Evolution of Imipenem-Relebactam Resistance Following Treatment of Multidrug-Resistant Pseudomonas aeruginosa Pneumonia.

We report the emergence of imipenem-relebactam nonsusceptible Pseudomonas aeruginosa in 5 patients treated for nosocomial pneumonia for 10-28 days. Genome sequence analysis identified treatment-emergent mutations in MexAB-OprM and/or MexEF-OprN efflux operons that arose independently in each patient across distinct P. aeruginosa sequence types. Testing with efflux-inhibitor PAßN restored imipenem-relebactam susceptibility.

Candida Empyema Thoracis at Two Academic Medical Centers: New Insights Into Treatment and Outcomes.

BACKGROUND: Candida empyema thoracis (pleural empyema) is an uncommon manifestation of invasive candidiasis, for which optimal treatment is unknown. METHODS: This is a retrospective study of patients with Candida empyema at 2 academic medical centers from September 2006 through December 2015. RESULTS: We identified 81 patients with Candida empyema (median age, 62 years; 68% men). Sixty-five percent of patients underwent surgery or an invasive intervention of the thorax or abdomen within the preceding 90 days. Candida empyema originated from intrathoracic (51%) or intra-abdominal sources (20%), spontaneous esophageal rupture (12%), pleural space manipulation (9%), and pneumonia (6%). Eighty-four percent and 41% of patients were intensive care unit residents and in septic shock, respectively, within 3 days of diagnosis. Causative species were Candida albicans (65%), Candida glabrata (26%), Candida parapsilosis (11%), Candida tropicalis (4%), Candida krusei (2%), and Candida dubliniensis (1%). Bacteria were recovered from empyemas in 51% of patients. Concurrent candidemia was diagnosed in only 2% of patients. Management included pleural drainage and antifungal treatment in 98% and 85% of patients, respectively. Mortality at 100 days was 27%, and it was highest for cases stemming from esophageal rupture (67%). Spontaneous esophageal rupture and echinocandin rather than fluconazole treatment were independent risk factors for death at 100 days (P = .003 and .04, respectively); receipt of antifungal therapy was an independent predictor of survival (P = .046). CONCLUSIONS: Candida empyema mortality rates were lower than reported previously. Optimal management included pleural drainage and fluconazole treatment. Superiority of fluconazole over echinocandins against Candida empyema needs to be confirmed in future studies.

Invasive Fungal Infections after Anti-CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy: State of the Evidence and Future Directions.

Studies describing invasive fungal infections (IFIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. Although post-CAR-T-cell IFIs appear to be uncommon, they are associated with significant morbidity and mortality. Specific risk factors for IFIs in CAR-T-cell recipients have not been fully characterized and are often extrapolated from variables contributing to IFIs in patients with other hematologic malignancies or those undergoing hematopoietic cell transplant. Optimal prophylaxis strategies, including the use of yeast versus mold-active azoles, also remain ill-defined. Further research should investigate key risk factors for IFIs and establish an evidence-based approach to antifungal prophylaxis in these patients in order to improve clinical outcomes.

Isavuconazole Is as Effective as and Better Tolerated Than Voriconazole for Antifungal Prophylaxis in Lung Transplant Recipients.

BACKGROUND: Invasive fungal infections (IFIs) are common following lung transplantation. Isavuconazole is unstudied as prophylaxis in organ transplant recipients. We compared effectiveness and tolerability of isavuconazole and voriconazole prophylaxis in lung transplant recipients. METHODS: A single-center, retrospective study of patients who received isavuconazole (September 2015-February 2018) or voriconazole (September 2013-September 2015) for antifungal prophylaxis. IFIs were defined by EORTC/MSG criteria. RESULTS: Patients received isavuconazole (n = 144) or voriconazole (n = 156) for median 3.4 and 3.1 months, respectively. Adjunctive inhaled amphotericin B (iAmB) was administered to 100% and 41% of patients in the respective groups. At 1 year, 8% of patients receiving isavuconazole or voriconazole developed IFIs. For both groups, 70% and 30% of IFIs were caused by molds and yeasts, respectively, and breakthrough IFI (bIFI) rate was 3%. Outcomes did not significantly differ for patients receiving or not receiving iAmB. Independent risk factors for bIFI and breakthrough invasive mold infection (bIMI) were mold-positive respiratory culture and red blood cell transfusion >7 units at transplant. Bronchial necrosis >2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI. Isavuconazole and voriconazole were discontinued prematurely due to adverse events in 11% and 36% of patients, respectively (P = .0001). Most common causes of voriconazole and isavuconazole discontinuation were hepatotoxicity and lack of oral intake, respectively. Patients receiving ≥90 days prophylaxis had fewer IFIs at 1 year (3% vs 9%, P = .02). IFIs were associated with increased mortality (P = .0001) and longer hospitalizations (P = .0005). CONCLUSIONS: Isavuconazole was effective and well tolerated as antifungal prophylaxis following lung transplantation.

