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Indian Journal of Medical Microbiology
Medknow Publications on behalf of Indian Association of Medical Microbiology
ISSN: 0255-0857 EISSN: 1998-3646
Vol. 29, Num. 1, 2011, pp. 22-27

Indian Journal of Medical Microbiology, Vol. 29, No. 1, January-March, 2011, pp. 22-27

Original Article

Multidrug-resistant Enterobacteriaceae including metallo-β-lactamase producers are predominant pathogens of healthcare-associated infections in an Indian teaching hospital

1 Northumbria Healthcare NHS Foundation Trust, Rake Lane, NE 28 8NH, England,
2 Guwahati Medical College, Bhangagarh, Guwahati-781 032, India,

Correspondence Address: J B Sarma, Northumbria Healthcare NHS Foundation Trust, Rake Lane, NE 28 8NH, England, jayanta.sarma@nhs.net

Date of Submission: 17-May-2009
Date of Acceptance: 25-Nov-2010

Code Number: mb11006

PMID: 21304190

DOI: 10.4103/0255-0857.76519

Abstract

Purpose: A study was carried out in an Indian teaching hospital in 2009 to detect the rate of surgical site infections (SSI) and peripheral vascular access site infections.
Materials and Methods:
The study was a point-prevalence study involving over 300 patients. The presence of infection was determined according to the CDC criteria. Swabs were taken from the infected sites and identification and sensitivity were carried out using VITEK® 2 automated system. Characterisation of β-lactamase was carried out at ARRML, Colindale, London.
Results:
The rate of SSI was 15% for the clean and clean-contaminated categories while that for the dirty contaminated category was 85% (NNIS risk index 0). Cultures yielded definite or probable pathogens from 64% (9/14) of the patients with SSI. In 1/3 rd of the cultures, Staphylococcus aureus was grown and the rest had Enterobacteriaceae, either extended-spectrum β-lactamase (ESBL) producers or Amp-C hyperproducers and, alarmingly, three isolates were positive for newly recognised New Delhi metallo-β-lactamase-1 (NDM-1). In medicine, 87% (n = 99) of the patients had a peripheral IV access device, 55% developed associated phlebitis/infection and, in seven, probable pathogens were isolated (Candida species and Escherichia coli producing ESBL and NDM-1, respectively, Staphylococcus aureus and Enterococcus faecium). All ESBL and metallo-β-lactamase producers were resistant to multiple classes of antimicrobials, the latter being sensitive only to colistin and tigecycline. The study also found that all post-operative patients were on antibiotics, 92% on IV [213 defined daily doses (DDD)/100 post-op patients] limited mainly to the third-generation cephalosporins (26%) and aminoglycosides (24%) and imidazole derivatives (30%). In medicine, 83% (n = 82) were on IV antibiotics (123 DDD/100 bed-days), limited mainly to the third-generation cephalosporins (74%).
Conclusion:
Indiscriminate use of antibiotics is a major problem predisposing patients to harm by multi-resistant pathogens. Carbapenems were in little use in this hospital, but the selection pressure exerted by cephalosporins and other unrelated classes was sufficient to select NDM-1-producing strains due to co-selection, suggesting a role of single plasmid carrying resistance genes to multiple classes.

Keywords: healthcare-associated infections, surgical site infections, extended-spectrum β-lactamase , metallo-β-lactamase, meticillin-resistant S. aureus

Introduction

Establishing the burden of healthcare-associated infections (HCAI) is a prerequisite before any institutional improvement programme can begin so that the success can be measured against the baseline rate. [1] Improper usage of antimicrobials complicates the problem of HCAI by encouraging multi-resistance in nosocomial pathogens, and treatment options are fast running out, particularly against gram-negative nosocomial pathogens. [2],[3] SSI [4],[5] and peripheral IV access device [2] infections are two major HCAI avoidable by relatively simple means, avoiding the associated morbidity and extra cost and saving thousands of lives.

Materials and Methods

In August 2009, a single-day point-prevalence survey was carried out to determine the prevalence of SSI and peripheral vascular access site infections and pattern of antimicrobial usage in an Indian tertiary teaching hospital, typical of over 200 such teaching hospitals, situated in north east India. This study followed an initial inspection visit to the hospital in August 2008 to assess the infection control practices in the hospital.

All post-operative patients (n = 66), which constitutes 27% of all patients (n = 244) in four male and two female surgical wards, were included in the survey. In medicine, all patients (n = 99) in two male wards were included in the study. Post-operative patients were stratified according to the pre-operative NNIS Risk Index score. [6],[7]

A doctor carried out the observation of the surgical and peripheral vascular access sites and determined whether there was an infection according to the CDC definition. [8] Specimens were collected from any infected site using Sterilin® swabs with Amies transport-medium (Sterilin Limited, Caerphilly, CF819FW). All antibiotics prescribed for post-operative and medical patients were noted from the medical records.

