Indian Journal of Medical Microbiology Medknow Publications on behalf of Indian Association of Medical Microbiology ISSN: 0255-0857 EISSN: 1998-3646 Vol. 29, Num. 3, 2011, pp. 213-217

Indian Journal of Medical Microbiology, Vol. 29, No. 3, July-September, 2011, pp. 213-217

Review Article

Is screening patients for antibiotic-resistant bacteria justified in the Indian context?

S Bhattacharya

Consultant Microbiologist, Tata Medical Center, Newtown, Rajarhat, Kolkata - 700 156, India
Correspondence Address: S Bhattacharya, Consultant Microbiologist, Tata Medical Center, Newtown, Rajarhat, Kolkata - 700 156, India, drsanjay1970@hotmail.com

Date of Submission: 21-Jun-2011 
Date of Acceptance: 22-Jun-2011

Code Number: mb11056

PMID: 21860099

DOI: 10.4103/0255-0857.83902

Abstract

Keywords: Antibiotics, bacteria, India, multi-drug resistance, screening

Introduction

The emergence of antimicrobial resistance (AMR) is a global health problem. The problem of AMR has affected the management and outcome of wide spectrum of infections which include MDR (multi-drug-resistant) and extensively drug-resistant tuberculosis, artemisinin resistance in malaria, anti-retroviral resistance in human immunodeficiency virus (HIV), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), multi-resistant Gram-negative bacilli (including those found in Escherichia coli, Klebsiella and Enterobacter, Pseudomonas and Acinetobacter species) and antibiotic-resistant shigellosis and gonorrhoea. AMR contributes to mortality, and poses a significant challenge to the control of infectious diseases. AMR increases the cost of healthcare and compromises the healthcare security of nations and economies through the spread of resistant pathogens by trade and travel. According to WHO, lack of comprehensive and coherent plans and resources, a weak surveillance system, poor drug quality, irrational use of antibiotics and other antimicrobial agents (including the use of antibiotics in animal husbandry) and inadequacy of infection prevention and control efforts have been the principle drivers of AMR. ^[1] This year on April 7, which is celebrated as the World Health Day by the World Health Organisation, the WHO introduced a six-point policy package for combating of antibiotic resistance. These included (1) a comprehensive national plan with societal engagement, (2) strengthening surveillance and laboratory capacity, (3) ensuring uninterrupted access to essential medicines of assured quality, (4) regulate and promote rational use of medicines, and reduce use of antimicrobials in food producing animals in animal husbandry, (5) enhance infection prevention and control and (6) foster innovations and research and development of new tools. ^[1] The SEARO (South East Asia Regional Office) is spearheading the regional response of WHO′s global strategy for containment of AMR.

