The Globalization of Antibiotic Resistance — India and Cambodia

This article originally appeared in the February 2012 issue of Infectious Disease Alert.

By Ellen Jo Baron, PhD, D(ABMM), Professor of Pathology and Medicine, Stanford University; Medical School Director, Clinical Microbiology Laboratory, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.

Conflict of interest: Ellen Jo Baron is a co-founder and Secretary-Treasurer of Diagnostic Microbiology Development Program, a non-profit corporation that builds laboratory capacity in the resource-poor world. (More information at www.dmdp.org)

During November, 2011, I attended separate meetings dedicated to exploring the incidence of antimicrobial resistance in two areas of the developing world, India and Cambodia. The first, sponsored jointly by the American Society for Microbiology (ASM), the European Society for Clinical Microbiology and Infectious Diseases (ESCMID), and the Indian Association of Medical Microbiologists (IAMM), was named the "International Workshop on Antimicrobial Resistance" and was held at the Haffkine Institute in Mumbai, India. Organized by Prof. Lance Peterson (ASM representative), Prof. Abhay Chowdhary (Director of Haffkine Institute), Prof. V. Ravi (President of the IAMM), and Prof. Guiseppe Cornaglia (President of ESCMID), the workshop brought together around 250 participants, principally from India, to discuss various aspects of antimicrobial resistance over a 2.5 day program.

One key topic was susceptibility methods, including the use of new molecular tools and a comparison between laboratory practice guidelines established by the Clinical Laboratory Standards Institute (CLSI; used throughout the U.S. and in those resource-poor laboratories in the rest of the world fortunate enough to have support from an outside non-governmental organization) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST; used in Europe and in many parts of the developing world). Since the CLSI changed many of the breakpoints used to determine resistance to cephalosporins and carbapenem antibiotics, the two guidelines are very similar with regard to methods and interpretive criteria. Also presented were talks on the epidemiology of resistance among viruses, parasites and fungi, in addition to the major focus on bacteria.

Of interest to infectious diseases practitioners in the U.S. was the prevalence of drug resistance among gram-negative bacteria, particularly given the numbers of American workers who travel back and forth between India and the U.S. and the rise in medical tourism to India, as these travelers are potentially capable of bringing a dangerously drug-resistant bacterium back with them to a hospital or clinic in the U.S. A recent publication from Sweden highlighted this problem, showing that 7 of 8 tourists returning from India were colonized with an extended spectrum beta-lactamase producing organism that they had acquired overseas. One of the most recently recognized such hitchhikers is the New Delhi type 1 metallo-beta-lactamase (NDM-1), now an emerging pathogen in the United States. According to Dr. Ashok Rattan, Chairman of Laboratory Medicine at Medanta Medicity Medical School Gurgaon, near New Delhi, one of the presenters, use of antibiotics has increased dramatically in India in recent years. Dr. Rattan previously published that between 2005 and 2009, the units of antibiotics sold increased by about 40%. Increased sales of cephalosporins were particularly striking, with sales (in units sold) increasing by 60% over the 5-year period.2 In 2010, one survey from a hospital in Mumbai showed that NDM-1 was carried by 92% of carbapenem resistant Enterobacteriaceae, including Klebsiella, Enterobacter species, and E. coli.1 This is not the only resistance mechanism in Enterobacteriaceae from India, as another survey revealed The organisms were collected from two different sites, Chennai (formerly Madras) in the southeast with 4% carbapenem-resistant isolates from >3500 Enterobacteriaceae tested and Haryana in the north central area near New Delhi with 24% carbapenem-resistant organisms (all K. pneumoniae) from among only 198 tested.

Reasons for this alarming situation include broad availability of antibiotics, many obtained over-the-counter without prescriptions and many of low quality or suffering from inadequate storage conditions leading to loss of potency and thus enhancing the chance that patients' isolates will develop resistance. Additional reasons are inadequate dosing when antibiotics are taken, poor infection control processes in many hospitals, and somewhat surprisingly, the lack of adequate public hygiene and inadequate water treatment facilities. Yes, bacteria producing NDM-1 were found in drinking water and water sources in the community in New Delhi.9 (9) But another reason for the rapid spread of these resistant organisms is the lack of ability of local laboratories to isolate the organisms and perform adequate antimicrobial susceptibility tests.

Unfortunately, methods for testing the organisms are changing, with no one method considered optimal except for molecular methods, which are beyond the capabilities and resources of those laboratories most likely to encounter the organisms.5,7 When countries do not have surveillance information on the extent of resistant organisms in their patients and the environment, there is very little incentive to develop national policies on antibiotic utilization, including limiting distribution to accredited providers.

This is clearly a major problem in Cambodia, where the first National Workshop on the Containment of Antibiotic Resistance was held in Phnom Penh November 16-18. The conference was initiated by scientists from the Institute of Tropical Medicine, Antwerp, Belgium, which supports the laboratory at the Sihanouk Hospital Center of Hope, and workers from Mahidol Oxford Tropical Medicine Research Unit, who support microbiology at Angkor Hospital for Children in Siem Reap (home of the Angkor Wat). Conveners and supporters also included the Cambodian Ministry of Health, World Health Organization, Fondation Merieux, University Research Company (URC) Cambodia, and numerous other NGO's including my own Diagnostic Microbiology Development Program, which supports laboratories in Battambang, Kampong Cham, Takeo, and Phnom Penh.

