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The purpose of this single-center retrospective case series was to evaluate the efficacy and safety of 300-mg once-monthly intravenous (IV) pentamidine prophylaxis in 702 adult allogeneic hematopoietic stem cell transplant (HSCT) patients. We observed no cases of Pneumocystis jirovecii pneumonia (PJP) following IV pentamidine administration. Breakthrough Nocardia and Toxoplasma infections were observed in 7 (1%) and 5 (0.7%) patients, respectively. The most commonly reported adverse event was nausea. Monthly IV pentamidine is a reasonable alternative to trimethoprim-sulfamethoxazole (TMP-SMX).

Mycobacterium abscessus is an emerging nontuberculous mycobacterium (NTM) pathogen infecting susceptible people with cystic fibrosis (CF) and non-CF bronchiectasis. Here, we demonstrated the activity of an FDA-approved drug, disulfiram, against drug-susceptible and drug-resistant M. abscessus strains utilizing in vitro and intracellular macrophage assays and a zebrafish embryo infection model.

Critically ill patients are characterized by substantial pathophysiological changes that alter the pharmacokinetics (PK) of hydrophilic antibiotics, including carbapenems. Meropenem is a key antibiotic for multidrug-resistant Gram-negative bacilli, and such pathophysiological alterations can worsen treatment outcomes. This study aimed to determine the population PK of meropenem and to propose optimized dosing regimens for the treatment of multidrug-resistant Klebsiella pneumoniae in critically ill patients. Two plasma samples were collected from eligible patients over a dosing interval. Nonparametric population PK modeling was performed using Pmetrics. Monte Carlo simulations were applied to different dosing regimens to determine the probability of target attainment and the cumulative fraction of response, taking into account the local MIC distribution for K. pneumoniae. The targets of 40% and 100% for the fraction of time that free drug concentrations remained above the MIC (ƒT>MIC) were tested, as suggested for critically ill patients. A one-compartment PK model using data from 27 patients showed high interindividual variability. Significant PK covariates were the 8-h creatinine clearance for meropenem and the presence of an indwelling catheter for pleural, abdominal, or cerebrospinal fluid drainage for the meropenem volume of distribution. The target 100% ƒT>MIC for K. pneumoniae, with a MIC of ≤2 mg/liter, could be attained by the use of a continuous infusion of 2.0 g/day. Meropenem therapy in critically ill patients could be optimized for K. pneumoniae isolates with an MIC of ≤2 mg/liter by using a continuous infusion in settings with more than 50% isolates have a MIC of ≥32mg/L.

This objective of this study was to compare clinical outcomes in hospitalized patients with Pseudomonas aeruginosa pneumonia (PNA) or bloodstream infection (BSI) receiving beta-lactam antibiotic (BLA) infusions with and without the guidance of therapeutic drug monitoring (TDM). A retrospective, parallel cohort study was conducted at two academic medical centers between December 2015 and January 2020, UF Shands Gainesville, which uses BLA TDM for select patients (BLA TDM), and UF Health Jacksonville, which does not use BLA TDM (No-BLA TDM). All hospitalized adult patients with respiratory or blood culture positive for P. aeruginosa who met diagnosis criteria for lower respiratory tract infection with a positive P. aeruginosa respiratory culture and who received ≥48 h of intravenous BLA with in vitro susceptibility within 72 h of positive culture collection were included. The primary outcome was a composite of presumed treatment failure defined as the presence of any of the following from index-positive P. aeruginosa culture collection to the end of BLA therapy: all-cause mortality, escalation of and/or additional antimicrobial therapy for P. aeruginosa infection after 48 h of treatment with susceptible BLA due to worsening clinical status, or transfer to a higher level of care (i.e., the intensive care unit [ICU]). Analyses were adjusted for possible confounding with inverse probability of treatment weighting (IPTW). Two-hundred patients were included (BLA TDM, n = 95; No-BLA TDM, n = 105). In IPTW-adjusted analysis of the primary composite endpoint, BLA TDM demonstrated a significant decrease in presumed treatment failure compared to No-BLA TDM (adjusted odds ratio [aOR] 0.037, 95% confidence interval [CI] [0.013 to 0.107]; P

