in combination with sulbactam at either 9 g/day or 12 g/day. The primary outcome was the 28-day mortality rate in the intention-to-treat population. A total of 88 patients received colistin in combination with sulbactam at a dosage of either 12 g/day (n = 45) or 9 g/day (n = 43). Trends toward a lower mortality rate were observed in the 12 g/day group at 7 days (11.1% vs. 23.3%), 14 days (33.3% vs. 41.9%), and 28 days (46.7% vs. 58.1%). The microbiological cure rate at day 7 was significantly higher in the 12 g/day group (90.5% vs. 58.1%; p = 0.02). Factors associated with mortality at 28 days were asthma, cirrhosis, APACHEII score ≥ 28, and a dosage of sulbactam of 9 g/day for mortality at any timepoint. Treatment with colistin combined with sulbactam at 12 g/day was not superior to the combination treatment with sulbactam at 9 g/day. However, due to being an interim analysis, this trial was underpowered to detect mortality differences.

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 [...].

Vibrio vulnificus Necrotizing Fasciitis in Upper Limbs and Septicemia Following Pinch Injury by Mud Crab: A Case Report.

Vibrio vulnificus necrotizing fasciitis is a rare emergency and has a high mortality rate condition occurring among patients with cirrhosis, iron overload states, chronic renal failure, malignancy, HIV, or immunosuppressive medications. Here, we report a case of nonfoodborne Vibrio infection caused by V. vulnificus presenting as bilateral necrotizing fasciitis on the hands and lower arms after a pinch injury by a mud crab in a 64-year-old man with hypertension presenting with acute fever, bilateral hand swelling, and pain. The patient was treated with emergency fasciotomy and intravenous antibiotics. The outcome of such cases depends on early diagnosis and appropriate surgical and medical management.

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.

Impact of Inappropriate Empirical Antibiotic on Outcomes in Community-acquired Third Generation Cephalosporin Resistant Enterobacterales Bacteremia.

BACKGROUND: Currently, third generation cephalosporin resistant Enterobacterales (3GCRE) are becoming more common in community-acquired infection, leading to increasing consumption of carbapenems. Because community-acquired 3GCRE infections are generally less severe and of lower pathogenicity, the impact of inappropriate empirical antibiotics among patients with community-acquired 3GCRE bacteremia remains unknown. MATERIALS AND METHODS: This prospective cohort study included adult patients with 3GCRE bacteremia from April 2018 to December 2021. Participants were followed for 30 days to measure the primary outcome of mortality. Propensity score analysis was performed to adjust for treatment selection bias. RESULTS: A total of 155 patients met the eligible criteria (42 participants in the appropriate antibiotics group, and 113 participants in the inappropriate antibiotics group). Eight participants in the inappropriate antibiotics group never received appropriate antibiotics, three of whom died before microbiological results were made available. The most common clinical syndromes were urinary tract infection (56.8%) and biliary tract infection (22.6%). The overall 30-day mortality rate was 12.9%, 14.3% in the appropriate empirical antibiotics group and 12.4% in the inappropriate empirical antibiotics group. After propensity score weighted adjustment, the 30-day mortality rate in the inappropriate group was non-inferior to the appropriate group (mean difference 1.9%; 95% confidence interval: -10.1 - 14.0). From the multivariate analysis, acute respiratory failure and primary bacteremia were associated with 30-day mortality. CONCLUSION: Among patients with community-acquired 3GCRE bacteremia, inappropriate empirical treatment given within 24 hours after the onset of bacteremia was non-inferior to appropriate antibiotics. In the setting of a high prevalence of 3GCRE carriage in community, adjustment to carbapenem might be tolerable among patients with community-acquired infections. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03765749.

Rare manifestation of ocular immune reconstitution inflammatory syndrome from mycobacterium scrofulaceum infection in a patient with AIDS.