One reason that this conference could be achieved is the growing ability of at least some local laboratories in Cambodia to perform reliable microbiology testing, albeit so far limited and only with the help of volunteers from abroad. The increasing expertise of local microbiologists is a hopeful sign for the future, where previously there were minimal resources available for patients who were not in the upper political or economic (actually they occur together) echelons.

Although MRSA had not penetrated Cambodia in any serious way 3 years ago, with only 3.5% of children colonized, as determined from a large scale surveillance conducted in Siem Reap in 2008 and reported last year, this has changed dramatically, at least at some centers who presented data at the workshop.6 Representatives from the Sihanouk Hospital, located in the capital city Phnom Penh, presented data from 500 blood culture isolates recovered from adult patients since 2007. The results revealed 22% of S. aureus isolates were MRSA.This high rate of MRSA was not limited to Phnom Penh. Pharmacist Nhem Somary from Kampong Cham (located 124 km northeast of Phnom Penh and also on the Mekong River), presented her data showing 45% MRSA among staphylococcal isolates from all sites. The laboratory in the hospital in Takeo, a town 77 km south of Phnom Penh, found that 22% of S. aureus were MRSA.

And not surprisingly, multi-drug resistant gram negative bacteria are rampant in Cambodia, which is the 37th poorest country in the world according to some measurements, with an annual per capita income of around US $2100. Half of the bloodstream E. coli isolated at the Sihanouk Hospital laboratory were ESBL positive and multi-drug resistant; 70% of Salmonella typhi (the most common blood culture organism) demonstrated decreased susceptibility to fluoroquinolones and were multi-drug resistant.

These numbers were echoed by scientists from the United States Naval Army Medical Research Unit (NAMRU-2) who conducted targeted surveillance of S. typhi in Cambodia. Their well-controlled results revealed multi-drug resistance in 56% of all strains tested. The Kantha Botha pediatric hospitals (located in several major cities of Cambodia) reported on a recent increase in Salmonella cholerasuis bloodstream infections, primarily in children <2 years old. They also showed dramatic decreases in susceptibilities to amoxicillin-clavulanate, ofloxacin, and ceftriaxone in E. coli urinary tract isolates since 2003.

At Kampong Cham, although Pseudomonas aeruginosa isolates were quite susceptible to most antibiotics (only piperacillin and ceftazidime showed resistance, and then only <5%), more than half of the Klebsiella species showed resistance to all cephalosporins and the E. coli isolates were pan-resistant to all major antibiotics tested except imipenem. The Institute Pasteur, which receives reference cultures for testing from a number of clinics and other facilities throughout the country, so the data are gathered from a convenience sample rather than epidemiologically conducted surveillance, reported 20% MRSA, 30% ESBL in E. coli, 18% carbapenem resistance among Acinetobacter species, and a worrisome 3.5% resistance to cefixime among Neisseria gonorrhoeae.

Although there is a clear need based on the data and many presenters requested government action, a national policy on antimicrobial stewardship was not put forth by the Ministry of Health officials at the workshop. Instead, they have decided to focus on improving infection control efforts where they felt they had sufficient resources to make some progress. In a country where antibiotics of varying reliability are available universally to anyone with the money to pay for them, the situation of drug resistance is likely to become even worse in the future. Thus the name of the conference "...Containment of Antibiotic Resistance..." would seem to be more wishful than prescient, at least for the near future.

Physicians in the industrialized world need to realize the potential for the presence of multi-drug resistant organisms (MDRO's) in patients with compatible travel history, and institute appropriate infection control and treatment algorithms.10 (10) Microbiology laboratories also need to be notified so that they will perform all available tests necessary to detect MDRO's in samples sent from these types of patients. Given that there is a growing movement in the developed world to perform surveillance cultures on patients at risk for carriage of MDRO's, surely travelers returning from the developing world should be added to that category.

References

1. Deshpande, P., et al. New Delhi Metallo-beta lactamase (NDM-1) in Enterobacteriaceae: treatment options with carbapenems compromised. J Assoc Physicians India 2010; 58:147-149.

2. Ganguly, N. K., et al.. Rationalizing antibiotic use to limit antibiotic resistance in India. Indian J Med Res 2011; 134:281-294.

3. Kumarasamy, K. K., 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.

4. Mochon, A.B., et al. New Delhi Metallo-_-Lactamase (NDM-1)-Producing Klebsiella pneumoniae: Case Report and Laboratory Detection Strategies. J Clin Microbiol 2011; 49:1667-70.

5. Naas, T., et al. Evaluation of a DNA microarray, the check-points ESBL/KPC array, for rapid detection of TEM, SHV, and CTX-M extended-spectrum beta-lactamases and KPC carbapenemases. Antimicrob Agents Chemother. 2010; 54:3086-3092.

6. Nickerson, E. K., et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus carriage in children in Cambodia. Am J Trop Med Hyg 2011; 84:313-317.

7. Seah, C. et al. Comparative evaluation of a chromogenic agar medium, the modified Hodge test, and a battery of meropenem-inhibitor discs for detection of carbapenemase activity in Enterobacteriaceae. J Clin Microbiol 2011; 49:1965-1969.

8. Tangden, T. O. et al. Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extended-spectrum beta-lactamases: a prospective study with Swedish volunteers. Antimicrob Agents Chemother 2010; 54:3564-3568.

9. Walsh, T. R. et al. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infect Dis 2011; 11:355-362.

10. CDC. Detection of Enterobacteriaceae Isolates Carrying Metallo-Beta-Lactamase — United States, 2010. MMWR 2010. 58:750.