CITATION: Jesudason M, Shanahan P, Amyes SGB, Thomson CJ. 1997. Boston, MA: APUA website. <www.apua.org>.


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Antibiotic susceptibility patterns of common enteric pathogens in India
Mary Jesudason1 and Philippa Shanahan, SGB Amyes and CJ Thomson2
1Department of Microbiology, Christian Medical College and Hospital, Vellore, South India
2Department of Medical Microbiology, University of Edinburgh Medical School, Edinburgh, UK

Resistance to antibiotics by common enteric pathogens has reached alarming levels in India. Previously susceptible organisms, responsible for some of this country's more serious health threats such as typhoid fever and gastroenteritis are showing increasing resistance to first-choice antimicrobials. This rise in resistance may be associated with population patterns, particularly crowded living conditions. The availability of antibacterial drugs without prescription may also encourage their indiscriminate use and may help to maintain high resistance levels. India's medical profession may further be contributing to the problem by prescribing injudiciously.

The Department of Microbiology, Christian Medical College and Hospital, Vellore, South India, has been regularly monitoring the antibiotic susceptibility patterns of common enteric pathogens to frequently used antibacterial agents. In addition, a study was conducted in 1989 to determine the possible reservoir of resistant genes within local populations. We examined the incidence and type of resistance in the commensal fecal flora of healthy individuals in Vellore and three surrounding villages. Volunteers above five years of age were recruited who had not been treated with antibiotics during the prior two weeks. Results show that a vast majority of the population carries commensal bacteria resistant to trimehtoprim, ampicillin or chloramphenicol. Often the organisms isolated were resistant to all three drugs. Surprisingly, there was little difference in degrees of resistance between villages and urban areas, though it might be assumed so, given that antibiotics are more freely available to the urban population.1

Salmonella typhimurium
Over the years, we have isolated
S. typhimurium in substantial numbers. In 1996, we saw isolates that were multidrug resistant, and had a cluster outbreak in one of our wards. Some of these patients suffered nosocomial infections, though spread was contained once control measures were instituted. This strain was resistant to ampicillin , chloramphenicol, tetracycline, furozolidone, cefazolin, gentamycin and nalidixic acid; it was sensitive to the fluorinated quinolone, ciprofloxacin.

During an outbreak of gastroenteritis (GE) due to MDR S. typhimurium,2 trimethoprim MIC was determined for 96 strains. Eighty-four (87.5%) were resistant to 10 ml/L Tp and this was HLR (MIC >1000 mg/L Tp) in 83 (86.5%). Transfer experiments showed that both trimethoprim and multidrug resistance were plasmid-mediated.

Salmonella typhi
Since 1990, medical microbiologists and clinicians in India have been concerned with the emergence of multidrug resistant
S. typhi, the pathogen for typhoid fever.3,4 This strain has shown resistance to ampicillin, chloramphenicol and co-trimoxazole, the drugs of choice in the treatment of this disease. During March 1992, while monitoring its isolation on a monthly basis, we recorded a record 48 of 61 S. typhi isolates (78%) as being multidrug resistant. Although 1997 saw a decrease in their frequency, multidrug resistant S. typhi still accounts for about 30% of isolates from blood cultures. Fortunately, during this period we continued to isolate chloramphenicol-sensitive strains. Their relative frequency appeared to be unaffected by the epidemic of multidrug resistance. The two strains behaved as though they were epidemiologically independent pathogens.5

To study multidrug resistant S. typhi in depth, we looked at 15 strains. In transfer studies, we were able to demonstrate that resistance to ampicillin, chloramphenicol and co-trimoxazole was transferred 'en block' to recipient E. coli, suggesting that resistance is mediated by an autotransferring plasmid.3 Four different plasmid profiles were identified, and plasmid sizes ranged from between 110 and 150.6 Plasmid-mediated antibiotic R genes were identified with specific probes in hybridization experiments.

Ciprofloxacin is the drug of choice when confronted with multidrug resistant S. typhi. A clinical trial, begun in 1989, showed that during 1989 and 1990, patients typically responded to ciprofloxacin therapy after a mean of 3 days.7 MICs of this drug to multidrug resistant S. typhi were between 0.0009 to 0.0039 mcg/ml. However, during and after 1993, anecdotal information suggested that occasional patients with typhoid fever showed a delayed response to this antibiotic. During this same time period, we also noticed an upward shift in MIC values in our laboratory, to 0.25 to 0.5 mcg/ml;8 however, thus far, all strains have been in the sensitive MIC range.