Immune reconstitution inflammatory syndrome (IRIS) is a common complication following the initiation of antiretroviral therapy (ART). The most commonly associated pathogens include Mycobacterium tuberculosis and Cryptococcus spp.[1] IRIS following nontuberculosis mycobacteria (NTM) infection is uncommon, particularly, IRIS following NTM conjunctivitis.[2] Herein, we present a case of Mycobacterium scrofulaceum conjunctivitis with peripheral ulcerative keratitis and orbital cellulitis in a 45-year-old patient with AIDS who developed IRIS 1 month after starting ART therapy. A combination of both systemic and topical antibiotics together with corticosteroids were used and resulted in a satisfactory outcome with no early recurrence. This case demonstrated a rare ocular IRIS manifestation involving both the external eye and orbit and to the author's knowledge is the first case in the literature in which M. scrofulaceum has been found to be involved in the eye.

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.

Optimization of Linezolid Dosing Regimens for Treatment of Vancomycin-Resistant Enterococci Infection.

BACKGROUND: Linezolid, an oxazolidinone antibiotic, is recommended for vancomycin-resistant enterococci (VRE). However, 100% free-drug concentration above the minimum inhibitory concentration (fT>MIC) and an area under the curve of free drug to MIC ratio (fAUC24/MIC) >100 were associated with favorable clinical outcome with less emerging resistance. A plasma trough concentration (Ctrough) of linezolid ≥9 µg/mL was also related to hematologic toxicity. Thus, linezolid dose optimization is needed for VRE treatment. The study aimed to determine the in vitro linezolid activity against clinical VRE isolates and linezolid dosing regimens in critically ill patients who met the target pharmacokinetics/pharmacodynamics (PK/PD) for VRE treatment. MATERIALS AND METHODS: Enterococcal isolates from enterococcal-infected patients were obtained between 2014 and 2018 at Phramongkutklao Hospital. We used Monte Carlo simulation to calculate the probability of target attainment, and the cumulative fraction of response (CFR) of the free area under the curve to MIC ratio (fAUIC24) was used to calculate the fAUC24/MIC 80 - 100 and fT/MIC >85 - 100% of the interval time of administration for clinical response and microbiological eradication as well as the Ctrough ≥9 µg/mL for the probability of hematologic toxicity. RESULTS: For linezolid MIC determination, the MIC median (MIC50), MIC for 90% growth (MIC90), and range for linezolid were 1.5 µg/mL, 2 µg/mL, and 0.72 - 2 µg/mL, respectively. A dosing regimen of 1,200 mg either once daily or as a divided dose every 12 h gave target attainments of fAUC24/MICs >80 and >100, which exceeded 90% for MICs ≤1 and ≤1 µg/mL, respectively, with a rate of hematologic toxicity <15%. If the expected fT>MICs were >85% and 100%, a 1,200-mg divided dose every 12 h could cover VRE isolates having linezolid MICs ≤1 µg/mL and ≤0.75 µg/mL. Even 600 mg every 8 h and 1,200 mg as a continuous infusion gave a higher target attainment of fAUC24/MIC and a fT>MIC and the target CFR, but those regimens gave Ctrough ≥9 µg/mL rates of 40.7% and 99.6%. CONCLUSION: The current dosing of 1,200 mg/day might be optimal treatment for infection by VRE isolates with documented MICs ≤1 µg/mL. For treatment of VRE with a MIC of 2 µg/mL or to achieve the target CFR, the use of linezolid with other antibiotic combinations might help achieve the PK/PD target, provide better clinical outcome, and prevent resistance.

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.

First-Line Antiretroviral Regimen Failure and Determinants in an Urban HIV Clinic at Phramongkutklao Hospital, Bangkok, Thailand: 20 Years Experience.

