Propensity Score and Desirability of Outcome Ranking Analysis of Ertapenem for Treatment of Nonsevere Bacteremic Urinary Tract Infections Due to Extended-Spectrum-Beta-Lactamase-Producing Enterobacterales in Kidney Transplant Recipients.

There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) in kidney transplant (KT) recipients. We evaluated the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22; P = 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29; P = 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages.

Efficacy of ß-lactam/ß-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).

BACKGROUND: Whether active therapy with ß-lactam/ß-lactamase inhibitors (BLBLI) is as affective as carbapenems for extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) bloodstream infection (BSI) secondary to urinary tract infection (UTI) in kidney transplant recipients (KTRs) remains unclear. METHODS: We retrospectively evaluated 306 KTR admitted to 30 centers from January 2014 to October 2016. Therapeutic failure (lack of cure or clinical improvement and/or death from any cause) at days 7 and 30 from ESBL-E BSI onset was the primary and secondary study outcomes, respectively. RESULTS: Therapeutic failure at days 7 and 30 occurred in 8.2% (25/306) and 13.4% (41/306) of patients. Hospital-acquired BSI (adjusted OR [aOR]: 4.10; 95% confidence interval [CI]: 1.50-11.20) and Pitt score (aOR: 1.47; 95% CI: 1.21-1.77) were independently associated with therapeutic failure at day 7. Age-adjusted Charlson Index (aOR: 1.25; 95% CI: 1.05-1.48), Pitt score (aOR: 1.72; 95% CI: 1.35-2.17), and lymphocyte count ≤500 cells/µL at presentation (aOR: 3.16; 95% CI: 1.42-7.06) predicted therapeutic failure at day 30. Carbapenem monotherapy (68.6%, primarily meropenem) was the most frequent active therapy, followed by BLBLI monotherapy (10.8%, mostly piperacillin-tazobactam). Propensity score (PS)-adjusted models revealed no significant impact of the choice of active therapy (carbapenem-containing vs any other regimen, BLBLI- vs carbapenem-based monotherapy) within the first 72 hours on any of the study outcomes. CONCLUSIONS: Our data suggest that active therapy based on BLBLI may be as effective as carbapenem-containing regimens for ESBL-E BSI secondary to UTI in the specific population of KTR. Potential residual confounding and unpowered sample size cannot be excluded (ClinicalTrials.gov identifier: NCT02852902).

Characteristics, outcome and risk factors for mortality of paediatric patients with ICU-acquired candidemia in India: A multicentre prospective study.

BACKGROUND: The epidemiology, clinical profile and outcome of paediatric candidemia vary considerably by age, healthcare settings and prevalent Candida species. Despite these differences, few comprehensive studies are undertaken. This nationwide study addresses this knowledge gap. METHODS: 487 children who contracted ICU-acquired candidemia at 23 Indian tertiary care centres were assessed for 398 variables spanning demography, clinical characteristics, microbiology, treatment and outcome. RESULTS: Both neonates (5.0 days; range = 3.0-9.5) and non-neonatal children (7.0 days; range = 3.0-13.0) developed candidemia early after ICU admission. Majority of neonates were premature (63.7%) with low birthweight (57.1%). Perinatal asphyxia (7.3%), pneumonia (8.2%), congenital heart disease (8.4%) and invasive procedures were common comorbidities, and antibiotic use (94.1%) was widespread. C tropicalis (24.7%) and C albicans (20.7%) dominated both age groups. Antifungal treatment (66.5%) and removal of central catheters (44.8%) lagged behind. Overall resistance was low; however, emergence of resistant C krusei and C auris needs attention. The 30-day crude mortality was 27.8% (neonates) and 29.4% (non-neonates). Logistic regression identified admission to public sector ICUs (OR = 5.64), mechanical ventilation (OR = 2.82), corticosteroid therapy (OR = 8.89) and antifungal therapy (OR = 0.22) as independent predictors of 30-day crude mortality in neonates. Similarly, admission to public sector ICUs (OR = 3.62), mechanical ventilation (OR = 3.13), exposure to carbapenems (OR = 2.18) and azole antifungal therapy (OR = 0.48) were independent predictors for non-neonates. CONCLUSIONS: Our findings reveal a distinct epidemiology, including early infection with a different spectrum of Candida species, calling for appropriate intervention strategies to reduce candidemia morbidity and mortality. Independent factors identified in our regression models can help tackle these challenges.

Predictors of mortality in solid organ transplant recipients with bloodstream infections due to carbapenemase-producing Enterobacterales: The impact of cytomegalovirus disease and lymphopenia.

