Dilip Mathai

Early Dissemination of NDM-1- and OXA-181-Producing Enterobacteriaceae in Indian Hospitals: Report from the SENTRY Antimicrobial Surveillance Program, 2006-2007

ABSTRACT Among 39 carbapenem-resistant Enterobacteriaceae (2.7% overall; Escherichia coli, Enterobacter cloacae, and Klebsiella pneumoniae strains) isolated in 2006 and 2007 in India, 15 strains carried bla NDM-1 and 10 harbored a gene encoding a variant of the carbapenemase OXA-48, named bla OXA-181. One E. cloacae strain harbored bla VIM-6, and one K. pneumoniae strain carrying bla OXA-181 also possessed bla VIM-5. Multiple pulsed-field gel electrophoresis patterns and clonal dissemination within and among sites were observed. Isolates producing NDM-1 were disseminated in Indian health care facilities as early as 2006.

Risk Factors for Tuberculosis

The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli.

Outbreak of Scrub Typhus in Southern India during the Cooler Months

Abstract: Orientia tsutsugamushi, the agent of scrub typhus, is a strict intracellular bacterium which is found in many parts of Asia including India. During the past few years, the number of patients with rickettsial infection and scrub typhus has increased, especially during the cooler months. We report in this study a recent outbreak of scrub typhus recorded during the cooler months (October 2001 to February 2002) in patients admitted to our hospital with acute febrile illness associated with diverse signs and symptoms. Overall, 28 patients were clinically and serologically confirmed to have scrub typhus. Fever for more than one week was the only common manifestation. Myalgias was the next most common feature (52%), and rash was observed in only 22% of the cases. Seventeen patients treated with doxycycline recovered in 1 to 3 days, as well as two patients who received chloramphenicol. In five patients who received ciprofloxacin, fever subsided only after five days. Finally three patients (10.7%) died, including one patient treated with doxycycline. These data indicate that scrub typhus is a reemerging infectious disease in India with a possibility of drug resistance. This reemergence emphasizes the need for further prospective studies to design effective control measures.

Multilocus Genotyping of Cryptosporidium sp. Isolates from Human Immunodeficiency Virus-Infected Individuals in South India

ABSTRACT This study characterized cryptosporidial infections in 48 human immunodeficiency virus-infected individuals in India by multilocus genotyping. Cryptosporidium hominis, C. parvum, C. felis, C. muris, and C. meleagridis were identified. Cpgp40/15 PCR-restriction fragment length polymorphism identified six subgenotypes. Cryptosporidial diarrhea was associated with decreased CD4 counts, below 200 (P = 0.009), but not high viral loads.

Predictors of multi-organ dysfunction in heatstroke

Background: Heatstroke is a medical emergency that results from failure of thermoregulatory mechanism coupled with an exaggerated acute phase response, causing an elevation in core body temperature that rises above 40°C, producing multi-organ dysfunction. It carries a high mortality rate, and in survivors, a risk of permanent neurological damage. Objective: To investigate predictors of multiple organ dysfunction syndrome in patients presenting with heatstroke. Methods: We investigated 28 patients admitted to a hospital in southern India during the period January 1998 to December 2001. Using a standard form, we collected data on the patients’ characteristics, laboratory data, and outcome, and compared those with multiple organ dysfunction with those without such dysfunction. Results: We found that more than three quarters of the studied patients developed multiple organ dysfunction, with the most common dysfunction being respiratory failure. Among the selected predictors, metabolic acidosis 14 of 16 patients, 87.5%; p = 0.011, elevated CPK 17 of 19 patients, 89.5%; p = 0.005, and liver enzymes elevated more than twice the normal (11 of 18 patients, 61%; p = 0.02) had the highest correlation with dysfunction of two or more organs. Conclusions: The high mortality observed in heatstroke is secondary to multi-organ dysfunction, and among the various parameters assessed, high levels of CPK (>1000 IU/l), metabolic acidosis, and elevated liver enzymes are predictive. Aggressive measures to lower the body temperature with other supportive therapy could substantially reduce the mortality.

Evaluation of the in vitro activity of six broad-spectrum β-lactam antimicrobial agents tested against recent clinical isolates from India: a survey of ten medical center laboratories

The widespread use of beta-lactam antimicrobial agents as first-line therapy for the treatment of serious infections has led to the development of various resistances that have compromised the use of some agents. In certain countries, the lack of local or national surveillance programs limits the ability to detect these resistant strains and prevent their dissemination. A 10 medical center study in India was initiated to benchmark prevailing resistance rates for a range of bacterial pathogens to beta-lactams, and it found high rates of beta-lactamase-mediated resistance in Escherichia coli and Klebsiella spp. These rates included: cephalosporins (55.6-61.3% resistance), with extended-spectrum beta-lactamase (ESBL) phenotypes noted in over 60% of E. coli isolates and in Salmonella spp. (3.2-8.1%). Imipenem, a carbapenem, was the only antimicrobial agent tested with 100% activity against Enterobacteriaceae. Cefpirome was the most active of the tested cephalosporins, and all were fully active against methicillin-susceptible staphylococci with the exception of ceftazidime. Molecular and susceptibility characterization of 52 selected ESBL-producing strains showed a high level of co-resistance with aminoglycosides and fluoroquinolones, and clonal dissemination of resistant strains within medical centers. Collaborative studies, such as those presented here, can accurately detect changes in resistance patterns, and their continued use may help limit the further development and spread of bacterial resistances in India.

