Bradley J. Gardiner

Is Fosfomycin a Potential Treatment Alternative for Multidrug-Resistant Gram-Negative Prostatitis?

BACKGROUND Multidrug-resistant gram-negative bacterial (MDR-GNB) infections of the prostate are an increasing problem worldwide, particularly complicating transrectal ultrasound (TRUS)-guided prostate biopsy. Fluoroquinolone-based regimens, once the mainstay of many protocols, are increasingly ineffective. Fosfomycin has reasonable in vitro and urinary activity (minimum inhibitory concentration breakpoint ≤64 µg/mL) against MDR-GNB, but its prostatic penetration has been uncertain, so it has not been widely recommended for the prophylaxis or treatment of MDR-GNB prostatitis. METHODS In a prospective study of healthy men undergoing a transurethral resection of the prostate for benign prostatic hyperplasia, we assessed serum, urine, and prostatic tissue (transition zone [TZ] and peripheral zone [PZ]) fosfomycin concentrations using liquid chromatography-tandem mass spectrometry, following a single 3-g oral fosfomycin dose within 17 hours of surgery. RESULTS Among the 26 participants, mean plasma and urinary fosfomycin levels were 11.4 ± 7.6 µg/mL and 571 ± 418 µg/mL, 565 ± 149 minutes and 581 ± 150 minutes postdose, respectively. Mean overall prostate fosfomycin levels were 6.5 ± 4.9 µg/g (range, 0.7-22.1 µg/g), with therapeutic concentrations detectable up to 17 hours following the dose. The mean prostate to plasma ratio was 0.67 ± 0.57. Mean concentrations within the TZ vs PZ prostate regions varied significantly (TZ, 8.3 ± 6.6 vs PZ, 4.4 ± 4.1 µg/g; P = .001). Only 1 patient had a mean prostatic fosfomycin concentration of <1 µg/g, whereas the majority (70%) had concentrations ≥4 µg/g. CONCLUSIONS Fosfomycin appears to achieve reasonable intraprostatic concentrations in uninflamed prostate following a single 3-g oral dose, such that it may be a potential option for prophylaxis pre-TRUS prostate biopsy and possibly for the treatment of MDR-GNB prostatitis. Formal clinical studies are now required.

Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis

OBJECTIVES As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. METHODS Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. RESULTS Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. CONCLUSIONS Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L.

Fosfomycin for treatment of prostatitis: new tricks for old dogs

Treatment options for prostatitis caused by multidrug-resistant gram-negative bacilli are limited. We report two cases cured with oral fosfomycin and provide a pharmacokinetic analysis of fosfomycin predose concentrations during treatment.

Role of Secondary Prophylaxis With Valganciclovir in the Prevention of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients

Background Cytomegalovirus (CMV) is a major contributor to morbidity and mortality in solid organ transplant recipients (SOTRs). Ganciclovir and valganciclovir are highly effective antiviral drugs with a well-established role in primary prophylaxis and treatment of CMV disease. Our objective in this study was to examine the effect of secondary prophylaxis (SP) on the risk of relapse in SOTRs following an episode of CMV disease. Methods We performed a retrospective cohort study of SOTRs from 1995 to 2015 and used propensity score-based inverse probability of treatment weighting methodology to control for confounding by indication. A weighted Cox model was created to determine the effect of SP on time to relapse within 1 year of treatment completion. Results Fifty-two heart, 34 liver, 79 kidney, and 5 liver-kidney transplant recipients who completed treatment for an episode of CMV infection/disease were included. A total of 120 (70.6%) received SP (median duration, 61 days; range, 5-365) and 39 (23%) relapsed. SP was protective against relapse from 0 to 6 weeks following treatment completion (hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.05-0.69). However, after 6 weeks, risk of relapse did not significantly differ between the 2 groups (HR, 1.18; 95% CI, 0.46-2.99). Conclusions Our findings demonstrate that use of SP following treatment of CMV disease did not confer long-term protection against relapse, although it did delay relapse while patients were receiving antivirals. This suggests that SP has limited clinical utility in the overall prevention of recurrent CMV disease.