Treatment of carbapenemase-producing Enterobacterales bloodstream infections in solid organ transplant recipients is challenging. The objective of this study was to develop a specific score to predict mortality in solid organ transplant recipients with carbapenemase-producing Enterobacterales bloodstream infections. A multinational, retrospective (2004-2016) cohort study (INCREMENT-SOT, ClinicalTrials.gov NCT02852902) was performed. The main outcome variable was 30-day all-cause mortality. The INCREMENT-SOT-CPE score was developed using logistic regression. The global cohort included 216 patients. The final logistic regression model included the following variables: INCREMENT-CPE mortality score ≥8 (8 points), no source control (3 points), inappropriate empirical therapy (2 points), cytomegalovirus disease (7 points), lymphopenia (4 points), and the interaction between INCREMENT-CPE score ≥8 and CMV disease (minus 7 points). This score showed an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI] 0.76-0.88) and classified patients into 3 strata: 0-7 (low mortality), 8-11 (high mortality), and 12-17 (very-high mortality). We performed a stratified analysis of the effect of monotherapy vs combination therapy among 165 patients who received appropriate therapy. Monotherapy was associated with higher mortality only in the very-high (adjusted hazard ratio [HR] 2.82, 95% CI 1.13-7.06, P = .03) and high (HR 9.93, 95% CI 2.08-47.40, P = .004) mortality risk strata. A score-based algorithm is provided for therapy guidance.

Evaluation of in-vitro colistin susceptibility and clinical profile of carbapenem resistant Enterobacteriaceae related invasive infections.

PURPOSE: To determine the colistin susceptibility. To compare E-test vs broth-microdilution (BMD) method for invasive carbapenem resistant Enterobacteriaceae (CRE) infections. To study treatment options for the CRE. To analyze the clinical profile and outcome of CRE infections. METHODS: Antimicrobial susceptibility testing was performed for 100 invasive CRE isolates. Gradient diffusion and BMD methods were performed to determine colistin MICs. Essential agreement (EA), categorical agreement (CA), very major error (VME), and major error (ME) were worked out between BMD method and E-test. The clinical profile of patients was analyzed. RESULTS: The majority of the patients suffered from bacteremia [47(47%)]. Klebsiella pneumoniae was the most common organism isolated overall as well as among bacteremic isolates. 9(9%) CRE isolates were colistin resistant by BMD of which six were Klebsiella pneumoniae. There was 97% CA between E-test and BMD. EA was 68%. VME was found in three out of nine colistin resistant isolates. No ME was found. Among the other antibiotics tested for CRE isolates, the highest susceptibility was seen to tigecycline [43(43%)] followed by amikacin [19 (19%)]. The most common underlying condition was post solid organ transplantation [36(36%)]. A higher survival rate was seen among non-bacteremic CRE infections (58.49%) than bacteremic CRE infections (42.6%). Four out of nine patients with colistin resistant CRE infections survived and had a satisfactory outcome. CONCLUSION: Klebsiella pneumoniae was the most common organism causing invasive infection. Survival rates were higher in non-bacteremic CRE infections than bacteremic infections. Good CA was seen between E-test and BMD for colistin susceptibility, but the EA was poor. VME was more common than ME when E-tests were used for colistin susceptibility testing resulting in false susceptibility. Tigecycline and aminoglycosides are possible adjunct drugs for the treatment of invasive CRE infections.

Significance of Adopting Nucleic Acid Amplification Technique for Blood Donor Screening in a Resource Limited Setting: A Study from a Single Centre in South India.

Nucleic acid Amplification testing (NAT) has helped improve blood safety and detect window period and Occult Hepatitis B infections (OBI) This study was aimed at determining the following in blood donors: 1. seroprevalence of HIV, HBV & HCV, malarial parasite and Syphlis 2. NAT and seroyield for HIV, HBV and HCV 3. viral load in NAT yield donations 4. Pattern of HBV serological markers in HBV NAT yield donations 80,809 blood donations were screened over an 8 year period (2012-2019) for antiHIV I and II, HBsAg, antiHCV antibodies, malarial parasite and VDRL. Seronegative samples were tested by NAT using a multiplex PCR in a pool of six. NAT yield samples were tested for viral load and HBV serological markers. Seropositive samples were tested for NAT and checked for seroyield. SPSS windows version 24.0 was used for statistical analysis. 1.07% of blood donors were found to be seropositive with 0.08%, 0.86%, 0.09%, 0.03% and 0 for anti HIV I and II, HBsAg, antiHCV, VDRL and Malarial parasite respectively. Out of 79,938 seronegative samples, 20 samples (0.025%) were NAT positive for Hepatitis B with a NAT yield OF 1:3997. Out of the 20 NAT positive samples, 17 were OBI and three were window period infections. 14 NAT yield samples subjected to a HBV viral load assay showed a range of < 6-146 IU/ml. Minipool NAT in pools of six is able to indentify both OBI and window period infections. NAT could significantly improve the blood safety in a resource limited setting like India.

