The treatment of choice for Stenotrophomonas maltophilia is trimethoprim-sulfamethoxazole (SXT). Fluoroquinolones (FQs) have in vitro activity against S. maltophilia; however, there is limited published information on their effectiveness. The purpose of this study is to compare the effectiveness of FQs and SXT for the treatment of S. maltophilia. A retrospective review of 98 patients with S. maltophilia infections who received SXT or FQ monotherapy was conducted. Patients >18 years old with a positive culture for S. maltophilia and clinical signs of infection who received treatment for >48 h were included. Microbiological cure and clinical response were evaluated at the end of therapy (EOT). In-hospital mortality and isolation of nonsusceptible isolates were also evaluated. Thirty-five patients received SXT, and 63 patients received FQ; 48 patients received levofloxacin, and 15 patients received ciprofloxacin. The most common infection was pulmonary. The overall microbiological cure rate at EOT was 63%. Thirteen of 20 patients (65%) who received SXT and 23 of 37 patients (62%) who received FQ had microbiological cure at EOT (P ‫؍‬ 0.832). The overall clinical success rate was 55%, 52% for those who received FQ and 61% for those who received SXT (P ‫؍‬ 0.451). In-hospital mortality was 24%, with similar rates in the two groups (25% for FQ versus 22% for SXT; P ‫؍‬ 0.546). Development of resistance on repeat culture was 30% for FQ and 20% for SXT (P ‫؍‬ 0.426). Fluoroquinolone and SXT monotherapies may be equally effective for the treatment of S. maltophilia infections. Resistance was documented in subsequent isolates of S. maltophilia in both groups.

Background Effective therapies to combat COVID-19 are urgently needed. Hydroxychloroquine (HCQ) has in vitro antiviral activity against SARS-CoV-2, but the clinical benefit of HCQ in treating COVID-19 is unclear. Randomized controlled trials are needed to determine the safety and efficacy of HCQ for the treatment of hospitalized patients with COVID-19. Methods We conducted a multicenter, double-blind, randomized clinical trial of HCQ among patients hospitalized with laboratory confirmed COVID-19. Subjects were randomized in a 1:1 ratio to HCQ or placebo for five days and followed for 30 days. The primary efficacy outcome was a severe disease progression composite endpoint (death, ICU admission, mechanical ventilation, ECMO, and/or vasopressor use) at day 14. Results A total of 128 patients were included in the intention-to-treat analysis. Baseline demographic, clinical, and laboratory characteristics were similar between HCQ (N=67) and placebo (N=61) arms. At day 14, 11 (16.4%) subjects assigned to HCQ and 6 (9.8%) subjects assigned to placebo met the severe disease progression endpoint, but this did not achieve statistical significance (P=.350). There were no significant differences in COVID-19 clinical scores, number of oxygen-free days, SARS-CoV-2 clearance, or adverse events between HCQ and placebo. HCQ was associated with a slight increase in mean corrected QT interval, an increased D-dimer, and a trend towards an increased length of stay. Conclusions In hospitalized patients with COVID-19, our data suggest that HCQ does not prevent severe outcomes or improve clinical scores. However, our conclusions are limited by a relatively small sample size, and larger randomized controlled trials or pooled analyses are needed.

Polymyxin B is used as a last treatment resort for multidrug-resistant Gram-negative bacterial infections. The objectives of this study were to examine the population pharmacokinetics of polymyxin B and investigate factor(s) influencing pharmacokinetic variability. Four serial blood samples each were collected from 35 adult patients at steady state. The concentrations of individual polymyxin B components were analyzed using a validated liquid chromatography / tandem mass spectrometry assay and combined to derive total concentrations. A maximum likelihood expectation maximization approach was used to fit the data. Various demographic variables were investigated as potential covariates for clearance and volume of distribution (V ) using linear regression analysis. A one-compartment model fit to the data satisfactorily (r = 0.96). The best-fit mean ± SD for clearance and V were 2.5 ± 1.1 L/h and 34.3 ± 16.4 L, respectively. Creatinine clearance was found to be a statistically significant covariate of clearance, but the magnitude was deemed clinically insignificant.

Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CL CR ] Ն 80 ml/min) at baseline, whereas 14 had renal insufficiency (CL CR Ͻ 80 ml/min). The mean AUC of polymyxin B Ϯ the standard deviation in the normal renal function cohort was 63.5 Ϯ 16.6 mg·h/liter compared to 56.0 Ϯ 17.5 mg·h/liter in the renal insufficiency cohort (P ϭ 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 Ϯ 7.0 mg·h/liter versus 29.7 Ϯ 11.2 mg·h/liter, P ϭ 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.KEYWORDS polymyxins, dosing adjustment, drug exposure P arenteral polymyxins (polymyxin B and polymyxin E [colistin]) have become one of the most important antibiotics for therapy of extensively drug-resistant Gramnegative bacterial infections over the past decade, including infections caused by carbapenem-resistant nonfermenters and carbapenem-resistant Enterobacteriaceae. The similarities and differences between polymyxin B and colistin have been reviewed elsewhere (1). Polymyxin B has been increasingly used due to the active drug form used, more straight-forward dosing, more favorable pharmacokinetics, and potentially lower incidence of nephrotoxicity than colistin (2, 3). Current U.S. Food and Drug Administration-approved prescribing information recommends polymyxin B dosing adjustment in patients with renal insufficiency (package inserts from Bedford Laboratories,

Risk factors for nephrotoxicity onset associated with polymyxin B were identified. In conjunction with susceptibility and other pharmacokinetic/pharmacodynamic data, our results can be used to optimize treatment for MDR Gram-negative infections.