Ceftazidime-avibactam (CTZ-AVI) as a treatment for hospitalized adult patients with complicated intra-abdominal infections.

ABSTRACT Avibactam, a novel β-lactamase inhibitor, has recently been co-formulated with ceftazidime and approved for use in patients with complicated intra-abdominal and urinary tract infections, where no better treatment alternative exists. The basis for its FDA approval has been the extensive clinical experience with ceftazidime and the demonstration in vitro and in animal models that the addition of avibactam reverses resistance to ceftazidime in extended-spectrum β-lactamase and some carbapenemase-producing Enterobacteriaceae. Early clinical data are promising, with efficacy demonstrated in patients with complicated intra-abdominal and urinary tract infections. This review will summarize the in vitro, animal and clinical data available on this agent to date.

Editorial Commentary: Chronic Lung Allograft Dysfunction in Lung Transplant Recipients: Another Piece of the Puzzle

Over the past 40 years, lung transplantation has evolved into a life-saving procedure for patients with end-stage lung disease. While great progress has beenmade, average survival remains much lower than for other solid organ transplant recipients. This is largely due to the development of chronic lungallograftdysfunction (CLAD), which heralds a relatively rapid progression to graft failure [1]. Different subtypes of CLAD are described, including bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome. The lung allograft differs from the heart, kidney, and liver in that it is continuously exposed to the external environment and is therefore susceptible to recurrent injury and infection. It also contains abundant immune cells, presumably an evolutionary response to manage these exposures. While the pathogenesis of CLAD is not completely understood, many risk factors have been identified including primary graft dysfunction, acute cellular rejection, lymphocytic bronchiolitis, humoral rejection, gastroesophageal reflux and microaspiration, bronchoalveolar lavage neutrophilia, autoimmune sensitization, air pollution, and infection [1–3]. Historically, the focus of much research has been on the role of autoimmunity/graft rejection [4]. However, CLAD does develop in patients who have never had any rejection and does not respond well to increased immunosuppression [1]. In the early days of lung transplantation, the development of cytomegalovirus (CMV) infection (especially pneumonitis) was common and problematic. CMV was recognized as being associated with BOS/CLAD in the 1990s, and while there are some conflicting results, the majority of studies have found CMV to be a risk factor [5–10]. Following the introduction of ganciclovir and then valganciclovir, the morbidity and mortality of posttransplantation CMV has dropped dramatically; use of these drugs has also been associated with a reduction in the risk of the development of BOS [11]. Other human herpes viruses including human herpesvirus 6 [12, 13] and Epstein-Barr virus [14] as well as bacterial pathogens (Pseudomonas aeruginosa [15, 16]), and fungal pathogens (Aspergillus sp. [17]) have also been associated with an increased risk of CLAD in some but not all studies. One of the only effective treatments for CLAD is azithromycin, which is widely used. However, it is unclear whether its benefit in CLAD is due to its antimicrobial properties (and activity against atypical pathogens such as Chlamydophila pneumoniae, which have also been shown to contribute to BOS [18]) or its antiinflammatory properties [19, 20]. Recently, it has become apparent that respiratory viral infections likely play a key role in the pathogenesis of CLAD [21, 22]. In this edition of Clinical Infectious Diseases, Fisher et al shed more light on this issue [23]. Their study is the largest and most detailed to address this question to date; it expands the spectrum of viruses associated with CLAD and strengthens the case for possible causality. Of note, a time-dependent analysis has identified a temporal association. Most identifiable potential confounders were examined and controlled for in their analysis, although a few, such as air pollution, were not. Only symptomatic patients were tested; in one previous prospective study, asymptomatic patients were included, and an association was identified between a positive test for virus and CLAD regardless of the presence of symptoms [22]. It is not clear what proportion of their cohort was actually tested for respiratory viruses and, therefore, how many tested negative or how many cases may have been missed. Finally, limited information regarding the details of CMV infection in their cohort was included, although it is noted that CMV pneumonia was not a significant predictor of CLAD in their univariate and multivariate models. As the authors point out, many earlier studies were limited by the drawbacks of older testing modalities, particularly their poor sensitivity [24]. The revolution in the development, commercialization, and dissemination of molecular multiplex Received 23 September 2015; accepted 24 September 2015; published online 12 November 2015. Correspondence: B. J. Gardiner, Division of Geographic Medicine and Infectious Disease, Tufts Medical Center, 800 Washington St, Boston, MA 02116 (bradgardiner@gmail.com). Clinical Infectious Diseases 2016;62(3):320–2

Absolute lymphocyte count: a predictor of recurrent cytomegalovirus disease in solid organ transplant recipients.