Multiple hepatic and splenic abscesses due to Burkholderia pseudomallei.

We report a case of melioidosis in an alcoholic and diabetic male patient presenting with multiple hepatic and splenic abscesses. Melioidosis is caused by an environmental bacterium Burkholderia pseudomallei. The clinical manifestations vary from asymptomatic infection to fulminant septic shock with abscesses in multiple internal organs. The treatment is prolonged with parenteral antibiotics in intensive phase followed by oral antibiotics in eradication phase till disease resolution. Due to varied clinical presentations, high index of suspicion coupled with adequate laboratory support is essential for rapid diagnosis and prompt initiation of optimal antibiotic therapy.

Clinical Spectrum, Molecular Characterization, Antifungal Susceptibility Testing of Exophiala spp. From India and Description of a Novel Exophiala Species, E. arunalokei sp. nov.

Introduction: Exophiala spp. are important opportunist pathogens causing subcutaneous or even fatal disseminated infections in otherwise both immunosuppressed and healthy individuals but there are no systematic studies on the isolates of Exophiala species from India. Methods: Twenty-four isolates of Exophiala species were retrieved from the National Culture Collection of Pathogenic Fungi (NCCPF) and identified phenotypically and by molecular methods (ITS region sequencing) followed by antifungal susceptibility testing (AFST) as per CLSI-M38A3 guidelines. A review of the literature of cases from India was performed up to 1st January 2021 using the Medline and Cochrane database. Results: E. dermatitidis (n = 8), E. jeanselmei (n = 6), E. spinifera (n = 6), E. mesophila (n = 1), E. oligosperma (n = 1), E. xenobiotica (n = 1) were identified and the sequencing of ITS, ß-tubulin and ß-actin revealed a novel species, E. arunalokei sp. nov. (n = 1). The ITS sequence phylogram of E. jeanselmei revealed that the majority (83%) formed a separate cluster close to type A while majority (75%) of E. dermatitidis were type B. The MIC50 (mg/L) of amphotericin, itraconazole, voriconazole, micafungin, caspofungin, anidulafungin, and posaconazole, was 1, 0.25, 0.125, 0.12, 0.125, 0.062, and 0.062, respectively. Sixteen more cases were identified on the literature review and a significant association of E. dermatitidis with history of surgical procedures (p = 0.013), invasive disease (p = 0.032) and of E. mesophila with tuberculosis (p = 0.026) was seen. Conclusion: This, to the best of our knowledge is the first study from India elucidating the molecular and clinical characteristics of Exophiala species and the first Indian report of human infection due to E. xenobiotica and E. arunalokei.

Activity of novel lactone ketolide nafithromycin against multicentric invasive and non-invasive pneumococcal isolates collected in India.

BACKGROUND: India is among the nations reporting substantial healthcare burden linked to pneumococcal infections. Nafithromycin is a novel lactone ketolide antibiotic, which recently entered Phase 3 development in India for the indication of community-acquired bacterial pneumonia (CABP). OBJECTIVES: To assess the in vitro activity of nafithromycin against serotyped invasive and non-invasive Streptococcus pneumoniae isolates, collected from nine medical centres across India. METHODS: A total of 534 isolates of S. pneumoniae were collected during 2015-20 and serotyped as per CDC protocol. A subset of erythromycin-non-susceptible S. pneumoniae (n = 200) was screened for the presence of erm(B) and mef(A/E) genes. A subset of MDR isolates (n = 54) were also subjected to MLST. The MICs of antibiotics were determined by the reference agar-dilution method (CLSI). Susceptibilities of the comparators were interpreted as per CLSI criteria. RESULTS: Fifty-nine distinct serotypes were identified among the 534 isolates. Among erythromycin-non-susceptible isolates, erm(B) and mef(A/E) genes were found in 49% and 59% strains respectively, while MLST showed clonal diversity. Azithromycin (67.6% non-susceptible) and clindamycin (31.8% non-susceptible) showed limited activity. Penicillin (for non-meningitis) or quinolone non-susceptibility was low (<11% and <6%, respectively). Nafithromycin showed potent activity with MIC50 and MIC90 of 0.015-0.03 and 0.06 mg/L, respectively, regardless of the macrolide resistance mechanisms. CONCLUSIONS: Indian pneumococcal isolates show poor susceptibilities to macrolides, in concordance with the global trend. Nafithromycin overcomes erm as well as mef-mediated macrolide resistance mechanisms expressed individually or concurrently in S. pneumoniae. This study supports continued clinical development of nafithromycin for pneumococcal infections including CABP.

