Vikas Manchanda

Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis

BACKGROUND The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. METHODS We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. FINDINGS We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacteriums total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. INTERPRETATION Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori. FUNDING World Health Organization.

Intravenous Colistin Administration in Neonates

Background: Nosocomial infection due to multidrug-resistant Gram-negative pathogens in intensive care units is a challenge for clinicians and microbiologists, and has led to resurgence of parenteral colistin use in the last decade. Safety and efficacy data regarding intravenous colistin (colistimethate) use in neonates is sparse. We present our experience of efficacy and safety of colistimethate in the treatment of sepsis in critically sick term and preterm neonates. Methods: The records of the neonates who received colistimethate in a neonatal intensive care unit of a tertiary care center from January 2009 to December 2009 were reviewed. Results: Eighteen critically sick neonates (10 term and 8 preterm) received 21 courses of colistimethate (dose ranging from 50,000 to 75,000 IU/kg/d) for treatment of pneumonia, blood stream infections, meningitis, and empyema thoracis. The isolated pathogens in decreasing order of frequency were Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonos aeruginosa, and Enterobacter. Mean duration of colistimethate was 13.1 days/course (range: 5–21 days). At least one other antibiotic was coadministered in all courses. A favorable clinical outcome occurred in 16 of 21 (76%) courses, 5 patients died due to severe sepsis with multiple organ dysfunction. Microbiologic clearance was documented in 17 courses. Increase in serum creatinine by >0.5 mg/dL above baseline in 2 babies was associated with the presence of multiple organ dysfunction syndrome in both and coadministration of netilmicin in one. Conclusions: Colistimethate intravenous administration appears to be safe and efficacious for multidrug-resistant Gram-negative infections in neonates, including preterm and extremely low birth weight neonates.

Comparative evaluation of griseofulvin, terbinafine and fluconazole in the treatment of tinea capitis

Tinea capitis (TC) is a common childhood fungal infection which, if untreated, can cause long‐term scarring. A number of antifungal drugs with proven efficacy are available for the treatment of TC. However, varying dosage schedules, changes in epidemiology, and rising drug resistance are factors that hamper treatment in some cases. A prospective, non‐blinded, cross‐sectional study of three commonly used drugs (terbinafine, griseofulvin, and fluconazole) was undertaken in children aged ≤12 years, presenting to a pediatric superspecialty hospital. The comparative efficacies of these three drugs were evaluated. A total of 75 patients (25 in each treatment group) who completed the designated treatment protocol were included in the final analysis. Of these, 60% had non‐inflammatory TC and 56% had an ectothrix pattern on hair microscopy. Trichophyton violaceum was the most commonly isolated fungus. Cure rates of 96%, 88%, and 84% were achieved with griseofulvin, terbinafine, and fluconazole, respectively. Overall, seven patients required prolonged therapy. No side effects to therapy were seen. Griseofulvin remains the drug of choice in the treatment of TC. Terbinafine was the second best agent and offered the advantage of a shorter course of therapy. Fluconazole had comparatively low cure rates but was easier to administer than the other two medications.

Emergence of Non-Ceftriaxone-Susceptible Neisseria meningitidis in India

Meningococcal disease is endemic in Delhi, and there has been an increase in the number of cases of meningococcal disease occurring in Delhi in recent years (4). Antimicrobial therapy is the cornerstone of meningococcal disease management. Expanded-spectrum cephalosporins (ceftriaxone and cefotaxime) are widely accepted antimicrobials for the treatment of patients suspected of having meningococcal disease (1, 5). In India, there has been a paucity of studies on the antimicrobial sensitivity of Neisseria meningitidis. Drug susceptibility testing on the isolates obtained from a recent spurt of cases in and around Delhi in early 2005 revealed increased resistance to ciprofloxacin while all isolates were susceptible to ceftriaxone (4). We report on the emergence of clinical isolates of N. meningitidis that were found to be nonsusceptible to ceftriaxone and cefotaxime and were associated with potential therapeutic failure to ceftriaxone therapy.

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.