PURPOSE: HIV treatment involves antiretroviral therapy (ART) endeavoring to suppress viral load to an undetectable level. Virologic failure occurs when ART fails to suppress and sustain an individual's viral load to less than 200 copies/mL after 6 months of therapy. In Thailand, the data among first-line antiretroviral regimen failure and determinants remains limited, especially in urban HIV clinics. We aimed to demonstrate factors of first-line antiretroviral regimen failures in an urban HIV/AIDS clinic at Phramongkutklao Hospital. PATIENTS AND METHODS: A nested case control 1:4 study was conducted. Data were collected from the electronic patient database among naïve people living with HIV/AIDS (PLWHA), aged ≥18 years and receiving ART continuously for at least 2 years at Phramongkutklao Hospital from 1 January 2000 to 31 December 2019. Multiple logistic regression was used to identify the determinants of virologic failure. Adjusted HRs (AHRs) with 95% CIs were used to declare statistical significance. RESULTS: Of 200 PLWHA included in the study, 40 participants experienced HIV virologic failure. The median time after starting ART to virologic failure was 24 months (IQR 7-96.0). Univariate and multivariate analysis showed significant factors affecting first-line antiretroviral regimen failure included being female (37.5 vs 26.88%, adjusted odds ratio 5.08 [1.05-24.6, p-value 0.043], age ≤40 yr. (62.5 vs 49.6%, adjusted odds ratio 4.59 [1.47-14.37], p-value 0.009), CD4+count ≤200 cell/µL (77.5 vs 52.5%, adjusted odds ratio 4.83 [1.28-18.9], p value 0.02), tuberculosis (42.5 vs 7.5%, adjusted odds ratio 8.66 [2.37-31.56], p value <0.001) and initiation of ART at CD4+ count <350 cell/µL (72.5 vs 48.13%, adjusted odds ratio 31.36 [6.51-151.22], p value <0.001). Estimated prevalence of virologic failure in Phramongkutklao Hospital was 5.34%. CONCLUSION: Our study revealed factors favoring virologic failure included being female, younger age, CD4+ count <200 cells/µL, tuberculosis and initiation of ART at CD4+ count <350 cell/µL. Multidisciplinary HIV comprehensive care teams should encourage patient adherence and support patients along HIV continuum of care to prevent virologic failure and drug resistance, especially among patients initiating ART at low CD4+ count and tuberculosis co-infection.

Clinical manifestations and prognostic factors for Streptococcus agalactiae bacteremia among nonpregnant adults in Thailand.

BACKGROUND: Streptococcus agalactiae infection in nonpregnant adults is an emerging disease with increasing burden. This study described epidemiologic, clinical characteristics, and treatment options among patients with S. agalactiae bacteremia, and determined the factors associated with mortality. METHODS: Medical records from all adult patients with S. agalactiae isolated from blood cultures from 2006 to 2016 were retrospectively reviewed. Patients, who had mixed bacteremia, were transferred to other hospitals, or missing records were excluded from the study. RESULTS: During the study period, S. agalactiae was isolated from 282 individuals. Increasing trend was observed, with peak incidence from May to July. Study criteria were met among 238 patients. Most patients (64%) had underlying medical conditions, with diabetes as the most common disease, followed by malignancy, chronic kidney disease and alcoholism. The most common manifestations were primary bacteremia, followed by arthritis, cellulitis, meningitis, osteomyelitis and endocarditis. Three patients had transient bacteremia. Thirty-day mortality was 16.4%, with age of ≥65 years, alteration of consciousness, absence of fever, high Pitt bacteremia score (≥4) and shock, as associating factors on univariate analysis. In a subgroup of patients with prolonged intravenous antibiotic, penicillin G treatment was identified as a protective factor against mortality. Multivariate analysis found independent associating factors of 30-day mortality were high Pitt bacteremia score and absence of fever. CONCLUSION: S. agalactiae bacteremia in nonpregnant adults showed an increasing trend. High mortality was observed, especially among those with severe clinical manifestations at presentation. Penicillin G is still the drug of choice for the definite intravenous treatment.

Does Vancomycin Resistance Increase Mortality? Clinical Outcomes and Predictive Factors for Mortality in Patients with Enterococcus faecium Infections.

