Yanina Dubrovskaya

Monotherapy with Fluoroquinolone or Trimethoprim-Sulfamethoxazole for Treatment of Stenotrophomonas maltophilia Infections

ABSTRACT 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.

Fidaxomicin versus Conventional Antimicrobial Therapy in 59 Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation with Clostridium difficile-Associated Diarrhea

ABSTRACT 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.

Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections

ABSTRACT Polymyxins are reserved for salvage therapy of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Though synergy has been demonstrated for the combination of polymyxins with carbapenems or tigecycline, in vitro synergy tests are nonstandardized, and the clinical effect of synergy remains unclear. This study describes outcomes for patients with CRKP infections who were treated with polymyxin B monotherapy. We retrospectively reviewed the medical records of patients with CRKP infections who received polymyxin B monotherapy from 2007 to 2011. Clinical, microbiology, and antimicrobial treatment data were collected. Risk factors for treatment failure were identified by logistic regression. Forty patients were included in the analysis. Twenty-nine of 40 (73%) patients achieved clinical cure as defined by clinician-documented improvement in signs and symptoms of infections, and 17/32 (53%) patients with follow-up culture data achieved microbiological cure. End-of-treatment mortality was 10%, and 30-day mortality was 28%. In a multivariate analysis, baseline renal insufficiency was associated with a 6.0-fold increase in clinical failure after adjusting for septic shock (odds ratio [OR] = 6.0; 95% confidence interval [CI] = 1.22 to 29.59). Breakthrough infections with organisms intrinsically resistant to polymyxins occurred in 3 patients during the treatment. Eighteen of 40 (45%) patients developed a new CRKP infection a median of 23 days after initial polymyxin B treatment, and 3 of these 18 infections were polymyxin resistant. The clinical cure rate achieved in this retrospective study was 73% of patients with CRKP infections treated with polymyxin B monotherapy. Baseline renal insufficiency was a risk factor for treatment failure after adjusting for septic shock. Breakthrough infections with organisms intrinsically resistant to polymyxin B and development of resistance to polymyxin B in subsequent CRKP isolates are of concern.

Risk factors for nephrotoxicity onset associated with polymyxin B therapy

OBJECTIVES Polymyxin B is an active agent against many MDR Gram-negative bacteria, but nephrotoxicity is a major hindrance to its widespread use. To guide its optimal use, we determined the risk factors for nephrotoxicity onset associated with polymyxin B. METHODS In a multicentre, retrospective, cohort study, we evaluated adult patients with normal renal function who received ≥72 h of polymyxin B therapy. Pertinent information was retrieved from medical records; patients were followed for up to 30 days after therapy was started. The primary endpoint of this study was the onset of nephrotoxicity. A Cox proportional hazards model was used for analysis. RESULTS A total of 192 patients (52.1% male, 67.7% Caucasian) were evaluated. The mean ± SD age, actual body weight (ABW) and daily dose by ABW were 68.3 ± 17.2 years, 71.5 ± 20.4 kg and 1.5 ± 0.5 mg/kg, respectively. The median duration of therapy was 9.5 days. The overall prevalence rate of nephrotoxicity was 45.8% and the median onset of nephrotoxicity was 9 days. Independent risk factors for the onset of nephrotoxicity included daily dose by ABW (HR = 1.73; P = 0.022), concurrent use of vancomycin (HR = 1.89; P = 0.005) and contrast media (HR = 1.79; P = 0.009). Nephrotoxicity was seen earlier in the high-risk group (P = 0.003). CONCLUSIONS 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.

Fidaxomicin Therapy in Critically Ill Patients with Clostridium difficile Infection

ABSTRACT Fidaxomicin use to treat proven Clostridium difficile infection (CDI) was compared between 20 patients receiving care in critical care units (CCUs) and 30 patients treated on general medical floors. At baseline, the CCU patients had more initial CDI episodes, more severe and complicated disease, and more concurrent broad-spectrum antibiotic coverage. On multivariate analysis, the response to fidaxomicin therapy among the critically ill patients was comparable to that among patients in the general medical wards.