Congenital candidal onychomycoses: effective cure with ciclopirox olamine 8% nail lacquer

SIR, We are grateful to Dr Guerrini and colleagues for their interest in our study and we take this opportunity to clarify our opinions. We demonstrated the presence of high-risk mucosal human papillomavirus (HPV) genotypes from a considerable number of dysplastic naevi and primary melanomas using two different polymerase chain reaction (PCR)–enzyme-linked immunosorbent assay methods, concluding that the presence of the virus may be a cofactor in development and progression of these pathologies. We agree with other colleagues that our results need further evaluation. In particular, PCR is a highly sensitive technique, able to detect the presence of total DNA from tissue samples at a level of about one genome per cell. All previous studies aimed to detect HPV DNA in skin cancer using PCR procedures were in most cases unable to conclude that the DNA detected was entirely derived from cancer cells. In fact, PCR procedures are not suitable to ascertain if the HPV DNA detected is derived exclusively from cancer cells, but rather if its presence is due to a tumour surface contamination. On the other hand, different methods, including immunohistochemistry (IHC) and in situ hybridization (ISH), have been demonstrated as more specific, but less sensitive than PCR methods. On the basis of these considerations, we are submitting for publication a second part of our studies, concerning the evaluation of the presence of mucosal high-risk HPV in primary melanoma and its colocalization with a tumoral melanocytic marker in the same section, using a very sensitive method that combines an enzyme-amplified fluorescent ISH with a chemiluminescent IHC method for the detection of the tumoral melanocytic marker HMB-45. The antimelanoma monoclonal antibody HMB-45 used in the chemiluminescent IHC is widely used in diagnostic pathology owing to its great specificity and sensitivity in identifying pigmented tumours such as malignant melanoma, while normal melanocytes are unreactive.

Bacterial pyoderma in children and therapeutic options including management of community‐acquired methicillin resistant Staphylococcus aureus

Primary pyoderma are frequently observed in outpatient clinics. Among the wide spectrum of bacterial agents Staphylococcus aureus and Streptococcus spp. are the commonest agents responsible for these pyoderma. Community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) infections are increasing as a clinical problem world-wide with skin and soft tissue infections being the most common manifestations. 1–3 In contrast to nosocomial-acquired methicillin-resistant S. aureus (MRSA) infections, CAMRSA infections (a) often occur in individuals who are immunocompetent without MRSA-associated risk factors, (b) tend to be susceptible to most nonbeta-lactam antibiotics, (c) can be virulent and fatal, and (d) have a type IV staphylococcal cassette chromosome (SCCmec) genetic element (which carries mecA , the methicillin-resistance gene) that is distinct from types I, II, and III SCCmec elements, which are associated with hospital-acquired MRSA infections. 1,2,4 Additionally, CAMRSA have the pvl gene, a virulence gene encoding a leukocyte-killing toxin, Panton-Valantine leukocidin. 5

To study the incidence and risk factors of early onset neonatal sepsis in an out born neonatal intensive care unit of India

Objectives: The objective was to study the Incidence and risk factors of early-onset neonatal sepsis in an out born neonatal intensive care unit (NICU) of New Delhi, India. Study Design and Setting: Prospective descriptive study over a period of 1 year. Patients and Methods: All out born neonates admitted within 72 h of life, with clinical features of sepsis with two or more high-risk factors for sepsis were enrolled and samples for sepsis screen and cultures were taken prior to administration of antibiotics in all cases. Standard data collection form was used to collect all demographic data and clinical characteristics of neonates. Bacterial isolates were identified, and their resistance patterns were analyzed using the Vitek 2 C system. Results : Among the 440 admissions to NICU during the study period, 82 neonates (19%) with early onset sepsis were enrolled. The mean (standard deviation) weight and hours of life at admission were 2016 ± 724.04 g and 23.05 ± 2.89 h, respectively. Incidence of early onset sepsis was 18/1000 patient. Twenty-eight (34%) neonates were home delivered. Low birth weight (68%), prematurity (46%), and poor hygiene/cord care (46%) were common risk factors while lethargy/refusal to feed (77%), hypothermia (47.5%), and respiratory distress (44%) were common clinical presentations. Sepsis screen and blood culture were positive in 57% and 18% (n = 15), respectively. Klebsiella pneumonie (36%), Staphylococcus aureus (21%), and Escherichia coli (14%) were common organisms. Case fatality rate was 14% (12/82). Conclusion: Clinical sepsis along with sepsis screen is a good marker of neonatal sepsis: Incidence of early onset sepsis varies in out born neonates and many factors affect it like place of delivery, perinatal risk factors, and immediate practices done in newborn.