The optimal dosing regimen for meropenem in critically ill patients undergoing continuous renal replacement therapy (CRRT) remains undefined due to small studied sample sizes and uninformative pharmacokinetic (PK)/pharmacodynamic (PD) analyses in reported studies. The present study aimed to perform a population PK/PD meta-analysis of meropenem using available literature data to suggest the optimal treatment regimen. A total of 501 meropenem concentration measurements from 78 adult CRRT patients pooled from nine published studies were used to develop the population PK model for meropenem. PK/PD target (40% and 100% of the time with the unbound drug plasma concentration above the MIC) marker-based efficacy and risk of toxicity (trough concentrations of >45 mg/L) for short-term (30 min), prolonged (3 h), and continuous (24 h) infusion dosing strategies for meropenem were investigated. The impact of CRRT dose and identified covariates on the PD probability of target attainment (PTA) and predicted toxicity was also examined. Meropenem concentration data were adequately described by a two-compartment model with linear elimination. Trauma was identified as a pronounced modifier for endogenous clearance of meropenem. Simulations demonstrated that adequate PK/PD targets and low risk of toxicity could be achieved in non-trauma CRRT patients receiving meropenem regimens of 1 g every 6 h infused over 30 min, 1 g every 8 h infused over 3 h, and 2 to 4 g every 24 h infused over 24 h. The impact of CRRT dose (25 to 50 mL/kg/h) on PTA was clinically irrelevant, and continuous infusion of 3 to 4 g every 24 h was suitable for trauma CRRT patients (MICs of ≤0.5 mg/L). A population PK model was developed for meropenem in CRRT patients, and different dosing regimens were proposed for non-trauma and trauma CRRT patients.

Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight 50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values

Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality (P

Although linezolid is effective for multidrug-resistant TB (MDR-TB) tuberculosis treatment, it is associated with cytopenias after 4 weeks of administration. Data on toxicities with long-term use of linezolid and drug pharmacodynamics in MDR-TB treatment are limited, and concerns about toxicity present barriers to wider implementation. This was a secondary analysis of a prospective cohort study of patients treated for MDR-TB in the country of Georgia from 2015 to 2017. Intensive blood sampling 4 to 6 weeks after treatment initiation with linezolid 600 mg daily was performed for pharmacokinetic (PK) analysis, including linezolid trough concentration (C(min)) and area under the curve from 0 to 24 hours (AUC(0–24)). Linezolid exposure was defined using literature-reported thresholds. Cytopenias were defined using an NIH adverse event (AE) scale. Logistic regression was used to evaluate the relationship between linezolid exposure and cytopenias. Among 76 patients receiving linezolid in their baseline treatment regimen and who had PK data available, cytopenia AEs occurred in 30 (39.5%) for an incidence rate of 46 per 100 person-years. The median duration of linezolid therapy was 526 days. No patients required dose reduction or interruption due to cytopenias. Median linezolid C(min) was 0.235 mg/L (interquartile range [IQR], 0.069 to 0.529), and median AUC(0–24) was 89.6 mg·h/L (IQR, 69.2 to 116.2). Cytopenias were associated with linezolid PK parameters (C(min) > 2 mg/L and AUC(0–24) > 160 mg·h/L). Cytopenias occurred frequently with long-term use of linezolid 600 mg/day and were associated with PK parameters but did not result in the need for treatment interruption in the management of a cohort of patients with MDR-TB.

Tunneled central venous catheter (TCVC) related infection remains a challenge in the care of hemodialysis patients. We aimed to determine the best antimicrobial lock therapy (ALT) to eradicate coagulase-negative staphylococci (CoNS) biofilms. We studied the colonization status of the catheter every 30 days by quantitative blood cultures (QBC) drawn through all catheter lumens. Those patients with a significant culture (i.e.,100 to 1,000 CFU/mL) of a CoNS were classified as patients with a high risk of developing catheter-related bloodstream infections (CRBSI). They were assigned to receive daptomycin, vancomycin, teicoplanin lock solution, or the standard of care (SoC) (i.e., heparin lock). The primary endpoint was to compare eradication ability (i.e., negative QBC for 30 days after ending ALT) rates between different locks and the SoC. A second objective was to analyze the correlation between ALT exposure and isolation of CoNS with antimicrobial resistance. Daptomycin lock was associated with a significant higher eradication success than with the SoC: 85% versus 30% (relative risk [RR] = 14, 95% confidence interval [CI] = 2.4 – 82.7); followed by teicoplanin locks with a 83.3% success (RR = 11.7; 95% CI = 2 – 70.2). We observed CoNs isolates with a higher teicoplanin MIC in patients with repeated teicoplanin locks exposure (coefficient = 0.3; 95% CI = 0.11 – 0.47). However, teicoplanin MICs decreased in patients treated with vancomycin locks (coefficient = −0.56; 95% CI = −0.85 – −0.02). Methicillin-resistance decreased with accumulative ALT (RR = 0.82; 95% CI = 0.69 – 0.98). In this study, daptomycin locks achieve the highest eradication rate of CoNS from hemodialysis catheters in vivo.