Specimens were shipped within 24 h in triple-containment packaging with labelling and marking meeting the United Nation′s requirements for transportation of "Biological Substance, Category B" to the Microbiology Laboratory, North Tyneside General Hospital, a laboratory accredited by the Clinical Pathology Accreditation (UK) Ltd. Swabs were plated to CLED, Blood agar and a chromogenic selective MRSA agar medium (MRSA Select® , Bio-Rad Laboratories, Marnes-la-Coquette, France) and incubated at 37ºC overnight aerobically. In addition, swabs were also plated to fastidious anaerobic agar and incubated anaerobically for 48 hours at 37ºC. Isolated colonies were identified and antimicrobial sensitivity testing was carried out, including detection of extended-spectrum β-lactamase (ESBL) and potential carbapenemase production by VITEK® 2 identification and antibiotic susceptibility testing (ID/AST) system (bioMerieux, Basingstoke, UK), which incorporated the Advanced Expert System (AES™), a software which validates and interprets susceptibility test results and detects antibiotic-resistance mechanisms. The EUCAST (http://www.eucast.org) susceptibility breakpoints were used. ESBL production was further confirmed by the double-disc synergy test and then by the Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL), Health Protection Agency (HPA), London. Potential carbapenemase production by Enterobacteriaceae isolates was confirmed and the enzyme was confirmed as New Delhi metallo-β-lactamase-1 (NDM-1) by the ARMRL, HPA, London.

Disclaimer

The study was carried out under the auspices of the North East Clinical Excellence Foundation, Guwahati, as per permission granted by the Director of Medical Education, Assam, and the hospital authority, which includes shipping of the swabs to a laboratory outside the country.

Results

One female ward had no SSI detected while the other had 31%, with a bed-occupancy of 93% and 100%, respectively. In the male wards, the SSI rates were 12%, 17%, 20% and 41%, with a bed-occupancy of 74%, 100%, 65% and 100%, respectively.

The average age of the surgical patients was 39 years (median, 37 years) and that of the patients who developed SSI was 43 years (median, 40 years), a difference that is not significant. This is by any measure a young cohort and the majority had no or a few co-morbidities [American Society of Anaesthesiologists (ASA) score ≤2]. The age of the medical patients in the two wards was also relatively low (average 38 years; median, 35 years).

Observed SSI

The NNIS Risk Index score based on (1) the ASA score 3, 4 or 5, (2) an operation classified as contaminated or dirty and (3) duration of procedure (longer than the 75 th percentile for the procedure) predicts the rate of SSI; the SSI rates for patients with scores of 0, 1, 2 and 3 are predicted as 1.5, 2.9, 6.8 and 13.0, respectively. [6],[7] Based on the study cohort (ASA score ≤2) and the procedure completed within the stipulated time (i.e., NNIS risk index 0), the predicted rate of SSI for clean and clean-contaminated procedures should have been 1.5%, but the observed rates were at 18% (7/39) and 10% (2/21), respectively (15% if both the categories were combined), while that of the dirty contaminated category was 83% (5/6) [Table - 1]. In medicine, 87% of the patients had a peripheral IV access device, of which 55% developed associated phlebitis/infection.

Microbiology

Cultures yielded definite or probable pathogens from 64% (n = 9) of the patients with SSI. In 1/3 rd of the patients (n = 3), Staphylococcus aureus (67% meticillin resistant - MRSA) was the cause; the remaining 2/3 rd (n = 6) had species of Enterobacteriaceae (n = 11) - ESBL (predominantly blaCTX-15), Amp-C hyper-producers and joint ESBL and Amp-C producers constituted the majority (73%), and, alarmingly, a newly recognised metallo-β-lactamase (MBL) (bla NDM-1 ) [3],[9] was detected in the rest (27%, n = 3) of the isolates. The three NDM-1 organisms, viz. Enterobactor cloacae, Escherichia coli and Klebsiella pneumoniae, were isolated from three patients in two separate male and one female wards. The two male patients were co-infected with an additional organism (Escherichia coli and Klebsiella pneumoniae., respectively); similarly the female patient was also co-infected with an additional Escherichia coli [Table - 2].