Convalescent plasma - Is it useful for treating SARS Co-V2 infection?

The world is challenged with the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic. Although preventive measures such as social distancing, personal protective equipment and isolation would decrease the spread of the infection, a definitive treatment is still under way. Antivirals, immunisation, convalescent plasma (CP) and many more modalities are under trial, and there has been no definite answer to the management of COVID-19 infection. All patients so far have received the standard and symptomatic care. It is shown that the SARS-CoV 2 is a respiratory pathogen, and 80% of the infected patients would recover from the illness and it is the 20% of the infected patients require hospitalisation and even critical care. CP has been used to treat recent epidemic respiratory infections such as Middle East respiratory syndrome and severe acute respiratory syndrome (SARS) infections with promising results. The CP of a recovered individual contains antibodies which neutralise the virus and decrease the viral replication in the patient. It is a classic adaptive immunotherapy and has been applied in the prevention and treatment of many infectious diseases. CP is plasma taken from a person who has recovered from an infection, which contains neutralising antibodies against the said infection. Giving CP to susceptible individuals or infected patients is a form of passive antibody therapy and in the case of SARS-CoV-2, is expected to provide protection by viral neutralisation and antibody-dependent cytotoxicity and phagocytosis. The adaptive response is to a specific antigen-binding array of molecules that are foreign to the host. The human response to viruses uses both the innate and the adaptive arms in its attempt to rid the host of the invading pathogen. The humoral response is a component of the adaptive immune response that allows for antibodies to bind to foreign invading pathogens, marks the pathogens and their toxins for phagocytosis and recruits further phagocytic cells to the site via the activation of the complement system and eventually prevents the pathogen from infecting target cells. Studies from Wuhan from various institutions during the research on COVID-19 infections during December 2019 have also shown promising results. Till date, randomised controlled studies for the use of CP in SARS-CoV-2 infection are lacking, and many countries have invited institutions to participate in clinical trials. The Indian Council of Medical research and the Central Drugs Standard Control Organisation, Government of India, have allowed the use of CP as an investigational drug under a trial basis. Internationally, agencies such as the USFDA, American Association of Blood Banks, European Blood Safety and British Blood Transfusion Society have also come out with various guidelines for the use of CP in COVID-19 infection. This article will review the current guidelines for the use of CP and compare the various guidelines of different agencies.

Two cases of Nocardia bacteraemia in solid organ transplant recipients.

Nocardiosis is an opportunistic infection occurring in immunosuppressed patients. While disseminated nocardiosis is common in immunosuppressed patients, Nocardia bacteraemia is rare. There are few reports of Nocardia bacteraemia following solid organ transplantation. We report two cases of Nocardia bacteraemia in solid organ transplant recipients-Nocardia cyriacigeorgica bacteraemia in liver transplant recipient and concomitant Nocardia farcinica bacteraemia and cyclosporiasis in a heart transplant recipient. Prompt recognition of early bacteraemia with initiation of antibiotic therapy may avoid the complications of disseminated disease in the solid organ transplant recipients.

Invasive pneumococcal disease in children aged younger than 5 years in India: a surveillance study.

BACKGROUND: Invasive pneumococcal disease continues to be a major cause of morbidity and mortality among children younger than 5 years of age in India. We aimed to provide nationally representative data for the pattern of disease due to Streptococcus pneumoniae, trends in the serotype of invasive pneumococci, and invasive pneumococci antimicrobial resistance patterns, in India. METHODS: In this prospective hospital-based and retrospective laboratory-based surveillance study, we prospectively enrolled children aged younger than 5 years with suspected or proven invasive pneumococcal disease from 18 hospitals or institutional centres and retrospectively included laboratory-confirmed pneumococcal isolates from ten sentinel laboratories, together representing 11 states in India. Eligibility criteria were fever higher than 38°C without localising symptoms, clinical presentation of suspected meningitis or pneumonia, and evidence of radiographic pneumonia. We cultured blood and other normally sterile body fluids, reconfirmed and serotyped pneumococcal isolates, and established antimicrobial susceptibility using standard study protocols. FINDINGS: Between Jan 1, 2011, and June 30, 2015, we enrolled 4377 patients. Among 361 (8%) patients with culture-proven pneumococcal disease, all clinical data were known for 226 (63%); among these patients, 132 (58%) presented with pneumonia, 78 (35%) presented with meningitis, and 16 (7%) had other clinical conditions. 131 (3%) died overall and 29 (8%) patients with invasive pneumococcal disease died. Serotypes 14 (52 [14%] of 361), 1 (49 [14%]), 5 (37 [10%]), and 19F (33 [9%]) were the most common. Penicillin non-susceptibility occurred in isolates from 29 (8%) patients, co-trimoxazole resistance occurred in 239 (66%), erythromycin resistance occurred in 132 (37%), and chloramphenicol resistance occurred in 33 (9%). We found multidrug resistance in 33 (9%) of 361 patients. INTERPRETATION: The proportion of positive blood cultures, number of isolates, geographical representation, and data generated over the 4·5 years of the study are representative of data for most of India. Continued surveillance is warranted as the decision to introduce protein conjugated vaccine in India is made. FUNDING: GlaxoSmithKline India.