Epidemiology of multi-drug-resistant bacterial infections in India

It is difficult to estimate the true burden of antibiotic resistance within India because of the lack of a mandatory national surveillance system, differing methodologies of antibiotic susceptibility testing, absence of mandatory quality assurance-quality control and accreditation requirements for testing laboratories and non-uniform sample selection strategies. In order to determine the true prevalence of the MDR organisms (MRSA, VRE, ESBL [extended spectrum beta-lactamase], carbapenem-resistant Gram-negative bacilli, etc), the following details might be useful: (a) define clearly the time period, patient demographics and geographical origin of patients; (b) describe laboratory method in detection/identification and antibiotic susceptibility testing; (c) give denominator data with regard to the total number of patient samples tested during the corresponding period; (d) de-duplicate positives when repeatedly isolated from the same patient within the same clinical episode; (e) differentiate screening samples from diagnostic samples, and invasive infections such as positive blood culture isolates from isolates from non-invasive infections (positive throat swab). Unfortunately, in many cases, such details are not available, and this compromises the quality of such reports. Reports from published literature suggest that prevalence of MRSA ranges from 8 to 71%, that of ESBL (or ESBL-producing Gram-negative bacilli) between 19 and 60%, that of VRE between 23 and 63% (the high VRE figures as reported from these centres may not representative for the whole country) and that of carbapenem-resistant Gram-negative bacilli between 5.3 and 59% [Table - 1]. ^{[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18]} All of these organisms are important causes of healthcare-associated infections (HCAIs), and in some cases infections arising from community. As for example MRSA can cause blood stream infections (BSI), skin and soft tissue infections and device-related infections, VRE can cause BSI, urinary tract infections (UTIs), endocarditis, ESBL and carbapenem-resistant organisms may cause hospital-acquired chest infection (including ventilator-associated pneumonia [VAP]), UTI and bacteraemia. Patients with MRSA BSI compared to those with methicillin-sensitive S. aureus BSI had a higher median total hospital cost ($113,852 vs. $42,137), higher hospital cost after infection ($51,492 vs. $17,603) and greater length of stay after infection (20.5 days vs. 10.5 days). ^[19] All of these infections are potentially life threatening and increase duration of hospital stay, morbidity and cost. Studies examining the economic impact of HCAI in India are sparse. In one study from Delhi, patients with hospital-acquired bacteraemia experienced a significantly longer total hospital stay (mean: 22.9 days), significantly longer intensive care unit (ICU) stay (mean: 11.3 days), a significantly higher mortality (mean: 54%) and cost significantly more (mean: US $14,818) than controls. ^[20] Data from the International Nosocomial Infection Control Consortium (INICC) reveal that the rate of central venous catheter (CVC)-associated BSI in the INICC ICUs was 7.6 per 1,000 CVC-days, the overall rate of VAP was 13.6 per 1,000 ventilator-days and rate of catheter-associated UTI (CAUTI) was 6.3 per 1,000 catheter-days. The frequencies of resistance of S. aureus to methicillin (MRSA) (84.1%), Klebsiella pneumoniae to ceftazidime or ceftriaxone (76.1%), Acinetobacter baumannii to imipenem (46.3%) and Pseudomonas aeruginosa to piperacillin (78.0%) were also far higher in the consortium′s ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 23.6% (CVC-associated BSI) to 29.3% (VAP). ^[21] Findings of the INICC covering 12 ICUs of seven Indian cities between 2004 and 2007 show that there were 9.06 HCAIs per 1,000 ICU-days. The CVC-related BSI (CVC-BSI) rate was 7.92 per 1,000 catheter-days, the VAP rate was 10.46 per 1,000 ventilator-days and the CAUTI rate was 1.41 per 1,000 catheter-days. Overall, 87.5% of all S. aureus HCAIs were caused by methicillin-resistant strains, 71.4% of Enterobacteriaceae were resistant to ceftriaxone and 26.1% to piperacillin-tazobactam; 28.6% of the Pseudomonas aeruginosa strains were resistant to ciprofloxacin, 64.9% to ceftazidime and 42.0% to imipenem. Length of stay was 4.4 days for those without HCAI, 9.4 days for those with CVC-BSI, 15.3 days for those with VAP and 12.4 days for those with CAUTI. Excess mortality was 19.0% (relative risk [RR] 3.87) for VAP, 4.0% (RR 1.60) for CVC-BSI and 11.6% (RR 2.74) for CAUTI. ^[22]