Fungal infections in lung transplantation.

Lung transplant is a potential life-saving procedure for chronic lung diseases. Lung transplant recipients (LTRs) are at the greatest risk for invasive fungal infections (IFIs) among solid organ transplant (SOT) recipients because the allograft is directly exposed to fungi in the environment, airway and lung host defenses are impaired, and immunosuppressive regimens are particularly intense. IFIs occur within a year of transplant in 3-19% of LTRs, and they are associated with high mortality, prolonged hospital stays, and excess healthcare costs. The most common causes of post-LT IFIs are Aspergillus and Candida spp.; less common pathogens are Mucorales, other non-Aspergillus moulds, Cryptococcus neoformans, Pneumocystis jirovecii, and endemic mycoses. The majority of IFIs occur in the first year following transplant, although later onset is observed with prolonged antifungal prophylaxis. The most common manifestations of invasive mould infections (IMIs) include tracheobronchial (particularly at anastomotic sites), pulmonary and disseminated infections. The mortality rate of tracheobronchitis is typically low, but local complications such as bronchomalacia, stenosis and dehiscence may occur. Mortality rates associated with lung and disseminated infections can exceed 40% and 80%, respectively. IMI risk factors include mould colonization, single lung transplant and augmented immunosuppression. Candidiasis is less common than mould infections, and manifests as bloodstream or other non-pulmonary invasive candidiasis; tracheobronchial infections are encountered uncommonly. Risk factors for and outcomes of candidiasis are similar to those of non lung transplant recipients. There is evidence that IFIs and fungal colonization are risk factors for allograft failure due to chronic rejection. Mould-active azoles are frontline agents for treatment of IMIs, with local debridement as needed for tracheobronchial disease. Echinocandins and azoles are treatments for invasive candidiasis, in keeping with guidelines in other patient populations. Antifungal prophylaxis is commonly administered, but benefits and optimal regimens are not defined. Universal mould-active azole prophylaxis is used most often. Other approaches include targeted prophylaxis of high-risk LTRs or pre-emptive therapy based on culture or galactomannan (GM) (or other biomarker) results. Prophylaxis trials are needed, but difficult to perform due to heterogeneity in local epidemiology of IFIs and standard LT practices. The key to devising rational strategies for preventing IFIs is to understand local epidemiology in context of institutional clinical practices.

Invasive Mold Infections After Chimeric Antigen Receptor-Modified T-Cell Therapy: A Case Series, Review of the Literature, and Implications for Prophylaxis.

Data on invasive mold infections (IMIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. We describe 2 patients with post-CAR-T-cell IMI (Fusarium, Mucorales) and review the published literature. We propose strategies to prevent IMIs in patients, based on the IMI rate and presence of neutropenia or steroid use.

Pharmacokinetics of Azole Antifungals in Cystic Fibrosis.

Defects in mucociliary clearance predispose cystic fibrosis (CF) patients to airway colonization and infection by various fungi, especially Aspergillus fumigatus. Although the clinical significance of airway fungal colonization is not clear, several studies have suggested its association with worsening lung function and increased risk of CF exacerbations. Antifungal triazole agents have been used in CF patients with airway fungal colonization or infections with varying results. Limited pharmacokinetic studies to date have demonstrated high inter-subject variability of triazole levels among CF patients. This review discusses the basic principles of pharmacokinetics, the pharmacokinetic changes associated with CF and the effect of CF on the pharmacokinetic principles of azole antifungals. The inconsistent azole serum levels in CF patients may be associated with sub-therapeutic (thus risk of therapeutic failure and/or emergence of azole-resistant fungi) or supratherapeutic exposures (thus potential risk of azole toxicity), suggesting that therapeutic dose monitoring is necessary in CF patients.

Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae.

We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidime-avibactam MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum ß-lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo-ß-lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (P < 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (P = 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (P < 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.

Tuberculosis and Transplantation.