To report on the therapy used for penicillin- and cephalosporin-resistant pneumococcal meningitis, we conducted an observational cohort study of patients admitted to our hospital with pneumococcal meningitis between 1977 and 2018. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations, we defined pneumococci as susceptible and resistant to penicillin with MIC values of ≤0.06 mg/L and > 0.06 mg/L, respectively; the corresponding values for cefotaxime (CTX) were ≤0.5 mg/L and >0.5 mg/L. We treated 363 episodes of pneumococcal meningitis during the study period. Of these, 24 had no viable strain, leaving 339 episodes with a known MIC for inclusion. Penicillin-susceptible strains accounted for 246 episodes (73%), penicillin-resistant strains for 93 (27%), CTX susceptible for 58, and CTX resistant for 35. Nine patients failed or relapsed and 69 died (20%), of whom 22% were among susceptible cases and 17% were among resistant cases. During the dexamethasone period, mortality was equal (12%) in both susceptible and resistant cases. High-dose CTX (300 mg/Kg/day) helped to treat failed or relapsed cases and protected against failure when used as empirical therapy (P = 0.02), even in CTX-resistant cases. High-dose CTX is a good empirical therapy option for pneumococcal meningitis in the presence of a high prevalence of penicillin and cephalosporin resistance, effectively treating pneumococcal strains with MICs up to 2 mg/L for either penicillin or CTX.

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.

Candida bloodstream infections are associated with high attributable mortality, where early initiation of adequate antifungal therapy is important to increase survival in critically ill patients. The exposure variability of micafungin, a first-line agent used for the treatment of invasive candidiasis, in critically ill patients is significant, potentially resulting in underexposure in a substantial portion of these patients. The objective of this study was to develop a population pharmacokinetic model including appropriate sampling strategies for assessing micafungin drug exposure in critically ill patients to support adequate area under the concentration-time curve (AUC) determination. A two-compartment pharmacokinetic model was developed using data from intensive care unit (ICU) patients (n = 19), with the following parameters: total body clearance (CL), volume of distribution of the central compartment (V1), inter-compartmental clearance (CL12), and volume of distribution of the peripheral compartment (V2). The final model was evaluated with bootstrap analysis and the goodness-of-fit plots for the population and individual predicted micafungin plasma concentrations. Optimal sampling strategies (with sampling every hour, 24 h per day) were developed with 1- and 2-point sampling schemes. Final model parameters (±SD) were: CL = 1.03 (0.37) (L/h/1.85 m2), V1 = 0.17 (0.07) (L/kg LBMc), CL12 = 1.80 (4.07) (L/h/1.85 m2), and V2 = 0.12 (0.06) (L/kg LBMc). Sampling strategies with acceptable accuracy and precision were developed to determine the micafungin AUC. The developed model with optimal sampling procedures provides the opportunity to achieve quick optimization of the micafungin exposure from a single blood sample using Bayesian software and may be helpful in guiding early dose decision-making.

Methicillin-resistant Staphylococcus aureus (MRSA) is an uncommon but serious cause of community-acquired pneumonia (CAP). A lack of validated MRSA CAP risk factors can result in overuse of empirical broad-spectrum antibiotics. We sought to develop robust models predicting the risk of MRSA CAP using machine learning using a population-based sample of hospitalized patients with CAP admitted to either a tertiary academic center or a community teaching hospital. Data were evaluated using a machine learning approach. Cases were CAP patients with MRSA isolated from blood or respiratory cultures within 72 h of admission; controls did not have MRSA CAP. The Classification Tree Analysis algorithm was used for model development. Model predictions were evaluated in sensitivity analyses. A total of 21 of 1,823 patients (1.2%) developed MRSA within 72 h of admission. MRSA risk was higher among patients admitted to the intensive care unit (ICU) in the first 24 h who required mechanical ventilation than among ICU patients who did not require ventilatory support (odds ratio [OR], 8.3; 95% confidence interval [CI], 2.4 to 32). MRSA risk was lower among patients admitted to ward units than among those admitted to the ICU (OR, 0.21; 95% CI, 0.07 to 0.56) and lower among ICU patients without a history of antibiotic use in the last 90 days than among ICU patients with antibiotic use in the last 90 days (OR, 0.03; 95% CI, 0.002 to 0.59). The final machine learning model was highly accurate (receiver operating characteristic [ROC] area = 0.775) in training and jackknife validity analyses. We identified a relatively simple machine learning model that predicted MRSA risk in hospitalized patients with CAP within 72 h postadmission.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [C(max)] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

A significant proportion of patients with Rhino-orbito-cerebral mucormycosis (ROCM) develop oroantral fistulas. Due to the unclear efficacy of crushed delayed-release posaconazole tablets (DRPT) via nasogastric tube in this group of patients, clinicians often use inferior alternatives like posaconazole suspension. In this prospective study, we report good plasma concentrations (median, 2,639 ng/mL; interquartile range [IQR], 1,690 to 3,575 ng/mL; and range, 1,004 to 4,835ng/mL) and complete cure and survival at 3 and 6 months in 19 such patients.