Background Recurrent cytomegalovirus (CMV) disease in solid organ transplant recipients frequently occurs despite effective antiviral therapy. We previously demonstrated that patients with lymphopenia before liver transplantation are more likely to develop posttransplant infectious complications including CMV. The aim of this study was to explore absolute lymphocyte count (ALC) as a predictor of relapse following treatment for CMV disease. Methods We performed a retrospective cohort study of heart, liver, and kidney transplant recipients treated for an episode of CMV disease. Our primary outcome was time to relapse of CMV within 6 months. Data on potential predictors of relapse including ALC were collected at the time of CMV treatment completion. Univariate and multivariate hazard ratios (HRs) were calculated with a Cox model. Multiple imputation was used to complete the data. Results Relapse occurred in 33 of 170 participants (19.4%). Mean ALC in relapse-free patients was 1.08 ± 0.69 vs 0.73 ± 0.42 × 103 cells/μL in those who relapsed, corresponding to an unadjusted hazard ratio of 1.11 (95% confidence interval, 1.03-1.21; P = .009, n = 133) for every decrease of 100 cells/μL. After adjusting for potential confounders, the association between ALC and relapse remained significant (HR, 1.11 [1.03-1.20]; P = .009). Conclusions Low ALC at the time of CMV treatment completion was a strong independent predictor for recurrent CMV disease. This finding is biologically plausible given the known importance of T-cell immunity in maintaining CMV latency. Future studies should consider this inexpensive, readily available marker of host immunity.

Microbial identification using DNA target amplification and sequencing: Clinical utility and impact on patient management

Abstract Broad-range polymerase chain reaction (PCR) is increasingly used in patients with culture-negative infections; however, few studies have assessed the diagnostic utility of this test in this context. We performed a retrospective cohort study of patients who had clinical specimens sent for broad-range PCR, aiming to evaluate performance and determine impact on patient management. Organisms were identified in 21/71 samples. High numbers of polymorphonuclear leukocytes on Gram stain (odds ratio [OR], 4.17; P = .04) and acute inflammation on histopathology (OR, 5.69; P = .02) were significantly associated with a positive result. Management was altered in 18 patients, 11 with positive and 7 with negative results. Overall, broad-range PCR assay had the highest impact in patients with microscopic evidence of inflammation. Physicians ordering this complex, difficult to interpret, and expensive test should carefully consider all available clinical information on an individualized basis to optimize its performance.

Evaluation of a two-stage testing algorithm for the diagnosis of respiratory viral infections

Abstract New on-demand multiplex molecular respiratory viral diagnostics offer superior performance although can be expensive and some platforms cannot process multiple specimens simultaneously. We performed a retrospective study reviewing results of patients tested for respiratory viruses following introduction of a two-stage testing algorithm incorporating an initial screen with Sofia® immunoassay then secondary Biofire Filmarray®, and compared to a period when only Filmarray® was used. Of 2976 testing episodes, 1814 underwent initial Sofia® then follow-up FilmArray®. A diagnosis of influenza was made by Sofia® in 282 patients, and by FilmArray® in an additional 163 (median time to result 1.12hours versus 3.46hours, P <0.001). Significantly more patients received their diagnosis within 90minutes in winter despite testing more samples (11.1% versus 3.4%, P <0.001), and approximately

A repeat offender: recurrent extraintestinal Clostridium difficile infection following fecal microbiota transplantation

36,000 was saved. An algorithmic approach to respiratory viral diagnosis can combine the advantages of accuracy and speed and be cost saving.