Mycobacterium tuberculosis is a major opportunistic pathogen in transplant recipients. Compared to that in the general population, the frequency of tuberculosis (TB) is 10 to 40 times higher in hematopoietic stem cell transplant (HSCT) recipients and 20 to 74 times higher in solid-organ transplant (SOT) recipients. Transplant recipients with TB are also more likely to develop disseminated disease, have longer time to definitive diagnosis, require more invasive diagnostic procedures, and experience greater anti-TB treatment-related toxicity than the general population. Specific risk factors for TB in SOT recipients include previous exposure to M. tuberculosis (positive tuberculin skin tests and/or residual TB lesions in pretransplant chest X ray) and the intensity of immunosuppression (use of antilymphocyte antibodies, type of basal immunosuppression, and intensification of immunosuppressive therapy for allograft rejection). Risk factors in HSCT recipients are allogeneic transplantation from an unrelated donor; chronic graft-versus-host disease treated with corticosteroids; unrelated or mismatched allograft; pretransplant conditioning using total body irradiation, busulfan, or cyclophosphamide; and type and stage of primary hematological disorder. Transplant recipients with evidence of prior exposure to M. tuberculosis should receive treatment appropriate for latent TB infection. Optimal management of active TB disease is particularly challenging due to significant drug interactions between the anti-TB agents and the immunosuppressive therapy. In this chapter, we address the epidemiology, clinical presentation, diagnostic considerations, and management strategies for TB in SOT and HSCT recipients.

Complications of invasive mycoses in organ transplant recipients.

INTRODUCTION: Opportunistic mycoses remain a significant complication in organ recipients. Areas covered: This review is an evidence-based presentation of current state-of-knowledge and our perspective on recent developments in the field Expert commentary: Invasive fungal infections are associated with reduced allograft and patient survival, increase in healthcare resource utilization, and newly appreciated but largely unrecognized immunologic sequelae, such as immune reconstitution syndrome. Given adverse outcomes associated with established infections, prophylaxis is a widely used strategy for the prevention of these infections. Currently available biomarkers that detect circulating fungal cell wall constituents i.e., galactomannan and 1, 3-ß-D-glucan have not proven to be beneficial as screening tools for employing targeted prophylaxis or as diagnostic assays in this patient population. However, subsets of patients at risk for opportunistic fungal infections can be identified based on clinically identifiable characteristics or events. Preventive strategies targeted towards these patients are a rational approach for optimizing outcomes.

Molecular identification of clinical Nocardia isolates from India.

The epidemiology of nocardiosis is evolving with increasing number of Nocardia spp. causing human infection. In recent years, molecular techniques have been used to identify Nocardia spp. There are limited data available on the spectrum of Nocardia spp. isolated from clinical samples in India. Here, a molecular study was carried on 30 clinical isolates maintained in our National Culture Collection to evaluate the techniques used for identifying the agents. The isolates were identified by sequencing two promising genes: the 16S rRNA gene and hsp65. Both hsp65 and the 16S rRNA gene could reliably identify 90 % of Nocardia isolates, i.e. N. farcinica, N. cyriacigeorgica, N. brasiliensis, N. otitidiscaviarum, N. amamiensis and N. pneumoniae. The mean percentage dissimilarity of sequence identification was higher using the hsp65 gene (4 %, range 0-7.9 %) compared with the 16S rRNA gene (2.3 %, range 0-8.9 %). Two isolates that showed ambiguous results in both the short segment of the 16S rRNA gene and hsp65 sequences could be resolved by sequencing a larger fragment (∼1000 bp) of the 16S rRNA gene. Both of these isolates were identified as N. beijingensis with similarities of 99.8 and 100 % compared with the standard strain. Genotyping of N. cyriacigeorgica strains was performed using hsp65 gene sequences and compared with previously described genotypes. Our N. cyriacigeorgica isolates belonged to genotype 1 (n = 4) and genotype 2 (n = 2). The present study highlights a wide spectrum of Nocardia spp. in India and emphasizes the need for molecular techniques for identification to the species level.

Mycoplasma genitalium: an emerging sexually transmitted pathogen.

Mycoplasma genitalium is a member of genital mycoplasmas, which is emerging as an important causative agent of sexually transmitted infections both in males and females. The advent of polymerase chain reaction and other molecular methods have made studies on M. genitalium more feasible, which is otherwise a difficult organism to isolate. Besides Chlamydia trachomatis, M. genitalium is now an important and established cause of non gonococcal urethritis (NGU) in men, more so in persistent and recurrent NGU. Multiple studies have also shown a positive association of M. genitalium with mucopurulent cervicitis and vaginal discharge in females as well. The evidences for M. genitalium pelvic inflammatory diseases and infertility are quite convincing and indicate that this organism has potential to cause ascending infection. Lack of clear association with M. genitalium has been reported for bacterial vaginosis and adverse pregnancy outcomes. Diagnosis of M. genitalium infections is performed exclusively using nucleic acid amplification tests (NAATs), owing to poor or slow growth of bacterium in culture. Although there are no guidelines available regarding treatment, macrolide group of antimicrobials appear to be more effective than tetracyclines. The present review provides an overview of the epidemiology, pathogenesis, clinical presentation and management of sexually transmitted infections due to M. genitalium.

Is routine medical examination of food handlers enough to ensure food safety in hospitals?