In this retrospective analysis including 173 patients in a tertiary referral center in South Korea, compared with the standard therapeutic regimen, clofazimine or moxifloxacin plus standard treatment regimen potentially did not induce a higher 1-year culture conversion rate in patients with Mycobacterium avium complex pulmonary disease who present with cavitary lesions (fibrocavitary or cavitary nodular bronchiectatic type).

In orthopedic oncology, the implant of a megaprosthetic device is standard of care after large-scale tumor resection involving segmental removal of bone. Infection remains the leading cause of implant failure, often resulting in major morbidity. Perioperative antibiotic practices for megaprosthetic reconstructions are not standardized and are based on guidelines for conventional joint arthroplasties. This study aims to evaluate the efficacy of current prophylactic strategies for megaprosthetic reconstructions. We conducted a retrospective review of megaprosthetic reconstructions performed at Duke University from 2001 to 2021. Logistic regression with GEE was used to assess whether a prolonged course of postoperative antibiotics is associated with infection risk. We assessed the microbial profile and corresponding susceptibilities of megaprosthetic infections through record review. Additionally, we designed a pharmacokinetic subgroup analysis using liquid chromatography—tandem mass spectrometry to quantify antibiotic concentrations in surgical tissue. Wilcoxon rank-sum tests were used to correlate tissue concentrations with infection risk. Out of 184 cases, 23 (12.5%) developed infection within 1 year. Extended postoperative antibiotics were not significantly associated with infection risk (P = 0.23). Among 18 culture-positive cases, 4 (22.2%) were caused by cefazolin-susceptible organisms. Median bone and muscle concentrations of cefazolin among cases that developed postoperative infection (0.065 ng/mL and 0.2 ng/mL, respectively) were significantly lower than those of cases that did not (0.42 ng/mL and 1.95 ng/mL, P

We investigated the treatment outcomes of patients with cavitary nodular bronchiectatic (C-NB)-type Mycobacterium avium complex (MAC) pulmonary disease (PD) via outcome comparisons between the fibrocavitary (FC) and C-NB types treated with guideline-based therapy (GBT) composed of daily three-drug oral antibiotics and injectable aminoglycoside. Additionally, we analyzed whether treatment with oral antibiotics alone would result in acceptable outcomes for the C-NB type. From 2002 to 2019, patients with cavitary MAC-PD who received three-drug oral antibiotics with or without an injectable aminoglycoside for ≥1 year were retrospectively enrolled at a tertiary referral center in South Korea. We compared the rates of culture conversion at 12 months according to the radiological type and treatment regimen. The overall culture conversion rate at 12 months of 154 patients with cavitary MAC-PD who received GBT was 75.3%. Among them, the culture conversion rates of 114 patients with the C-NB type were higher than that of 40 patients with the FC-type (80.7% versus 60.0%, respectively; P = 0.009). Of 166 patients with the C-NB-type treated with oral medications with or without an injectable drug, 83.7% achieved culture conversion at 12 months. The conversion rates of those who received oral medications alone and those treated with oral medications and an injectable aminoglycoside were similar (90.4% versus 80.7%, respectively; P = 0.117). In conclusion, the culture conversion rates of the patients with C-NB type treated with GBT were significantly higher than those of patients with the FC type. Additionally, the C-NB type could be treated with oral medications alone.

Antimalarial resistance threatens global malaria control efforts. The World Health Organization (WHO) recommends routine antimalarial efficacy monitoring through a standardized therapeutic efficacy study (TES) protocol. From June 2016 to March 2017, children with uncomplicated P. falciparum mono-infection in Siaya County, Kenya were enrolled into a standardized TES and randomized (1:1 ratio) to a 3-day course of artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP). Efficacy outcomes were measured at 28 and 42 days. A total of 340 children were enrolled. All but one child cleared parasites by day 3. PCR-corrected adequate clinical and parasitological response (ACPR) was 88.5% (95% CI: 80.9 to 93.3%) at day 28 for AL and 93.0% (95% CI: 86.9 to 96.4%) at day 42 for DP. There were 9.6 times (95% CI: 3.4 to 27.2) more reinfections in the AL arm compared to the DP arm at day 28, and 3.1 times (95% CI: 1.9 to 4.9) more reinfections at day 42. Both AL and DP were efficacious (per WHO 90% cutoff in the confidence interval) and well tolerated for the treatment of uncomplicated malaria in western Kenya, but AL efficacy appears to be waning. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended.

Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investigate the probability of target attainment (PTA) of the percentage of the dosing interval that the unbound drug concentration exceeded the MIC (%fT(>MIC)) to treat MRSA infections. Healthy subjects’ plasma and microdialysate concentrations from muscle and subcutaneous tissue following 600 mg every 12 h (q12h) and q8h and neurosurgical patients’ plasma and CSF concentrations following single 600-mg dosing were used. Plasma concentrations were described by a two-compartment model, and tissue concentrations were incorporated as three independent compartments linked to the central compartment by bidirectional transport (clearance in [CL(in)] and CL(out)). Apparent volumes were fixed to physiological interstitial values. Healthy status and body weight were identified as covariates for the volume of the central compartment, and creatinine clearance was identified for clearance. The CSF glucose concentration (GLUC) was inversely correlated with CL(in,CSF). Simulations showed a PTA of >90% in plasma and soft tissues for both regimens assuming an MIC of 1 mg/L and a %fT(>MIC) of 28.8%. Using the same target, patients with inflamed meninges (0.5

This is a retrospective single-center study of 24 patients who received ceftazidime-avibactam plus aztreonam (CZA/ATM) for the treatment of VIM-type-producing Gram-negative bacillus (GNB) infections. The bacteria isolated were Enterobacterales in 22 patients and Pseudomonas aeruginosa in 2. Sixteen out of 19 isolates showed synergistic activity. Two patients presented clinical failure at day 14, and the 30-day mortality was 17% (4/24).

Opisthorchiasis due to the liver fluke Opisthorchis felineus is highly prevalent in rural regions of Western Siberia, causing severe liver and bile duct maladies. Praziquantel administered as a three-dose regimen is the only drug used to treat O. felineus-infected individuals. A simpler single-dose treatment might serve as an alternative. The aim of this study was to compare the pharmacokinetic (PK) properties of single, ascending doses of praziquantel compared to multiple dosing in patients infected with O. felineus to contribute to updated treatment guidelines. Dried blood spots (DBSs) of 110 adults were collected at 11 time points post-drug administration at single oral doses of 20, 40, and 60 mg/kg, as well as 3× 20 mg/kg (4 h dosing interval). DBS samples were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and PK parameters were obtained for R-, S-, and R-trans-4-OH-praziquantel employing noncompartmental analysis. We observed the highest drug exposure for all analytes when the triple-dose scheme was used; area under the concentration-time curve from 0 to 24 h (AUC(0–24)) values of 8.04, 27.75, and 36.38 μg/mL·h were obtained, respectively. Maximal plasma concentrations (C(max)) values of 1.72, 4.89, and 2.69 μg/mL were calculated for R-, S-, and R-trans-4-OH-praziquantel, respectively, when patients were given a single 60-mg/kg dose, and they peaked at 1.5 and 2 h for the enantiomers and at 3 h for the metabolite. The herein-generated PK data, together with results that will be obtained from the integrated efficacy study, lay the groundwork for a possibly optimized treatment scheme for O. felineus-infected patients.

Tuberculosis is the most common cause of death in HIV-infected individuals. Rifampin and isoniazid are the backbones of the current first-line antitubercular therapy. The aim of the present study was to describe the time-dependent pharmacokinetics and pharmacogenetics of rifampin and isoniazid and to quantitatively evaluate the drug-drug interaction between rifampin and isoniazid in patients coinfected with HIV. Plasma concentrations of isoniazid, acetyl-isoniazid, isonicotinic acid, rifampin, and 25-desacetylrifampin from 40 HIV therapy-naive patients were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after the first dose and at steady state of antitubercular therapy. Patients were genotyped for determination of acetylator status and CYP2C19 phenotype. Nonlinear mixed-effects models were developed to describe the pharmacokinetic data. The model estimated an autoinduction of both rifampin bioavailability (0.5-fold) and clearance (2.3-fold). 25-Desacetylrifampin clearance was 2.1-fold higher at steady state than after the first dose. Additionally, ultrarapid CYP2C19 metabolizers had a 2-fold-higher rifampin clearance at steady state than intermediate or extensive metabolizers. An induction of isonicotinic acid formation from isoniazid dependent on total rifampin dose was estimated. Simulations indicated a 30% lower isoniazid exposure at steady state during administration of standard rifampin doses than isoniazid exposure in noninduced individuals. Rifampin exposure was correlated with CYP2C19 polymorphism, and rifampin administration may increase exposure to toxic metabolites by isoniazid in patients. Both findings may influence the risk of treatment failure, resistance development, and toxicity and require further investigation, especially with regard to ongoing high-dose rifampin trials.