Screening and the technology of screening for multi-drug-resistant infections

For any screening programme to be effective, it needs to fulfil certain basic principles. These include (a) the condition should be relatively common and potentially disabling, (b) the screening test should be available, sensitive, specific, acceptable, relatively easy to perform, repeatable and cost effective and (c) treatment or intervention should be readily available and there should be an agreed policy of whom to treat. ^[23] There is a well-established technology by conventional bacterial culture methods on agar plates for screening individuals for multi-resistant bacterial pathogens. The ChromID MRSA/VRE/ESBL plates (e.g., from bioMerieux) and MRSA select plates (from Bio-Rad) or BBL CHROM agar MRSA (from BD) are examples of this relatively simple technology, some of which are available in India commercially. Antibiotic-impregnated plates could be prepared in-house (e.g., mannitol salt agar with 4 mg/l of cefoxitin in contrast to the BD CHROM agar for MRSA that has 6 mg/l of cefoxitin). ^[24] For MRSA detection, swabs can be taken from nose/throat/perineum/groin/wounds, inoculated onto the antibiotic-impregnated agar plates (containing cefoxitin), incubated at 37°C for 18 to 24 hours and presumptive colonies identified specifically using routine biochemical (e.g., coagulase, catalase test after a Gram stain) and immunological (latex agglutination test for PBP2a- a marker for MRSA) tests. Using automated techniques (e.g., Vitek2) for specific identification or extended susceptibility testing on screening samples does not seem to be cost effective. Some standard operating procedures have suggested using Baird-Parker agar with ciprofloxacin, or mannitol salt agar (with 7% NaCl), along with enrichment culture in nutrient broth containing 7% NaCl for MRSA screening. However, these techniques may miss ciprofloxacin-sensitive MRSA strains, and direct agglutination tests for identification of MRSA from mannitol salt agar might be unreliable. For ESBL detection, the sample could be rectal swabs, urine or respiratory secretions (e.g., Brilliance ESBL agar from Oxoid and media containing 1 mg/l of cefotaxime or 4 mg/l of ceftazidime), ^[25] and for VRE (Enterococcosel agar containing 8 mg/l of vancomycin), ^[26] samples such as rectal swabs or stools samples could be used, and finally detection of carbapenamase-producing Enterobacteriaceae one can use MacConkey agar supplemented with 1 mg/l of imipenem. ^[27] Polymerase chain reaction (PCR)-based molecular systems such as Xpert MRSA and Xpert VanA using GeneXpert system from Cepheid are fully automated real-time PCR systems that have been able to bring down the turn-around time of MRSA or VRE detection from 2-3 days (based on culture methods) to a few hours. ^[28] However, the investment required for establishing a molecular biology laboratory facility is significant, and that increases the price of the test to a few thousands rupees as opposed to few hundred rupees compared to conventional culture-based methods.

Rationale of screening for resistant bacteria in the Indian context

The total expenditure on health in India per capita is $109 compared to $2784 in the UK, $6714 in the USA and $342 in China (2006 data from WHO). The infant mortality rate in India is 52/1,000 live births, maternal mortality ratio is 230/100,000 live births; only 31% of our population have access to improved sanitation, 12% still do not have access to improved drinking water and 41% of the population live below poverty line (earn less than $1 a day, 2005 data from WHO). ^[29] Confronted with these facts and priorities, it seems unlikely that we would have a national policy for screening patients in healthcare settings for multi-resistant bacteria soon. And perhaps, the broad-based 6 pronged strategies outlined by WHO is the long-term solution. However, the indirect cost on health and resources caused by the antibiotic-resistant bacteria is considerable, and often not taken into account while estimating the cost benefit of screening. It must also be noted that estimating this indirect cost (and thereby the cost benefit to a central pool of resources) is complex. An example of a decision rule to decide on a new infection control intervention (such as screening for multi-resistant bacteria) has been elegantly explained in the article by Graves et al. and can be expressed by the formula: ΔC/ΔE < λ, where ΔC is the total costs under a new intervention minus the total costs under an appropriate comparator (usually the existing practice), ΔE is the change in health outcomes that arises from a decision to invest in a new health intervention [the total number of QALYs (Quality-Adjusted Life Years) under a new intervention minus the total number of QALYs under an appropriate comparator] and λ is the decision maker′s maximum willingness to pay for each QALY. The value of ΔC is not an independent variable and is affected by not only the technology for screening (e.g., culture vs. PCR), but also the HCAI rates.[30] The cost saving derived by preventing HAI could be calculated by the formula pq, where p is the cost of maintaining a hospital bed/day and q is the number of bed-days lost because of an episode of HAI. ^[30] Again, in this formula, the value of p would be determined by the infrastructure and intervention facilities in a hospital, and the q value is dependent on the type of HAI (patients with blood stream infections may stay longer than a patient with UTI). The financial and organisational incentives for reducing HAI is dependent on the socioeconomic model of a healthcare setting, and is likely to be different for public sector hospitals and privately funded corporate hospitals. In the assessment of the cost-effectiveness of MRSA control programmes, the variables that need to be considered include the cost of the intervention (e.g., decolonisation treatment, selection of a different agent for antibiotic prophylaxis for surgery, cost of implementing patient isolation and barrier precautions) and the cost of MRSA infection. Laboratory costs for MRSA screening in comparison are quite low; in one hospital from Canada, these were found to be $8.34 per specimen with a total cost of $30,632 during 1996 for a 980-bed hospital. ^[31] In the Indian context, this is likely to be within a few hundred rupees (cost of chromogenic MRSA selective medium plus cost of additional tests for identification, besides overhead/infrastructure costs). It also needs to be recognised that screening for multi-resistant bacteria (e.g., MRSA) is not the standard practice in most Indian hospitals. Therefore, the initial investment required for education, technology implementation, creation of isolation facilities and implementing other infection control interventions (through suitably trained human resource such as infection control nurses and a clinical microbiologist) is likely to be considerable.