Twelve S. typhi strains isolated in Vellore, one in 1992 and and the remainder in 1994, showed reduced susceptibility to 4-quinolones (MIC of ciprofloxacin 0.256 mg/L). Plasmid-mediated antibiotic R genes were identified with specific probes in hybridization experiments.The gyrA gene from codons 24 to 185, which includes the "Quinolone Resistance Determining Region," was amplified by the PCR, and after separating the amplified stands, the DNA was sequenced. In 1994, nine isolates had a mutation in codon 83, changing serine to phenylalanine. Also, that year one strain had a mutation in codon 87, changing aspartate to tyrosine. Another 1994 strain had both mutations. The 1992 strain had no discernible alteration in the gyr A region, compared to the ciprofloxacin-sensitive isolates.9

Shigella
Shigella is the most common aetiologic agent of GE in Vellore. In the early 1980s, antibiotic susceptibility patterns of the commonly encountered S. flexneri and S. sonnei showed resistance to ampicillin, chloramphenicol and tetracycline.10 This is still the case today. Transfer studies have been carried out on these strains by standard methods, using E. coli J62-2 as a recipient. Resistance was transferable and probably plasmid-mediated. Antibiogram of transconjugants showed that SM and ampicillin resistances were linked most commonly with the Tp/Co.11

Since June 1989, we have encountered strains of Shigella resistant to nalidixic acid, a drug commonly used to treat shigellosis in children. Since newer quinolones are increasingly being used to fight various infections, and cross resistance among the quinolones is known to occur, we tested these nalidixic acid-resistant strains for susceptibility to four fluorinated quinolones: ciprofloxacin, ofloxacin, pefloxacin and enoxacin. MIC values were determined by the Kirby Bauer disc diffusion method. Five strains of S. flexneri (serotype 2) and one strain of S. shigae were found to be resistant to nalidixic acid, with MIC values greater than 10 mg/1; one strain had a MIC greater than 100 mg/1. MIC values of four newer quinolones showed that all six strains were resistant to ciprofloxacin, pefloxacin and enoxacin, but were moderately sensitive to ofloxacin. Our transfer experiments failed to demonstrate plasmid mediation.12

Vibrio cholerae
Initially, all strains of
V. cholerae 01 Eltor Ogawa isolated from feces in our laboratory were sensitive to antibiotics used to treat acute GE, including cholera. In July 1987, however, cotramoxazole-resistant strains were observed. MIC determinations showed that the resistance to Tp was HLR and could be transferred to recipient E. coli, again suggesting plasmid-mediatation. The resistance profile for the tranconjugants showed that 74% of the TpR strains studied were also resistant to chloramphenicol and 11% to ampicillin.13

In past years, all isolates of V. cholerae 01 were sensitive to nalidixic acid. Since October 1995, however, we have encountered strains resistant to this drug. This is rather alarming, as nalidixic acid is the drug of choice for empirical treatment of GE, especially in children, and is also considered to be the treatment of choice for Shigellosis. We studied the sensitivity of V. cholerae 01 to norfloxacin, a fluoroquinolone often used to treat GE. MIC studies confirmed all strains were sensitive to the drug.14

India, like many other developing nations, continues to face special challenges in the face of increasing antibiotic resistance. Careful studies, increased public awareness, and sound policies and practices will go a long way to help curb this threat to our quality of life.

References

  1. Amyes SGB, Tait S, Thomson CJ, Payne DJ, Nandivada LS, Jesudason MV, Mukundan U, Young HK. 1992. Antimicriob Chemother 29: 415-425.
  2. Koshi, G. Indian J Med Res 74: 635-641.
  3. Jesudason MV, John T. 1992. Indian J Med Res 95: 66-67.
  4. Gupta BL, Bhujwala RA, Shriniwas. 1990. Lancet 336: 252; Threlfall EJ, Ward LR, Rowe B, Raghupathi S, Chandrasekaran V, Vandepitte J, Lemmens P. 1992. Eur J Clin Microbiol Infec Dis 11: 990-993.
  5. Jesudason MV, John R, John TJ. 1996. Epidemiology & Infection 116 (2): 225-227.
  6. Shanahan PMA, Jesudason MV, Thomson CJ, Amyes SGB. 1998. J Clin Microbiol 36 (6): 1595-1600.
  7. Mathai D, Kuduva G, Keystone JS, Kuzavashy PP, Jesudason MV, Lalitha MK, Kaur A, Thomas M, John TJ, Pulimood BM. 1993. J Assoc Phys India 41(7): 428-430.
  8. Jesudason MV, Malathy B, John TJ. 1996. Indian J Med Res 103: 245-247.
  9. Brown JC, Shanaham PMA, Jesudason MV, Thomson CJ, Amyes SGB. 1996. J Antimicrob Chemother 37: 891-900.
  10. Jesudason MV, Lalitha MK, Koshi G. 1985. J Trop Med & Hyg 88: 355-358.
  11. Jesudason MV, Joseph D, Koshi G. 1989. Indian J Med Res 89: 297-299.
  12. Thirunarayanan MA, Jesudason MV, John TJ. 1993. Indian J Med Res 97: 239-241.
  13. Jesudason MV, John TJ. 1990. Trans Roy Soc Trop Med & Hyg 84 (1): 136-137.
  14. Jesudason MV, Saaya R. 1997. Indian J Med Res 105: 153-154.
 

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