Acute kidney injury (AKI) is a complication associated with vancomycin. Previous studies demonstrated that the combination of vancomycin and piperacillin-tazobactam increases the risk of AKI compared to vancomycin with meropenem or cefepime. These studies did not utilize area under the curve (AUC)-based dosing, which reduces vancomycin exposure and may decrease nephrotoxicity compared with trough-based dosing. This study evaluated the incidence of AKI in patients receiving AUC-dosed vancomycin with either concomitant piperacillin-tazobactam (VPT) or meropenem or cefepime (VMC). This retrospective cohort study included patients admitted to Sentara Norfolk General Hospital between October 2019 and September 2020 who received AUC-dosed vancomycin and concomitant piperacillin-tazobactam, meropenem, or cefepime for at least 48 h. The primary outcome was the incidence of AKI during treatment or within 24 h of discontinuation. A total of 435 patients (VPT, n = 331; VMC, n = 104) who received a median duration of 4 days of treatment were included. The incidence of AKI was significantly higher with VPT than with VMC (13.6% versus 4.8% [P = 0.014]). Multivariable analysis showed VPT to be an independent risk factor for the development of AKI (odds ratio [OR], 3.00 [95% confidence interval {CI}, 1.15 to 7.76]). VPT was associated with more frequent AKI than VMC, even with the relatively short courses of antimicrobial therapy administered in this population. In comparison with the precedent in the literature for trough-based vancomycin dosing, our results suggest that the use of AUC-based vancomycin dosing in combination with piperacillin-tazobactam, meropenem, or cefepime may result in a lower overall incidence of AKI.

Clofazimine (CFZ) is used to treat pulmonary non-tuberculous mycobacterial (NTM) infection; however, its pharmacokinetics remain unexplored in patients with pulmonary NTM, and the relationship between CFZ serum concentration and adverse effects has not been investigated. The objectives of this study were to characterize the pharmacokinetics of CFZ in pulmonary NTM disease treatment and to investigate the relationship between the steady-state CFZ serum concentration and adverse effects. A prospective observational study was conducted on 45 patients with pulmonary NTM treated with CFZ (UMIN000041053). A maximum of five serum samples per patient were taken at the CFZ trough, and serum concentration was measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The pharmacokinetics of CFZ were analyzed using a nonlinear mixed effect model. The relationships among steady-state CFZ serum concentration and adverse effects, pigmentation, and heart rate-corrected QT (QTc) interval were investigated. Twenty-six patients had M. avium or M. intracellulare infection and nineteen had M. abscessus infection. The primary CFZ dosage was 50 mg/day. The estimated apparent CFZ clearance, apparent volume of distribution, and half-life were 2.4 L/h, 2,960 L, and 36 days, respectively. The combined use of rifampicin and CFZ significantly reduced CFZ exposure by 22%. Although there was no relationship between CFZ serum concentration and pigmentation intensity, the QTc interval was significantly correlated with CFZ serum concentration. The estimation of accurate pharmacokinetics for CFZ required approximately 5 months of monitoring. The relationship between the serum concentration and specific adverse effects of CFZ confirmed that CFZ serum concentration was not associated with pigmentation but did affect the QTc interval.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT(>MIC)) and the time free concentration remained above four multiples of the MIC (fT(>4×MIC)) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Cardio-cerebrovascular disease (CCVD) is a major comorbidity of Coronavirus disease 2019 (COVID-19). However, the clinical characteristics and outcomes remain unclear. In this study, 102 cases of COVID-19 from January 22, 2020 to March 26, 2020 in Xixi Hospital of Hangzhou were included. Twenty cases had pre-existing CCVD. Results showed that compared with non-CCVD patients, those with CCVD are more likely to develop severe disease (15% versus 1%), and the proportion of pneumonia severity index grade IV was significantly higher (25% versus 3.6%). Computed tomography images demonstrated that the proportion of multiple lobe lesion involvement was significantly higher in the CCVD group than in the non-CCVD group (90% versus 63.4%). Compared with non-CCVD group, the levels of C-reactive protein, fibrinogen, D-dimer, and serum amyloid-A were higher, whereas the total protein and arterial partial PaO2 were lower in the CCVD group. Although no statistical difference was observed in the outcomes between groups, CCVD patients received more intensive comprehensive treatment to improve COVID-19 symptoms compared with non-CCVD patients. Integrated Chinese and Western medicine treatments have certain advantages in controlling the severe conversion rate and mortality of COVID-19. In addition, given that COVID-19 patients are usually related to coagulation disorders and thrombosis risk, the application of Chinese medicine in promoting blood circulation and removing stasis should be strengthened.