In medicine, 15% (7/47) of the infected patients had probable pathogen/s (n = 8), majority Candida species (C. albicans, n = 2, C. parapsilosis, n = 2) and one each of Escherichia coli-producing NDM-1, Escherichia coli-producing ESBL (blaCTX-15 ), meticillin-sensitive Staphylococcus aureus and Enterococcus faecium [Table - 3].

Enterobacteriaceae isolates were tested against a panel of antibiotics. ESBL producers and Amp C hyperproducers (n = 9) were resistant to multiple classes of antimicrobials - ampicillin 100%, piperacillin 89%, piperacillin-tazobactam 89%, cefotaxime 100%, cefoxitin 67%, cefpirome 100%, eftazidime 100%, ertapenem 11%, imipenem 0%, meropenem 0%, amikacin 22%, gentamicin 56%, tobramycin 78%, ciprofloxacin 100%, tigecycline 22% and colistin 0%. MBL (blaNDM-1 ) producers (n = 4) were resistant to all antimicrobials except colistin (100% sensitive) and tigecycline (50% sensitive; 50% intermediate).

Consumption of antimicrobials

Every single post-operative patient was on antibiotics, 92% on IV. The total consumptions were 213 defined daily doses (DDD)/100 post-op patients limited mainly to the third-generation cephalosporins (26%), aminoglycosides (24%) and imidazole derivatives (30%), with little or no usage of other classes [Figure - 1] and [Figure - 2].

In medicine, 83% of the patients were on antibiotics and all were on IV. The total consumption was 123 DDD/100 bed-days; the usage of antimicrobials was limited mainly to the third-generation cephalosporins (74%) [Figure - 3] and [Figure - 4].

Antibiotic regimens used in patients with SSI consisted at least two and, often, more of ceftriaxone, piperacillin with tazobactam, cefotaxime with salbactam, aztreonam, ofloxacin, imipenem, linezolid, gentamicin, amikacin, tinidazole, ornidazole and metronidazole [Figure - 1]. In medicine, monotherapy was generally observed but, in some cases, combinations of ceftriaxone, piperacillin with tazobactam, cefotaxim with salbactam, amikacin, and metronidazole were also observed.

Discussion

The study hospital is typical of over 200 Indian teaching hospitals based in north east India. The rate of SSI for the types of surgical interventions preformed is extremely high compared with the published bench marks, particularly for exploratory laperotomy, a clean procedure if the gastrointestinal tract is not entered. The high rate perhaps can be explained, to a degree, by the fact that the operating rooms (OR) in the hospital only have natural ventilation and, therefore, are not directly comparable to the hospitals in the developed countries where Plenum (conventional) ventilation system is the universal standard. Plenum ventilation contributes to the reduction of bacterial load in the operating theatre, reducing the incidence of surgical wound infection rates. But, the ventilation system is only one of the many factors that can contribute to a safe operating environment and, ever since the time of Lister, the significance of airborne bacteria as a source of infection for most types of operations continues to be a matter for debate and of dispute [10],[11],[12],[13] and of doubtful value in general and clean surgery other than joint prosthesis operations. [14] The first phase of a crossover study [15] carried out in a surgical suite that contained no environmental or traffic control systems and the second phase within a modern operating room suite containing a ventilation system that provided the OR with clinically sterile air showed that the rate of infection was essentially the same in both phases of the study; environmental air only occasionally served as the source of infecting organisms, which supports the conclusion that the most common source of infecting organisms in surgical infections is the patient or those around him and the most common time of contamination is during the surgical procedure itself. Surgical infections can best be minimized by meticulous observation of the fundamental principles of antisepsis and theatre discipline rather than by dependence on elaborate and costly ventilation systems. [14]

It would have been interesting to see SSI rates of other hospitals with no Plenum ventilation in the OR, but no comparable published data from the Indian hospitals are available.

In 2008, two important documents on SSI were published, [4],[16] emphasising the key aspects during the pre-operative, operative and post-operative phases of patient care in addition to effective interventions known to be important for some time, e.g. not shaving the surgical site until the day of the procedure, increasing emphasis on physiological parameters, e.g. blood glucose concentrations, oxygen tensions and body temperature.