Extended-Infusion versus Standard-Infusion Piperacillin-Tazobactam for Sepsis Syndromes at a Tertiary Medical Center

ABSTRACT Piperacillin-tazobactam (PTZ) is frequently used as empirical and targeted therapy for Gram-negative sepsis. Time-dependent killing properties of PTZ support the use of extended-infusion (EI) dosing; however, studies have shown inconsistent benefits of EI PTZ treatment on clinical outcomes. We performed a retrospective cohort study of adult patients who received EI PTZ treatment and historical controls who received standard-infusion (SI) PTZ treatment for presumed sepsis syndromes. Data on mortality rates, clinical outcomes, length of stay (LOS), and disease severity were obtained. A total of 843 patients (662 with EI treatment and 181 with SI treatment) were available for analysis. Baseline characteristics of the two groups were similar, except for fewer female patients receiving EI treatment. No significant differences between the EI and SI groups in inpatient mortality rates (10.9% versus 13.8%; P = 0.282), overall LOS (10 versus 12 days; P = 0.171), intensive care unit (ICU) LOS (7 versus 6 days; P = 0.061), or clinical failure rates (18.4% versus 19.9%; P = 0.756) were observed. However, the duration of PTZ therapy was shorter in the EI group (5 versus 6 days; P < 0.001). Among ICU patients, no significant differences in outcomes between the EI and SI groups were observed. Patients with urinary or intra-abdominal infections had lower mortality and clinical failure rates when receiving EI PTZ treatment. We did not observe significant differences in inpatient mortality rates, overall LOS, ICU LOS, or clinical failure rates between patients receiving EI PTZ treatment and patients receiving SI PTZ treatment. Patients receiving EI PTZ treatment had a shorter duration of PTZ therapy than did patients receiving SI treatment, and EI dosing may provide cost savings to hospitals.

Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency.

ABSTRACT 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 patients 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 [CLCR] ≥ 80 ml/min) at baseline, whereas 14 had renal insufficiency (CLCR < 80 ml/min). The mean AUC of polymyxin B ± the standard deviation in the normal renal function cohort was 63.5 ± 16.6 mg·h/liter compared to 56.0 ± 17.5 mg·h/liter in the renal insufficiency cohort (P = 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 ± 7.0 mg·h/liter versus 29.7 ± 11.2 mg·h/liter, P = 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.

Effectiveness and Tolerability of a Polymyxin B Dosing Protocol

TO THE EDITOR: Optimal dosing of polymyxin B is not well defined. Limited in vitro pharmacodynamic data suggest that polymyxin B killing correlates most closely with an area under the curve/minimum inhibitory concentration (AUC/MIC) ratio.1 At our institution, historical conventional dosing of polymyxin B was based on 15,000-25,000 units/kg/day in 2 divided doses, with adjustment for renal function based on the physician’s discretion. We implemented a new polymyxin B dosing protocol to address observed clinical failures. All patients were given a loading dose of polymyxin B 25,000 units/kg on day 1. Subsequent doses and dosing interval were adjusted as follows: creatinine clearance (CrCl) >80 mL/min: 25,000 units/kg administered once every 24 hours; CrCl 30-80 mL/min: 15,000 units/kg once every 24 hours; CrCl <30 mL/min or continuous renal replacement therapy: 15,000 units/kg once every 48 hours; and CrCl <10 mL/min or hemodialysis: 10,000 units/kg once every 72 hours. Polymyxin B doses were calculated using ideal body weight.2 The objective of this study was to evaluate the effectiveness and tolerability of the new protocol as compared to conventional dosing. Methods. A retrospective chart review of sequential patients who received polymyxin B before and after protocol implementation was conducted. Patients 18 years of age or older with infections caused by multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, or Acinetobacter baumannii who were treated with polymyxin B for 72 hours or longer were included. An isolate was considered to be multidrug-resistant if it was nonsusceptible to 3 or more antimicrobial classes.3 Only the first treatment course of polymyxin B was included. Microbiologic clearance, clinical response at the end of therapy that was based on the physician’s assessment as stable/improved or deteriorating, mortality at end of therapy and at the end of hospitalization, and nephrotoxicity assessed by risk, injury, failure, loss, and end-stage kidney disease (RIFLE) criteria were evaluated.4 Results. Forty patients in each group were compared (Table 1). The mean single dose of polymyxin B was significantly higher in the protocol group compared to the conventional group, with no significant difference between groups for the mean daily dose. Microbiologic eradication was 73.3% versus 54.5% (p = 0.06) in the protocol group and conventional group, respectively, and 73.3% versus 44.4% (p = 0.01) after exclusion of catheter-related bloodstream infections (CRBSIs), since all patients with CRBSIs in the conventional group had their catheters removed with subsequent negative cultures. Microbiologic eradication was 66.7% versus 25% (p = 0.05) for respiratory infections in the protocol and conventional groups, respectively.5 Clinical response was 65% and 58% (p = 0.49) in the protocol and conventional groups, respectively. Mortality at end of therapy was 15% in the protocol group and 20% in the conventional dosing group (p = 0.56). Mortality at end of hospitalization was 30% and 38% (p = 0.48) in the protocol and conventional groups, respectively. In the protocol group, 58% of the patients met RIFLE criteria for nephrotoxicity at the time of peak serum creatinine (SCr) level compared to 20% in the conventional dosing group (p = 0.002). One week after the last polymyxin B dose, nephrotoxicity was 26.3% in the protocol group and 15.4% in the conventional group (p = 0.67). Among patients 70 years of age and older, the nephrotoxicity rate at peak SCr was 59% in the protocol group and 14% in the conventional dosing group (p = 0.008); 1 week after the last polymyxin B dose, nephrotoxicity was 30.8% in the protocol group and 0% in the conventional group (p = 0.13). In patients who developed nephrotoxicity, the mean time to peak SCr was 9 days in both groups. In this single-center retrospective evaluation, we observed a trend toward better microbiologic eradication in the protocol group, with no significant difference in clinical response and mortality. Using polymyxin B once daily for a prolonged duration may put patients at increased risk of nephrotoxicity, particularly the elderly. We also conclude that a loading dose did not correlate with nephrotoxicity, given that the time to peak SCr was identical in both groups, and might provide some benefits.