Differences in pharmacokinetics/pharmacodynamics (PK/PD) target attainment are rarely considered when antifungals are switched in critically ill patients. This study intends to explore whether the antifungal de-escalation treatment strategy and the new intermittent dosing strategy of echinocandins in critically ill patients are able to achieve the corresponding PK/PD targets. The published population PK models of antifungals in critically ill patients and a public data set from the MIMIC-III database (n = 662) were employed to evaluate PK/PD target attainment of different dosing regimens of antifungals. Cumulative fraction of response (CFR) was calculated for each dosing regimen. Most guideline-recommended dosing regimens of fluconazole and voriconazole could achieve target exposure as de-escalation treatment in critically ill patients. For initial echinocandin treatment, achievement of the target exposure decreased as body weight increased, and the intermittent dosing strategy had a slightly higher CFR value in most simulations compared to conventional dosing strategy. For Candida albicans and Candida glabrata infection, caspofungin at the lowest dose achieved a CFR of >90%, while micafungin or anidulafungin required almost the highest doses simulated in this study to achieve the same effect. None of the echinocandins other than 150 mg every 24 h (q24h) or 200 mg q48h of caspofungin achieved the target CFR for Candida parapsilosis infection. These findings support the guideline-recommended dose of triazoles for antifungal de-escalation treatment and confirm the insufficient dosage of echinocandins in critically ill patients, indicating that a dosing regimen based on body weight or intermittent dosing of echinocandins may be required.

Faropenem (FRPM) is active against extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, but evidence for its efficacy is lacking. This study determined the correlation between the susceptibility by disk diffusion method and the MIC of FRPM for third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae, and the effectiveness of FRPM for the treatment of urinary tract infection (UTI) caused by these two bacteria in a retrospective cohort analysis. Of the 48 third-generation cephalosporin-resistant clinical isolates tested, 44 isolates produced ESBL, and 8 isolates produced AmpC, including 4 isolates produced both ESBL and AmpC. Thirty-seven isolates had an FRPM MIC of ≤1 mg/L, and seven had an FRPM MIC of 2 mg/L. An FRPM MIC of >2 mg/L was observed with four isolates. In a retrospective cohort analysis, 63 patients with UTI treated with FRPM were identified. All isolates of ESBL-producing E. coli (n = 54) and K. pneumoniae (n = 9) treated with FRPM showed disk diffusion zone diameters larger than 16.0 mm (estimated MIC, 2.2 mg/L). All patients completed the scheduled treatment courses with FRPM, but 28- and 90-day relapses happened in 10 patients (16%) and 16 patients (25%), respectively. No significant risk factors for the 28- and 90-day relapses were found. FRPM can be used according to disk diffusion susceptibility testing in UTI. Further investigations are necessary to assess the clinical breakpoint of FRPM for ESBL-producing Enterobacterales and the candidates most likely to benefit from using FRPM.

Inhaled formulations of amphotericin B are the most widely used antifungal prophylactic agents in lung transplant recipients, yet there are limited data on their safety. We performed a single-center retrospective cohort study of 603 consecutive patients who underwent lung transplantation between 2012 and 2017 and received antifungal prophylaxis with inhaled amphotericin B lipid complex (iABLC) from the day of transplantation until hospital discharge. Of 603 patients, 600 (99.5%) received ≥1 dose of iABLC, and 544 (90.2%) completed the recommended prophylactic course. In total, 4,128 iABLC doses (median, 5; range, 1 to 48 per patient) were administered; 24 patients received >3 months of therapy. Only one (0.2%) patient discontinued therapy due to a drug-attributable adverse event. During the first posttransplant year, 80 (13.3%) patients died (median time to death, 171 days; interquartile range [IQR], 80 to 272 days), and 3,352 (median, 6 per patient) lung biopsies were performed; 414 (68.7%) patients developed biopsy-proven acute cellular rejection. One-year adverse events in our cohort of lung transplant recipients treated with iABLC during transplant hospitalization matched national outcomes for rejection, graft loss, and death. iABLC is a safe and well-tolerated antifungal prophylactic agent in lung transplant recipients.