The prevalence of enterococcal infection, especially E. faecium, is increasing, and the issue of the impact of vancomycin resistance on clinical outcomes is controversial. This study aimed to investigate the clinical outcomes of infection caused by E. faecium and determine the risk factors associated with mortality. This retrospective study was performed at the Phramongkutklao Hospital during the period from 2014 to 2018. One hundred and forty-five patients with E. faecium infections were enrolled. The 30-day and 90-day mortality rates of patients infected with vancomycin resistant (VR)-E. faecium vs. vancomycin susceptible (VS)-E. faecium were 57.7% vs. 38.7% and 69.2% vs. 47.1%, respectively. The median length of hospitalization was significantly longer in patients with VR-E. faecium infection. In logistic regression analysis, VR-E. faecium, Sequential Organ Failure Assessment (SOFA) scores, and bone and joint infections were significant risk factors associated with both 30-day and 90-day mortality. Moreover, Cox proportional hazards model showed that VR-E. faecium infection (HR 1.91; 95%CI 1.09-3.37), SOFA scores of 6-9 points (HR 2.69; 95%CI 1.15-6.29), SOFA scores ≥ 10 points (HR 3.71; 95%CI 1.70-8.13), and bone and joint infections (HR 0.08; 95%CI 0.01-0.62) were significant risk factors for mortality. In conclusion, the present study confirmed the impact of VR-E. faecium infection on mortality and hospitalization duration. Thus, the appropriate antibiotic regimen for VR-E. faecium infection, especially for severely ill patients, is an effective strategy for improving treatment outcomes.

Vancomycin Area under the Curve and Pharmacokinetic Parameters during the First 24 Hours of Treatment in Critically Ill Patients using Bayesian Forecasting.

BACKGROUND: Currently, the achievement of the target area under the curve (AUC)/minimum inhibitory concentration ratio during the first 24 - 48 h of treatment is associated with reduced 30-day mortality and greater microbiological eradication in patients with methicillin-resistant Staphylococcus aureus bacteremia. This study aimed to determine the AUC and pharmacokinetic parameters on the first day of vancomycin administration based on the Bayesian theorem to optimize the dosing regimen in critically ill patients. MATERIALS AND METHODS: This retrospective study included participants meeting the following criteria: 1) ≥18 years old; 2) receipt of at least one dose of vancomycin; 3) measurement of 2 vancomycin serum concentrations during the first 24 h of treatment; and 4) an intensive care unit admission, mechanical ventilator use, or an Acute Physiology and Chronic Health Evaluation II score >15 points. The AUC on day 1 of treatment and the estimated vancomycin pharmacokinetic parameters were measured using PrecisePK software based on the Bayesian theorem. RESULTS: We obtained 132 vancomycin concentrations from 66 patients. The vancomycin pharmacokinetic parameters were as follows: AUC0-24, 571.09 (± standard deviation [SD] 188.62) mg/L·h; clearance (CL), 2.97 (± SD 1.81) L/h; volume of distribution (Vd), 50.60 (± SD 13.91) L; elimination rate constant, 0.062 (± SD 0.039) h-1; and half-life, 18.19 (± SD 15.96) h. Focusing on the vancomycin loading dose, AUC0-24 400 - 600 was achieved in 41.7, 46.1, 44.4, and 26.3% of patients with loading doses of <20, 20 - 24.9, 25 - 30, and >30 mg/kg, respectively. Whereas AUC0-24 ≥521 was achieved in 50, 50, 77.8, and 84.2% of patients with loading doses of <20, 20 - 24.9, 25 - 30, and >30 mg/kg, respectively. The CL of vancomycin was correlated with creatinine CL, whereas the Vd of vancomycin was significantly correlated with age and body weight. CONCLUSION: This study revealed that the higher Vd and CL values on the first day of vancomycin therapy were found in critically ill patients. Additionally, a higher vancomycin loading dose (25 - 30 mg/kg) might be required to achieve target of AUC0-24 during early phase of administration for critically ill patients.

Is Early Monitoring Better? Impact of Early Vancomycin Exposure on Treatment Outcomes and Nephrotoxicity in Patients with Methicillin-Resistant Staphylococcus aureus Infections.