Deliverable interventions following a positive screening test for multi-resistant bacteria

The knowledge from a screening test that a patient is colonised or infected with a multi-resistant bacteria is justified if there are definitive interventions available which might alter the clinical outcome and reduce healthcare-associated costs. These interventions may include notification to the concerned clinical and nursing team, infection control precautions such as isolation or cohort nursing of such patients, use of decolonisation treatment regimens (e.g., nasal mupirocin ointment, along with chlorhexidine body wash for MRSA colonised or infected patients), use of appropriate antibiotic prophylaxis during surgery or other invasive interventions and use of an appropriate agent for empirical antibiotic therapy in case of unconfirmed/unknown infection in a colonised patient. These deliverable interventions have been extensively tried and tested in case of MRSA. ^[32] However, for other multi-resistant pathogens (VRE, KPC, ESBL, NDM-1), the case is not clear yet. This is due to lack of consensus regarding optimal screening strategy (in terms of specimens, technology and frequency) and the absence of adequate decolonisation regimens (many of these may reside as part of the gut flora for a long time). In this situation, it is perhaps better for respective institutions to come up with their own screening strategy based on available evidence, local epidemiology and resources available and priorities.

Conclusion

Multi-antibiotic-resistant Gram-positive (MRSA, VRE) and Gram-negative (ESBL, AmpC, NDM-1) bacterial pathogens are clinical problem in some Indian hospitals. A sensitive, specific and cost-effective screening programme may help in the following ways: (a) Choice of antimicrobial therapy; (b) Provide baseline data in a hospital about epidemiology of multi-resistant pathogens and (c) Help in infection control by early identification of patients, thereby facilitating an informed decision about infection control interventions (decolonisation treatment, patient isolation, barrier and contact precautions). Although PCR-based approaches are available for some organisms (e.g., MRSA, VRE), in terms of cost and infrastructure requirements, a culture-based methodology for screening seems more justified on economic considerations. Since deliverable and cost-effective interventions are yet to be available for all categories of multi-resistant bacteria, it is being suggested that an institutional approach based on local priorities and epidemiology be taken initially, till evidence becomes available for formulation of a national policy. The resources could be directed to high-risk patients (such as those in ICUs, transplant recipients, those with previous hospitalisations and previous positive results), so that hospital-acquired infection rates and patient outcomes (both in quality and cost) could be improved. Screening for MDR bacteria is only of the many approaches needed to deal with the very major clinical problem concerning MDR organisms. Screening is not and cannot be substitute for the basic infection prevention and control measures such as clean hospitals, microbiologically satisfactory water and food quality, rational use of antibiotics (at the hospital and community level with involvement of general practitioners), and strict enforcement of preventative measures wherever indicated (e.g. hand hygiene, isolation, standard and contact precautions, etc).

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