It is of concern that data collected in this study showed that all post operative patients and majority of medical patients were receiving intravenous antibiotic therapy. It appears that continued prophylaxis was the reason in the majority, although, in a proportion, it was therapeutic for treating established SSI. In medicine, why such a large number of patients (83%) are receiving IV antibiotics requires investigation so that hazards associated with IV access can be reduced to a minimum. In this hospital, antimicrobial usage in the medicine department has increased from 70 in 2002 [5] to 123 DDD/100 bed-days in this study, which may be attributable to the fact that prescribed antibiotics have been made available free for the last few years due to better government funding. Ironically, these antimicrobials were causing harm rather than benefit by selecting out multi-resistant Enterobacteriaceae, both ESBL and MBL producers and MRSA. A staggering 87% in the medical wards had a peripheral IV access device, 55% developing phlebitis/infection. The incidence of phlebitis and bacterial colonization of the catheters increases when the catheters are left in place, >72 h being associated with an increased risk for infection. Peripheral catheter sites commonly are rotated at 72-96-h intervals to reduce both the risk for infection and the patient discomfort associated with phlebitis. [17]

While isolates producing ESBL remain sensitive to carbapenems, carbapenemase-producing isolates are resistant to all antibiotics except colistin and tigecycline, heralding an era of untreatable infections. [2] NDM-1 has recently been reported [3] from many locations in the Indian subcontinent following the original report of the first case. [9] A surveillance conducted in this hospital in 2002 revealed widespread problem of ESBL but not of carbapenemase. [18]

The fact that NDM-1 was detected in at least three species, viz. Escherichia coli, Klebsiella pneumoniae and Enterobactor cloacae, suggests that the problem is endemic spread within the species by transferable mobile genes carried on plasmids and high usage of ineffective antimicrobials in turn, selecting out both ESBL and MBL producers and helping the spread. Only one out of three patients with carbapenemase-producing Enterobacteriaceae was receiving a carbapenem (imipenem). The fact that carbapenems are in little use in this hospital testifies that selection pressure exerted by third-generation cephalosporins and even unrelated classes is sufficient to select carbapenem resistance due to co-selection/associated linkage selection as a single plasmid often carries resistance genes to multiple classes, [19] which makes strict control of antimicrobial prescribing urgent.

The issue of inappropriate and excessive usage of antibiotics, cephalosporins in particular, needs to be addressed head-on with a sense of urgency. Long sentence but correct. Here ′Prophylactic antimicrobial agents′ at the very beginning is the subject and the sentence is complete. [20]

The Bla CTX-M-15 gene borne on plasmid conferring acquired resistance to third-generation cephalosporins in Enterobacteriaceae first emerged in India in the mid-1990s, [21],[22] which is now the globally dominant ESBL. [23],[24] A recent paper [3] detects the presence of novel NDM-1 in nosocomial isolates of Enterobacteriaceae from Chennai, Mumbai, Varanasi, New Delhi, Bangalore, Pure, Kolkata, Hyderabad, Port Blair and Haryana, and from many locations in Pakistan; some isolates from Chennai and Haryana were from community-acquired urinary tract infections, suggesting that the problem is not restricted to hospitals. Further studies are required urgently to establish the extent of the spread both in hospital and community settings.

Emergence of carbapenemase in Indian hospitals and, potentially, in the community should serve as the last straw for the Indian government and regulatory agencies to impose strict statutory guidelines implementing interventions for limiting inappropriate usage of antimicrobials, particularly for the "post-surgical" prophylaxis. Enterobacteriaceae are part of the human gut flora. Dissemination of resistant clones carried as part of the normal human flora occurs unsuspected, which is amplified many folds by the selection pressure exerted by antimicrobials, and gives rise to infections in vulnerable patients that could be life-threatening.

Defensive practice, ignorance of rational antibiotic-prescribing principles, lack of awareness of the problem of the alarming rise in multi resistance and pharmaceutical promotions are possible contributing factors leading to unnecessary antimicrobial usage. Inadequate infection control is further compounding the problem. Research is needed to establish the prescribing habit of doctors in Indian hospitals and the influencing factors, including behavioural, so that an appropriate intervention strategy can be formulated to curb unnecessary prescribing. Most nosocomial infections are preventable by simple means even when resources are scarce, but would require an institutional approach with immediate and long-term measures led by effective leadership. [1] Given the lack of a clinical governance framework and presence of hundreds of small to medium-sized hospitals under unorganised private ownership in India, educational approach or government advisory alone is unlikely to be effective in meeting the challenge; statutory framework for preventing HCAI and curbing irrational usage of antimicrobials in India is urgently required.

Acknowledgement

Dr Neil Woodford, ARMRL, Health Protection Agency, Colindale, London.