Multidrug-Resistant Bacteroides fragilis Bacteremia in a US Resident: An Emerging Challenge

We describe a case of Bacteroides fragilis bacteremia associated with paraspinal and psoas abscesses in the United States. Resistance to b-lactam/b-lactamase inhibitors, carbapenems, and metronidazole was encountered despite having a recent travel history to India as the only possible risk factor for multidrug resistance. Microbiological cure was achieved with linezolid, moxifloxacin, and cefoxitin.

Single high dose gentamicin for perioperative prophylaxis in orthopedic surgery: Evaluation of nephrotoxicity

Background: Recent studies described an increase in acute kidney injury when high dose gentamicin was included in perioperative prophylaxis for orthopedic surgeries. To this effect, we compared the rate of nephrotoxicity for selected orthopedic surgeries where gentamicin was included (Gentamicin Group) to those where it was not included (Control Group) for perioperative prophylaxis and evaluated risk factors for nephrotoxicity. Methods: Spine, hip and knee surgeries performed between April 2011 and December 2013 were reviewed retrospectively. Gentamicin was given to eligible patients based on age, weight and Creatinine Clearance. Nephrotoxicity was assessed using Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) criteria. Results: Among selected surgeries (N = 1590 in Gentamicin Group: hip = 926, spine = 600, knee = 64; N = 2587 in Control Group: hip = 980, spine = 902, knee = 705), patients’ body weight, serum creatinine, comorbidities and surgery duration were similar in Gentamicin Group and Control Group. Gentamicin median dose was 4.5 mg/kg of dosing weight. Nephrotoxicity rate was 2.5% in Gentamicin Group and 1.8% in Control Group, p = 0.17. Most cases of nephrotoxicity were Risk category by RIFLE criteria (67% in Gentamicin Group and 72% in Control Group, p = 0.49). In logistic regression, risk factors for nephrotoxicity were hospital stay >1 day prior to surgery (odds ratio = 8.1; 95% confidence interval = 2.25–28.97, p = 0.001), knee or hip surgery (odds ratio = 4.7; 95% confidence interval = 2.9–9.48, p = 0.0005) and diabetes (odds ratio = 1.95; 95% confidence interval = 1.13–3.35, p = 0.016). Receipt of gentamicin was not an independent predictor of nephrotoxicity (odds ratio = 1.5; 95% confidence interval = 0.97–2.35, p = 0.07). Conclusion: In this cohort, rate of nephrotoxicity was similar between Gentamicin Group and Control Group. Single high dose gentamicin is a safe and acceptable option for perioperative prophylaxis in eligible patients undergoing orthopedic surgeries.