Optimal early vancomycin target exposure remains controversial. To clarify the therapeutic exposure range, we investigated the association between vancomycin exposure and treatment outcomes or nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. This retrospective study reviewed clinical data obtained from 131 patients with MRSA infections between January 2017 and September 2019. Clinical outcomes included treatment failure, 30-day mortality, microbiological failure, and acute kidney injury. We measured serum vancomycin levels after the first dose to 48 h and estimated vancomycin exposure using the Bayesian theorem. The minimum inhibitory concentration (MIC) of antimicrobial agents was determined using the broth microdilution method. Classification and Regression Tree analyses identified day 1 and 2 exposure thresholds associated with an increased risk of failure and nephrotoxicity. Treatment failure (27.9% vs. 33.3%) and 30-day mortality (26.6% vs. 31.74%) were numerically but not significantly reduced in patients with the area under the curve (AUC)24-48h/MICBMD ≥ 698. Patients with AUCss/MICBMD ≥ 679 exhibited a significantly increased risk of acute kidney injury (27.9% vs. 10.9%, p = 0.041). These findings indicate that AUCss/MICBMD ratios > 600 may cause nephrotoxicity. AUC/MICBMD at days 1 and 2 do not appear to be significantly associated with particular clinical outcomes, but further studies are needed.

Optimizing the Dosing Regimens of Tigecycline against Vancomycin-Resistant Enterococci in the Treatment of Intra-abdominal and Skin and Soft Tissue Infections.

Tigecycline was previously considered to have activity against vancomycin-resistant Enterococcus (VRE) isolates, but the optimal dose was not clarified. Thus, this study assessed the in vitro activity of tigecycline against clinical VRE isolates to determine its optimal regimens for complicated intra-abdominal (cIAIs) and complicated skin/soft tissue infections (cSSTIs). We used Monte Carlo simulation to calculate the probability of target attainment (PTA) and the cumulative fraction of response for the ratio of the free area under the curve to the minimum inhibitory concentration (MIC) (fAUIC24), which were 17.9 and 6.9 for treating cSSTIs and cIAIs, respectively. All clinical isolates were Enterococcus faecium. Only a maintenance dose of 200 mg/day tigecycline gave the target attainment of fAUIC24 >17.9, and PTA exceeded 90% for MIC ≤0.38 µg/mL. Meanwhile, this dose gave the target attainment of fAUIC24 >6.9, and PTA exceeded 90% for MIC ≤1 µg/mL. All simulated tigecycline dosing regimens met the fAUIC24 targets more than 90% of the cumulative fraction of response. Despite its apparent efficacy, a daily tigecycline dose of 200 mg is recommended for VRE isolates with MICs of ≤0.38 µg/mL and ≤1 µg/mL for treating cSSTIs and cIAIs, respectively.

Is Echocardiography Mandatory for All Streptococcus gallolyticus Subsp. pasteurianus Bacteremia?

BACKGROUND: Streptococcus gallolyticus, formerly known as one of the Streptococcus bovis group, is frequently associated with endocarditis. Current guidelines recommended diagnostic work-up for endocarditis among patients with S. gallolyticus bacteremia. However, S. gallolyticus subsp. pasteurianus, was found to be associated with neonatal sepsis and liver diseases and is less commonly associated with endocarditis compared with S. gallolyticus subsp. gallolyticus. Our study aimed to identify the risk factors for S. gallolyticus subsp. pasteurianus endocarditis to help select the patients for echocardiography. METHODS: In this retrospective cohort study, medical records from all adult patients with S. gallolyticus subsp. pasteurianus isolated from blood cultures at Phramongkutklao Hospital from 2009 to 2015 were reviewed. Patients who had mixed bacteremia or missing records were excluded from the study. RESULTS: During the study period, S. gallolyticus subsp. pasteurianus was isolated among 106 individuals. Mean age was 66.9±15.6 years. Most patients (61.3%) were male, with cirrhosis as the most common underlying diseases (46.2%), followed by malignancy and chronic kidney disease. Most common manifestations included primary bacteremia (44.3%), followed by spontaneous bacterial peritonitis (23.6%). Infective endocarditis was found among 9 patients. No patients with cirrhosis or single blood specimen of bacteremia had endocarditis (RR 0; p-value 0.003, and RR 1.35; p-value 0.079). The common complications associated with endocarditis were acute respiratory failure (RR 4.32; p-value 0.05), whereas acute kidney injury was a protective factor (RR 0; p-value 0.01). Among 76 patients who had records of 2-year follow-up, no new diagnosis of endocarditis or malignancy was observed. CONCLUSION: Among patients with S. gallolyticus subsp. pasteurianus bacteremia, echocardiography might not be needed among patients with cirrhosis and without sustained bacteremia.