References

1.Sarma JB, Ahmed GU. Infection control with limited resources: Why and how to make it possible? Indian J Med Microbiol 2010;28:11-6.  Back to cited text no. 1  [PUBMED]  Medknow Journal
2.Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother 2009;64:i29-36.  Back to cited text no. 2    
3.Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: A molecular, biological, and epidemiological study. Lancet Infect Dis 2010;10:597-602.   Back to cited text no. 3    
4.Surgical Site Infection, NICE Guideline 2008. National Institute for Health and Clinical Excellence Clinical Guideline 74. Available from: http://www.nice.org.uk/nicemedia/pdf/CG74NICEGuideline.pdf. [cited in 2008].  Back to cited text no. 4    
5.Sarma JB, Ahmed GU. Characterisation of methicillin resistant S. aureus strains and risk factors for acquisition in a teaching hospital in northeast India. Indian J Med Microbiol 2010;28:127-9.  Back to cited text no. 5  [PUBMED]  Medknow Journal
6.Gaynes RP, Culver DH, Horan TC, Edwards JR, Richards C, Tolson JS. Surgical Site Infection (SSI) Rates in the United States, 1992-1998: The National Nosocomial Infections Surveillance System Basic SSI Risk Index. Clin Infect Dis 2001;33:S69-77.  Back to cited text no. 6    
7.Culver DH, Horan TC, Gaynes RP, Martone WJ, Jarvis WR, Emori TG, et al. Surgical wound infection rates by wound class, operative procedure, and patient risk index: National Nosocomial Infections Surveillance System. Am J Med 1991;91:152S-7S.  Back to cited text no. 7    
8.Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008;36:309-32.  Back to cited text no. 8    
9.New carbapenemase, NDM-1, linked to India and Pakistan. ARMRL News, Health Protection Agency; vol. 23, 2009. p. 1-2.  Back to cited text no. 9    
10.Madeo M. The role of air ventilation and air sampling in reducing the incidence of surgical wound infection rates. Br J Theatre Nurs 1996;6:29-32.  Back to cited text no. 10    
11.Dharan S, Pittet D. Environmental controls in operating theatres. J Hosp Infect 2002;51:79-84.  Back to cited text no. 11    
12.Whyte W, Hambraeus A, Laurell G, Hoborn J. The relative importance of the routes and sources of wound contamination during general surgery. J Hosp Infect 1992;22:41-54.  Back to cited text no. 12    
13.Humphreys H, Taylor EW. Operating theatre ventilation standards and the risk of postoperative infection. J Hosp Infect 2002;50:85-90.  Back to cited text no. 13    
14.Ayliffe GA. Role of the environment of the operating suite in surgical wound infection. Rev Infect Dis 1991;13:S800-4.  Back to cited text no. 14    
15.Drake CT, Goldman E, Nichols RL, Piatriszka K, Nyhus LM. Environmental air and airborne infections. Ann Surg 1977;185:219-23.  Back to cited text no. 15    
16.Anderson DJ, Kaye KS, Classen D, Arias KM, Podgorny K, Burstin H, et al. Strategies to prevent surgical site infections in acute care hospitals. Infect Control Hosp Epidemiol 2008;29:S51-61.  Back to cited text no. 16    
17.Guidelines for the prevention of intravascular catheter-related infections. MMWR 2002;51:1-26. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5110a1.htm .  Back to cited text no. 17    
18.Sarma JB, Ahmed GU. Prevalence and risk factors for colonisation with extended spectrum â-lactamase producing enterobacteriacae vis-à-vis usage of antimicrobials. Indian J Med Microbiol 2010;28:217-20.  Back to cited text no. 18  [PUBMED]  Medknow Journal
19.Cantón R, Coque TM. The CTX-M â-lactamase pandemic. Curr Opin Microbiol 2006;9:466-75.  Back to cited text no. 19    
20.Antibiotic Prophylaxis in Surgery. Scottish Intercollegiate Guidelines Network, Guideline No. 104, ISBN 978 1 905813 34 6, July 2008. Available from: http://www.sign.ac.uk/guidelines/fulltext/104/index.html .  Back to cited text no. 20    
21.Walsh TR, Toleman MA, Jones RN. Comment on: Occurrence, prevalence and genetic environment of CTX-M â-lactamases in Enterobacteriaceae from Indian hospitals. J Antimicrob Chemother 2007;59:799-800; author reply 800-1.  Back to cited text no. 21    
22.Hawkey PM. Prevalence and clonality of extended-spectrum â-lactamases in Asia. Clin Microbiol Infect 2008;14:159-65.  Back to cited text no. 22    
23.Canton R, Coque TM. The CTX-M â-lactamase pandemic. Curr Opin Microbiol 2006;9:466-75.  Back to cited text no. 23    
24.Livermore DM, Canton R, Gniadkowski M, Nordmann P, Rossolini GM, Arlet G, et al. CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother 2007;59:165-74.  Back to cited text no. 24    

Copyright 2011 - Indian Journal of Medical Microbiology


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