Clinical and Microbiology Profile and Outcome of Diarrhea by Coccidian Parasites in Immunocompetent Children.

BACKGROUND: Several studies have reported prevalence of pediatric coccidian parasitic diarrhea, but there is little information about their clinical profile, management and outcome. This study reviews the clinical profile and treatment outcome of coccidian parasitic diarrhea in immunocompetent children. METHODS: Five thousand one hundred and twenty-three immunocompetent children younger than 15 years of age presenting with acute diarrhea to a tertiary care pediatric hospital during a period of 4 years (2009-2012) were included in the study. Their demographic details and clinical course were recorded, and feces specimens received in the microbiology laboratory were subject to microbiology culture, wet mount microscopy, modified Ziehl-Neelsen staining to detect intestinal coccidian parasites and rotavirus sandwich enzyme-linked immunosorbent assay test (if age less than 2 years). RESULTS: The prevalence of coccidian parasitic diarrhea in immunocompetent children was 1.13% (58 cases) with Cryptosporidium spp. accounting for 1.09% (56 cases). Most Cryptosporidium infections were in children younger than 2 years [38 (67.85%)] and during the monsoon season [32 (57.14%)] with common clinical features being watery or liquid feces [44 (78.57%)], vomiting [40 (71.43%)] and fever [35 (62.5%)]. Thirteen (81.25%) of the 16 cases of cryptosporidiosis with dehydration were less than 2 years of age. Fifty-one (87.93%) of the 58 children were hospitalized. Thirty-eight (67.85%) children with cryptosporidiosis received empiric antimicrobial agents for suspected enteric bacterial and protozoan parasitic infection, which were discontinued after coccidian parasites were detected. Median duration of hospitalization was 2 days with no mortality reported. CONCLUSIONS: Coccidian parasitic diarrhea affects immunocompetent children of all age groups. Unnecessary administration of antimicrobial agents to these children can be avoided by routinely screening pediatric diarrheal fecal specimens for coccidian parasites by a cost-effective method such as modified Ziehl-Neelsen staining.

Incidence, characteristics and outcome of ICU-acquired candidemia in India.

PURPOSE: A systematic epidemiological study on intensive care unit (ICU)-acquired candidemia across India. METHOD: A prospective, nationwide, multicentric, observational study was conducted at 27 Indian ICUs. Consecutive patients who acquired candidemia after ICU admission were enrolled during April 2011 through September 2012. Clinical and laboratory variables of these patients were recorded. The present study is an analysis of data specific for adult patients. RESULTS: Among 1,400 ICU-acquired candidemia cases (overall incidence of 6.51 cases/1,000 ICU admission), 65.2 % were adult. Though the study confirmed the already known risk factors for candidemia, the acquisition occurred early after admission to ICU (median 8 days; interquartile range 4-15 days), even infecting patients with lower APACHE II score at admission (median 17.0; mean ± SD 17.2 ± 5.9; interquartile range 14-20). The important finding of the study was the vast spectrum of agents (31 Candida species) causing candidemia and a high rate of isolation of Candida tropicalis (41.6 %). Azole and multidrug resistance were seen in 11.8 and 1.9 % of isolates. Public sector hospitals reported a significantly higher presence of the relatively resistant C. auris (8.2 vs. 3.9 %; p = 0.008) and C. rugosa (5.6 vs. 1.5 %; p = 0.001). The 30-day crude and attributable mortality rates of candidemia patients were 44.7 and 19.6 %, respectively. Logistic regression analysis revealed significant independent predictors of mortality including admission to public sector hospital, APACHE II score at admission, underlying renal failure, central venous catheterization and steroid therapy. CONCLUSION: The study highlighted a high burden of candidemia in Indian ICUs, early onset after ICU admission, higher risk despite less severe physiology score at admission and a vast spectrum of agents causing the disease with predominance of C. tropicalis.