Ertapenem is one of the carbapenems recommended for treating extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. However, efficacy data are limited. We compared 30-day mortality rates for patients receiving ertapenem and other carbapenems for treatment of ESBL-producing Enterobacterales bacteremia. A multicenter, retrospective study was performed from January 2013 to December 2020 at three hospitals. Patients who received only members of one group of carbapenems (group 1 or group 2) throughout their treatment for ESBL-producing Escherichia coli or Klebsiella pneumoniae bacteremia were enrolled. To compare 30-day all-cause mortality rates in the two groups, propensity score matching was used to control for selection bias. Subgroup analyses were performed for several subgroups. Secondary outcomes included Clostridioides difficile infection (CDI) and the emergence of multidrug-resistant Gram-negative bacteria within 90 days after initiation of carbapenem treatment. One-to-one propensity score matching yielded 162 pairs of patients from the total of 603 patients included. There was no difference in 30-day mortality rates between ertapenem and the other carbapenems in adjusted analyses (hazard ratio, 0.60 [95% confidence interval [CI], 0.29 to 1.22]) of the propensity score-matched cohorts. A similar result was obtained in a subgroup analysis of patients who suffered severe sepsis or septic shock and those who did not (P = 0.54 for interaction). Emergence of CDI (odds ratio [OR], 0.99 [95% CI, 0.44 to 2.20]) and carbapenem-resistant Enterobacterales (OR, 1.31 [95% CI, 0.51 to 3.53]) did not differ between the two groups. Our study suggests that the efficacy of ertapenem may be comparable to that of the other carbapenems in treatment of ESBL-producing E. coli and K. pneumoniae bacteremia.

Activated platelets have known antimicrobial activity against Staphylococcus aureus. Accelerated clearance of platelets induced by S. aureus can result in thrombocytopenia and increased mortality in patients. Recent studies suggest that P2Y12 inhibition protects platelets from accelerated clearance. We therefore evaluated the effect of P2Y12 inhibition on clinical outcomes in patients with S. aureus bacteremia across a large national cohort. Our retrospective cohort (2010 to 2018) included patients admitted to Veterans Affairs (VA) hospitals with blood cultures positive for S. aureus and treated with standard-of-care antibiotics. Employing propensity score-matched Cox proportional hazards regression models, we compared clinical outcomes in patients treated with clopidogrel for at least the 30 days prior to admission and continuing for at least 5 days after admission to patients without any P2Y12 inhibitor use in the year preceding admission. Mortality was significantly lower among clopidogrel users than P2Y12 inhibitor nonusers (n = 147 propensity score-matched pairs): the inpatient mortality hazard ratio (HR) was 0.11 (95% confidence interval [CI], 0.01 to 0.86), and 30-day mortality HR was 0.43 (95% CI, 0.19 to 0.98). There were no differences in 30-day readmission, 30-day S. aureus reinfection, microbiological clearance, or thrombocytopenia. Clopidogrel use at the time of infection reduced in-hospital mortality by 89% and 30-day mortality by 57% among a cohort of patients with S. aureus bacteremia. These results support the need to further study the use of P2Y12 inhibitors as adjunctive therapy in S. aureus bloodstream infections.

International audience; Human T-lymphotropic virus type 1 (HTLV-1) is estimated to affect 5 to 10 million people globally and can cause severe and potentially fatal disease, including adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The burden of HTLV-1 infection appears to be geographically concentrated, with high prevalence in discrete regions and populations. While most high-income countries have introduced HTLV-1 screening of blood donations, few other public health measures have been implemented to prevent infection or its consequences. Recent advocacy from concerned researchers, clinicians, and community members has emphasized the potential for improved prevention and management of HTLV-1 infection. Despite all that has been learned in the 4 decades following the discovery of HTLV-1, gaps in knowledge across clinical and public health aspects persist, impeding optimal control and prevention, as well as the development of policies and guidelines. Awareness of HTLV-1 among health care providers, communities, and affected individuals remains limited, even in countries of endemicity. This review provides a comprehensive overview on HTLV-1 epidemiology and on clinical and public health and highlights key areas for further research and collaboration to advance the health of people with and at risk of HTLV-1 infection.

We determined optimal vancomycin starting dose regimens in infants ≤180 days of age to achieve the highest probability of target attainment with an area under the concentration-time curve for 24 h (AUC(24)) of ≥400 using population pharmacokinetic (PK) modeling. Secondarily, determination of the relationship between serum creatinine (SCR) and vancomycin clearance in neonates was done. A retrospective population PK study was designed and included pediatric patients ≤180 days old who had received vancomycin and had a serum vancomycin concentration sampled. A population PK model was developed using Pumas (v1.0.5). Simulation was performed with various dosing regimens to evaluate the probability of AUC(24) target attainment and probability of trough of ≤20 mg/liter, and comparison to published models was performed. Individual clearance estimates, obtained from the final model, were plotted against SCR and faceted by age quartiles to assess the relationship between SCR and vancomycin clearance. A total of 934 patients were included in the study (58.6% male; median age, 43.6 days [range of 0 to 184]; median number of concentration samples, 1 [range of 1 to 29]). A one-compartment model was developed with body weight (WT), SCR, and postmenstrual age (PMA) identified as significant covariates on clearance. Plotting vancomycin clearance versus SCR demonstrated no clear relationship between the two at