Optimizing the Dosing Regimens of Daptomycin Based on the Susceptible Dose-Dependent Breakpoint against Vancomycin-Resistant Enterococci Infection.

Daptomycin, a lipopeptide antibiotic, is one of the therapeutic options used for the treatment of vancomycin-resistant enterococci (VRE). Recently, the Clinical and Laboratory Standards Institute (CLSI) M100 30th edition has removed the susceptibility (S) breakpoint for Enterococcus faecium and replaced it with a susceptible dose-dependent (SDD) breakpoint of ≤4 µg/mL, with a suggested dosage of 8-12 mg/kg/day. Herein, we aimed to determine the minimum inhibitory concentration (MIC) values of daptomycin against clinical VRE isolates and to study the appropriate daptomycin dosing regimens among critically ill patients based on the new susceptibility CLSI breakpoint. The MIC determination of daptomycin was performed using E-test strips among clinical VRE strains isolated from patients at the Phramongkutklao Hospital. We used Monte Carlo simulation to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the ratio of the free area under the curve to MIC (fAUC0-24/MIC) > 27.4 and fAUC0-24/MIC > 20 for survival and microbiological response, respectively, at the first day and steady state. Further, we determined that the simulated daptomycin dosing regimen met the minimum concentration (Cmin) requirements for safety of being below 24.3 mg/L. All of the 48 VRE isolates were E. faecium strains, and the percentiles at the 50th and 90th MIC of daptomycin were 1 and 1.5 µg/mL, respectively. At MIC ≤ 2 µg/mL, a daptomycin dosage of 12 mg/kg/day achieved the PTA target of survival and microbiological response at the first 24 h time point and steady state. For a MIC of 4 µg/mL, none of the dosage regimens achieved the PTA target. For CFR, a dosage of 8-12 mg/kg/day could achieve the 90% CFR target at the first day and steady state. All dosing regimens had a low probability of Cmin being greater than 24.3 mg/L. In conclusion, the MIC of VRE against daptomycin is quite low, and loading and maintenance doses with 8 mg/kg/day were determined to be optimal and safe.

Clinical Outcomes Of Colistin In Combination With Either 6-G Sulbactam Or Carbapenems For The Treatment Of Extensively Drug-Resistant Acinetobacter Baumannii Pneumonia With High MIC To Sulbactam, A Prospective Cohort Study.

PURPOSE: Extensively drug-resistant Acinetobacter baumannii (XDRAB) is an important cause of nosocomial pneumonia with limited therapeutic options. Colistin-based regimen is the recommended treatment. Which drugs should be combined with colistin remains uncertain. The aim of this study was to investigate the clinical outcomes of patients with XDRAB pneumonia who were treated with colistin, combined with either 6-g sulbactam or carbapenems, in the setting of high MIC to sulbactam. PATIENTS AND METHODS: In this prospective cohort study, hospitalized patients diagnosed with XDRAB pneumonia in Phramongkutklao Hospital were enrolled. The primary outcome was 28-day mortality. Secondary outcomes were 7- and 14-day mortality, length of stay, ventilator days and factors associated with mortality. RESULTS: From 1 July 2016 to 30 September 2017, 182 patients were included; 92 received colistin plus sulbactam and 90 received colistin plus carbapenems. Most of the patients were males diagnosed with ventilator-associated pneumonia in medical intensive care unit. Overall mortality rates at 7, 14, 28 days were 24.2%, 37.4%, and 53.3%, respectively. Mortality rates did not differ between sulbactam group and carbapenem groups at 7 days (19.6% vs 28.9%, p-value 0.424, adjusted HR 1.277; 95% CI = 0.702-2.322), 14 days (34.8% vs 40%, p = 0.658, adjusted HR 1.109; 95% CI = 0.703-1.749) and 28 days (51.1% vs 55.6%, p = 0.857, adjusted HR 1.038; 95% CI = 0.690-1.562). Length of stay, ICU days and ventilator days did not differ. Complications of treatment including acute kidney injury were not statistically different. CONCLUSION: In XDRAB pneumonia with high MIC to sulbactam, differences in mortality rates were not statistically significant between colistin plus 6-g sulbactam and colistin plus carbapenems.