In vitro antimicrobial susceptibility patterns of Propionibacterium acnes isolated from patients with acne vulgaris

INTRODUCTION Propionibacterium acnes has been implicated in the development of acne vulgaris. Rampant use of topical and systemic antibiotics for acne vulgaris has led to resistance due to selective pressure. This study aimed to determine antibiotic resistance of P. acnes. METHODOLOGY A total of 102 samples were collected from acne lesions and cultured onto sheeps blood agar and brain-heart infusion agar supplemented with 5 g/L glucose and 2 mg/L furazolidone) (BHIg) under aerobic and anaerobic conditions. Species identification was done by conventional methods and the VITEK2 Compact system. The isolates were tested for penicillin, erythromycin, clindamycin, ciprofloxacin, nadifloxacin, and tetracycline by E-test, and minimum inhibitory concentration (MIC) of minocycline was determined by agar dilution on BHIg. MIC results were interpreted as per EUCAST (European Committee on Antimicrobial Susceptibility Testing) and CLSI (Clinical Laboratory Standards Institute) guidelines. RESULTS P. acnes was the most common anaerobe (66%) isolated. Resistance rates using EUCAST and CLSI breakpoints were 10.6% and 6.1%, 7.6% and 0%, 7.8% and 0% for erythromycin, clindamycin, and minocycline, respectively. Tetracycline resistance was observed in 9.2% isolates irrespective of the interpretative criteria used. MIC50 and MIC90 values for nadifloxacin (0.25 and 1 µg/mL) were found to be twofold lower than those for ciprofloxacin (0.5 and 1 µg/mL). Similarly, MIC50 and MIC90 values for minocycline (0.125 and 0.5 µg/mL) were also two- to threefold lower than those for tetracycline (0.38 and 1 µg/mL). CONCLUSIONS To the best of our knowledge, this is the first study focusing on P. acnes resistance from India.

Predictors of adverse outcome in patients of tuberculous meningitis in a multi-centric study from India

INTRODUCTION This study aimed to investigate the factors which may predict mortality and neurological disability at one year follow up in patients of tuberculous meningitis (TBM) in India. METHODOLOGY Patients with TBM were prospectively enrolled from July 2012 to September 2014 from four tertiary care hospitals of Delhi. The demographic characteristics, clinical features and laboratory findings were collected and patients were followed up till 1 year. These were analyzed by univariate and multivariate multinomial logistic regression analysis to identify predictors of adverse patient outcome at 1 year follow up. RESULTS Out of 478 patients enrolled, 391 patients could be followed up to 1 year. Sixty-four patients (16.3%) died and 150 patients (39%) survived with one or more neurological disability. Altered sensorium, motor deficit, cranial nerve palsy, seizures, isolation of M. tuberculosis and presence of multi-drug resistance were independently associated with any adverse outcome (death or disability) but by multivariate analysis only motor deficit, altered sensorium and isolation of M. tuberculosis on culture produced a statistically significant model for prediction of patient outcome. CONCLUSION The three-predictor model with motor deficit, altered sensorium and isolation of M. tuberculosis produced a statistically significant model with correct prediction rate of 60.4%. These three variables predicted death with odds ratio of 39.2, 6.7 and 2.1 respectively in comparison to recovery whereas only motor deficit and isolation of M. tuberculosis predicted neurological disability at 1 year with odds ratio of 3.9, 2.4 respectively.