I nfections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) have been associated with poor outcomes. An overall mortality rate of 48% is reported for patients with CRKP, compared to 26% for those with carbapenem-susceptible K. pneumoniae infections (1). CRKP isolates confer resistance through the production of K. pneumoniae carbapenemases (KPCs), which are able to hydrolyze all currently available ␤-lactams, including carbapenems (2). Due to additional mechanisms of resistance commonly found in KPC-producing isolates, they often demonstrate resistance to other antimicrobial classes, including fluoroquinolones and aminoglycosides (2, 3). This limits therapeutic choices, as polymyxins (polymyxin B or colistin) and tigecycline may be the only antibiotics that retain in vitro and in vivo microbiological activity.CRKP infections are often treated with combination therapy (4, 5); however, the choice of agents is both limited and challenging. Combination therapy with aminoglycosides, if susceptibility is preserved, carries an increased risk of nephrotoxicity. Due to a high volume of distribution, low blood levels, and high MIC, tigecycline is a "last resort" option, particularly for bloodstream infections. High MICs of carbapenems preclude achieving therapeutic levels even with pharmacodynamically optimized dosing strategies. Although in vitro synergy against CRKP has been observed when polymyxin B is used in combination with rifampin, cefepime, aminoglycosides, carbapenems, or tigecycline, testing methods are nonstandardized, and therefore the clinical effect of synergy remains unclear (3,(6)(7)(8). Limited data have demonstrated survival benefits of combination therapy using polymyxin B or colistin with carbapenems and/or tigecycline for patients with CRKP bacteremia (4, 5). Given the frequently encountered challenges of combination therapy, we aimed to describe the outcomes for patients with CRKP infections treated with polymyxin B monotherapy and to identify risk factors for treatment failure. MATERIALS AND METHODSStudy design. This was a retrospective study in a tertiary care academic medical center in New York City. The study population included adult patients (aged Ն18 years) with CRKP infections who received polymyxin B monotherapy for Ն72 h. Only the first treatment course was included.Microbiology. Cases were identified from a microbiology lab report of CRKP isolates from 1 January 2007 to 15 August 2011 and by review of medical records. The Vitek-2 system (bioMérieux) used by our microbiology laboratory has built-in analysis software (version R05.01) that enables it to identify resistance phenotypes. Isolates were included if the ertapenem/imipenem MIC was reported as resistant by Vitek-2. For tigecycline and polymyxin B, susceptibility was defined as an MIC of Յ2 mg/liter by Etest, according to Food and Drug Administration (FDA) breakpoints for Enterobacteriaceae and Clinical and Laboratory Standards Institute (CLSI) breakpoints for Acinetobacter baumannii, respectively. Data collection. Patient...

Extended infusion (EI) administration of β-lactams can improve target attainment in critically ill patients with altered pharmacokinetics/pharmacodynamics. To optimize meropenem dosing in patients with severe sepsis/septic shock, our Antimicrobial Stewardship Program implemented a EI meropenem (EIM) protocol in an 18-bed Medical Intensive Care Unit in March 2014. In this retrospective study, we compared intensive care unit (ICU) mortality and clinical response in patients who received meropenem for ≥72 hours administered per EIM protocol of 1 g over 3 hours every 8 hours versus intermittent infusion (IIM) protocol of 500 mg over 30 minutes every 6 hours. Age, weight, comorbidities, severity of illness, and vasopressor use were comparable between groups (EIM protocol n = 52, IIM protocol n = 96). The IIM protocol group had higher rates of renal dose adjustment at meropenem initiation. Among 56 identified gram-negative (GN) pathogens, 94% had meropenem minimal inhibitory concentration ≤0.25 mg/L. The ICU mortality was lower (19 vs 37%; P = .032) and clinical response was higher (83% vs 46%; P < .01) in the EIM protocol versus IIM protocol group. Total vasopressor days were shorter (2 vs 3 days; P = .038), and white blood cell normalization rate was higher (87% vs 51%; P < .01) in the EIM protocol versus IIM protocol group. There was no difference in days of mechanical ventilation, duration of therapy, and ICU stay. The IIM protocol was also identified as an independent risk factor associated with ICU mortality (hazard ratio: 3.653, 95% confidence interval: 1.689-7.981; P = .001) after adjusting for Sequential Organ Failure Assessment score. In this cohort of patients with severe sepsis/septic shock and highly susceptible GN pathogens, there was improved mortality and clinical response in the EIM protocol group.

The feasibility of fidaxomicin versus vancomycin and metronidazole (conventional therapy) was assessed in 59 transplant recipients with 61 episodes of Clostridium difficile-associated diarrhea (CDAD). Overall clinical cure was achieved in 86% of episodes, and in 7% of episodes, infection recurred. Fidaxomicin was well tolerated. Clinical cures were not significantly different compared with conventional therapy (67% versus 89%, respectively; P ‫؍‬ 0.06). Univariate analysis of predictors for lack of clinical cure included continued use of broad-spectrum systemic antibiotics (P ‫؍‬ 0.026) and prior diagnosis of CDAD (95% confidence interval, 1.113 to 19.569; odds ratio, 4.667; P ‫؍‬ 0.041). New-onset vancomycin-resistant Enterococcus (VRE) colonization was not noted after fidaxomicin therapy alone. However, this occurred in 10 of 28 patients (36%) following conventional therapy, and 2 of 3 patients with subsequent bacteremia died.