Nosocomial food outbreaks due to infected food handlers is primarily due to inadequate knowledge and faulty practices of food handlers during diarrhoeal episodes. The aim of this study was to assess: 1) prevalence of enteropathogen infection among food handlers working in our hospital during 2007 to 2011 and 2) adequacy of precautions taken by them during gastroenteritis episodes. Stool samples submitted by food handlers during 2007 to 2011 were examined for the presence of enteropathogens by standard methodology. For the second part of the study, a questionnaire regarding practices during episodes of diarrhoea in food handlers or their family members was handed out to willing participants. During the years 2007, 2008, 2010 and 2011 respectively, 3.9%, 9.8%, 5.1% and 9.4% food handlers were found infected with enteropathogens. The most common parasite detected was Entamoeba histolytica. Bacterial enteropathogens prevalence was very low during these years. There was high awareness (78.8%) among the food handlers regarding routine testing of faeces. Only 64.7% knew that it was important to report for purpose of treatment and leave. While 9.4% had suffered from diarrhoeal episodes in between intervals of annual microbiological testing, only 4.7% took appropriate treatment and availed medical leave. A regular training programme on food safety should be established and emphasis should be laid on mandatory reporting and stool testing of kitchen personnel as well as abstaining from work till they are medically fit.

Characterization of low molecular weight antimicrobial peptide from human female reproductive tract.

BACKGROUND & OBJECTIVES: The mechanisms that protect female upper genital tract from ascending infection by microbes present in vagina are only partially understood. It is expected that epithelial cells in mucosal surfaces and their secretions directly interfere with microbial colonization and invasion. This study was aimed to demonstrate the expression of 2 kDa antimicrobial peptide which was identified and purified from female genital tract tissues using chromatographic techniques. METHODS: Low molecular weight proteins were isolated from human female reproductive tract tissues obtained from premenopausal women. Antimicrobial activity of these LMW proteins was assessed against different reproductive tract pathogens viz., Neisseria gonorrhoeae, Group B streptococcus, Gardnerella vaginalis, Escherechia coli and Candida albicans. The expression of these peptides were also documented in reproductive tract tissues with the help of hyperimmune sera raised against the rabbits. The purified peptide was characterized by N-terminal sequencing. RESULTS: Immunohistochemical and immunofluorescence studies demonstrated that 2 kDa peptide was expressed in the stratified squamous epithelial cells of the ectocervix while it was absent in columnar epithelial cells of upper genital tract. Upregulation of the expression of this peptide was observed in patients of chronic non-specific cervicitis and acute on chronic cervicitis. This purified antimicrobial peptide also showed broad spectrum antimicrobial activity against different reproductive tract pathogens. INTERPRETATION & CONCLUSIONS: Considering the emerging bacterial resistance against conventional antibiotics, isolation and understanding of the expression of antimicrobial peptides from female reproductive tissue extracts may provide some leads towards the development of strategies for the treatment of reproductive tract infections.

High prevalence of functional liver derangement in visceral leishmaniasis at an Indian tertiary care center.

BACKGROUND & AIMS: Functional derangement of liver in visceral leishmaniasis is reported infrequently in the literature. Because of this, many cases are wrongly diagnosed and treated as hepatitis. We therefore envisaged to assess the actual magnitude of liver function derangement in confirmed cases of visceral leishmaniasis at our hospital. METHODS: All confirmed kala-azar cases presenting over a period of 3 years at our tertiary care hospital were included in the study. A detailed assessment of their liver functions was performed at the time of diagnosis and at various intervals until their discharge. RESULTS: A total of 114 cases of microscopy-confirmed visceral leishmaniasis were included in the study. Of these, 15 (13%) had jaundice at the time of presentation, 58 (51%), 37 (32%), 27 (24%), and 24 (21%) had increased levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin, respectively. Eleven of the 114 cases had a fatal outcome, of whom 9 (82%) had some form of functional hepatic derangement. CONCLUSIONS: Thus, in our study, functional derangement of liver was found to be common in patients with visceral leishmaniasis. In some cases, hepatitis confounded and delayed the diagnosis of kala-azar.

Profile of fatal visceral leishmaniasis at an Indian tertiary care center.

Visceral leishmaniasis is a highly morbid and incapacitating infection, which usually presents with prolonged fever, weight loss and hepato-splenomegaly. Despite the availability of effective treatment, the disease can have a high mortality even at referral centers. A case series of fatal visceral leishmaniasis, encountered during a prospective, two year period is presented. All the patients died due to multisystem organ failure. However, delayed diagnosis due to atypical manifestations was an important factor contributing to the fatal outcome of the patients. Instead of relying solely on the classical clinical features of visceral leishmaniasis, simple laboratory findings like pancytopenia, altered albumin/globulin ratio and appositive aldehyde and rK 39 dipstick tests can help in making an early diagnosis even in atypical cases, thereby reducing the mortality of visceral leishmaniasis.