Adjunctive vitamin D for treatment of active tuberculosis in India: a randomised, double-blind, placebo-controlled trial

BACKGROUND Vitamin D has immunomodulatory effects that might aid clearance of mycobacterial infection. We aimed to assess whether vitamin D supplementation would reduce time to sputum culture conversion in patients with active tuberculosis. METHODS We did this randomised, double-blind, placebo-controlled, superiority trial at 13 sites in India. Treatment-naive patients who were sputum-smear positive, HIV negative, and had pulmonary tuberculosis were randomly assigned (1:1), with centrally labelled, serially numbered bottles, to receive standard active tuberculosis treatment with either supplemental high-dose oral vitamin D3 (four doses of 2·5 mg at weeks 0, 2, 4, and 6) or placebo. Neither the patients nor the clinical and laboratory investigators and personnel were aware of treatment assignment. The primary efficacy outcome was time to sputum culture conversion. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00366470. FINDINGS Between Jan 20, 2010, and Aug 23, 2011, we randomly assigned 247 participants to the vitamin D group (n=121) or the placebo group (n=126), of whom 211 participants (n=101 and n=110, respectively) were included in the primary efficacy analysis. Median time to culture conversion in the vitamin D group was 43·0 days (95% CI 33·3-52·8) versus 42·0 days (33·9-50·1) in the placebo group (log-rank p=0·95). Three (2%) patients died in the vitamin D group and one (1%) patient died in the placebo group; no death was considered attributable to the study intervention. No patients had hypercalcaemia. INTERPRETATION Our findings show that vitamin D supplementation did not reduce time to sputum culture conversion. Further studies should investigate the role of vitamin D in prevention or reactivation of tuberculosis infection. FUNDING Dalhousie University and Infectious Diseases Training and Research Centre.

Correlation of TEM, SHV and CTX-M extended-spectrum beta lactamases among Enterobacteriaceae with their in vitro antimicrobial susceptibility

PURPOSE The present study was carried out to characterize the ESBL types and evaluated their in vitro activity against a collection of Gram negative bacteria (GNB) from a multicentric Indian surveillance study. MATERIAL AND METHODS During January 2005 to June 2006, six tertiary care centres in India forwarded 778 non-duplicate GNB to our reference laboratory. Three hundred GNB from this collection were selected based on clinical significance and were used in the present study. Tested isolates included Escherichia coli (167), Klebsiella spp. (122) and Enterobacter spp. (11). ESBL screening and confirmation was performed for all the isolates. Minimum inhibitory concentration of imipenem, meropenem, ertapenem, levofloxacin, amikacin, piperacillin/tazobactam and ceftriaxone was determined by the E-test method. Molecular typing of the ESBLs was performed by polymerase chain reaction among the 121 selected isolates. RESULTS The study showed excellent susceptibility among the strains to imipenem (100%), meropenem (100%) and ertapenem (98.7%); good susceptibility to amikacin (89.7%) and piperacillin/tazobactam (85.3%) was observed. TEM and CTX-M were predominantly found in E. coli (39.2%) while, among the Klebsiella spp., TEM, SHV and CTX-M occurred together in 42.6% of the isolates. CONCLUSION More than one ESBL was produced by many strains, and this was correlated with increased resistance levels. Carbapenems continue to show good in vitro activity and ertapenem is a potential alternative to imipenem and meropenem. Continued antimicrobial resistance surveillance is warranted in light of these findings.

Post-exposure prophylaxis for blood borne viral infections in healthcare workers

Healthcare workers have a high risk of occupational exposure, more so in developing countries, with high incidence of blood borne diseases and prevalence of unsafe practices. Among the various blood borne diseases, the most common and important ones are HIV infection, hepatitis B, and hepatitis C. Most of the occupational transmission can be prevented and the “standard precaution” has been shown to reduce exposures and hence the transmission of infection. Healthcare workers have to be educated about post-exposure prophylaxis and each institution needs to adopt a clear protocol.

A comparison of the antimicrobial activity of meropenem and selected broad-spectrum antimicrobials tested against multi-drug resistant Gram-negative bacilli including bacteraemic Salmonella spp.: Initial studies for the MYSTIC programme in India

The evolution in India of multi-drug resistant pathogens possessing extended-spectrum beta-lactamases (ESBLs) threatens to compromise the clinical utility of third-generation cephalosporins and monobactams. Using selected resistant strains from a recent Indian 10 centre surveillance study that measured the prevailing incidence of resistance to beta-lactam antibiotics, the potential clinical utility of meropenem was assessed against nine other antimicrobial agents. A total of 212 Gram-negative bacilli were tested, of which 125 were confirmed by reference methods to be ESBL-producers. Meropenem was the most active of the test antimicrobials against these strains and the rank order of susceptibility was meropenem (99.1% susceptible) > piperacillin/tazobactam (76.9%) > ciprofloxacin (42.5%) > aminoglycosides (34.4-39.6%) = other beta-lactams (30.0-39.6%). Of the tested strains only two (Acinetobacter spp. and Pseudomonas putida) showed an intermediate susceptibility (8 mg/l) to meropenem. Of the 57 tested strains of Salmonella spp., three had an ESBL phenotype, confirmed two of the strains. This study confirms the high levels of resistance to beta-lactams agents in India reported elsewhere and also demonstrates, for Escherichia coli and Klebsiella spp., high levels of co-resistance between the tested beta-lactam agents and ciprofloxacin and the aminoglycosides, gentamicin and tobramycin. However, carbapenems such as meropenem, remain a therapeutic option.