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An increase in enteric fever cases due to Salmonella Paratyphi A in & around Chandigarh.

Background & objectives: Enteric fever is a major public health problem in India. It is classically caused by Salmonella enterica serotype Typhi. Salmonella enterica serotype Paratyphi A which had been reported less frequently from cases of enteric fever has shown an increasing trend since 1996 in India. There is also variation in the antimicrobial susceptibility of Salmonella Paratyphi A from different parts of the country. An attempt is therefore made to study the rate of isolation and antimicrobial susceptibility pattern of Salmonella Paratyphi A from cases of enteric fever coming to a tertiary care hospital at Chandigarh.

Methods: The blood samples of patients suspected of having enteric fever and admitted to Government Medical College and Hospital, Chandigarh, from January 2006 to April 2007 (11,240) were processed by conventional methods. Antimicrobial susceptibility was tested by Kirby-Bauer disc diffusion method. The minimum inhibitory concentration to two antibiotics- ciprofloxacin and chloramphenicol was determined by agar dilution technique. Simultaneously, retrospective analysis was done from January 2003-December 2005 to study any difference in the incidence and antimicrobial susceptibility pattern of Salmonella Paratyphi A among enteric fever patients.

Results: Of 305 total isolates, 231 were S. Typhi and 84 S. Paratyphi A rise. The number of Salmonella Paratyphi A cases rose from 27 in 2006 (34.18%) to 13 (40.63%) in four months of 2007. All were sensitve to ciprofloxacin and cefotaxime but MIC to ciprofloxacin was raised (0.125-0.5 [micro]g/ml). Resistance to nalidixic acid was 92.5 per cent. Chloramphenicol sensitivity re-emerged with 90 per cent isolates sensitive to it while sensitivity to ampicillin dropped (72.5%) as compared to previous years. Only one isolate was multi-drug resistant.

Interpretation & conclusion: The present study conferencing Salmonella Paratyphi A as the rapidly emerging pathogen of enteric fever. With increasing resistance to fluoroquinolones and possibility of re-emergence of sensitivity to chloramphenicol, the policy of empirical treatment of enteric fever needs to be rationalized.

Key words Antimicrobial susceptibility--enteric fever--incidence--Salmonella Paratyphi A

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Enteric fever is a major public health problem in India, accounting for more than 300,000 cases per year (1). It is classically caused by Salmonella enterica serotype Typhi. Salmonella enterica serotype Paratyphi A, which causes a milder form of the disease and had been reported less frequently (3-17%) from cases of enteric fever has shown an increasing trend since 1996 in India (2). A 5 year (1994-98) retrospective analysis at New Delhi showed the rise in proportion of Salmonella Paratyphi A from 6.5 per cent in (1994) to 44.9 per cent (1998) (3). Similar increase, 11.1 per cent (2001) to 59 per cent (2003) was reported from Calicut (1). Between 2001 to 2003 an unusually high rate of isolation was reported from Nagpur (46.15%) (4), Sevagram (53.33%) (5) and Rourkela (6). A variation in the antimicrobial susceptibility pattern of Sahnonella Paratyphi A was also seen from different parts of the country. The present study was carried out to study the rate of isolation and antimicrobial susceptibility pattern of Salmonella Paratyphi A from cases of enteric fever coming to a tertiary care hospital at Chandigarh, north west India.

Material & Methods

A prospective study was conducted on blood samples received in the microbiology department of Government Medical College and Hospital, Chandigarh, from January 2006 to April 2007 with special focus on Salmonella Paratyphi A. A total of 11,240 blood samples obtained during this period were subjected to blood culture. Salmonella species were isolated by standard techniques (7). Antimicrobial susceptibility patterns were determined using following commercial antibiotic discs (Hi-media, Mumbai): chloramphenicol (30 [micro]g), nalidixic acid (30 [micro]g), ampicillin (10 [micro]g), co-trimoxazole (25 [micro]g), ciprofloxacin (5 [micro]g) and cefotaxime (30 [micro]g). Antimicrobial susceptibility testing was done by Kirby Bauer disc diffusion method (8). The zone of inhibition was measured and compared with critical zone diameter in published tables (9) Each set of new antibiotic discs was tested with standard Escherichia coli NCTC 10418 (PGIMER, Chandigarh). Minimum inhibitory concentration (MIC) was performed for ciprofloxacin and chloramphenicol by agar dilution technique using Mueller-Hinton agar (MHA) (Hi-media, Mumbai) according to the criteria of CLSI (9). The concentrations used for MIC were doubling dilutions from 0.0625 to 4.0 [micro]g/ml for ciprofloxacin and from 1.0 to 64 [micro]g/ml for chloramphenicol. Simultaneously retrospective analysis was done from the records for samples received during January 2003 and December 2005 to study any difference in incidence and antimicrobial susceptibility pattern of Salmonella Paratyphi A among enteric fever patients.

Results & Discussion

A retrospective analysis of laboratory records at Government Medical College and Hospital, Chandigarh, from January 2003 to December 2005 showed an increasing rate of isolation of this organism from cases of enteric fever similar to the findings of prospective analysis during January 2006-April 2007. There was a dramatic rise in the number of Salmonella Paratyphi A isolates in the year 2006 (27; 34.18%) and in earlier months of the year 2007 (13; 40.63%) as compared to the previous years (Table I). In the month of March 2007, there was an unusually high occurrence of Salmonella Paratyphi A cases. Of the 10 Salmonella isolates obtained during this month, 7 were of Salmonella Paratyphi A. The increase in proportion of Salmonella Paratyphi A cases could possibly be due to high degree of clinical suspicion with mild fever cases being investigated for enteric fever, changing host susceptibility, change in virulence of the organism and widespread use of vaccines and quinolones against Salmonella Typhi in the past decade.

All the 40 isolates of Salmonella Paratyphi A obtained during January 2006 to April 2007 showed 100 per cent susceptibility to ciprofloxacin and cefotaxime (Table II), similar to the reports from Nagpur (4) and Rourkela (6). But resistance to nalidixic acid was high (92.5%). A study in Calicut reported 78.6 per cent resistance to nalidixic acid in the year 2002 and 100 per cent in the year 2003 (1). It is suggested that nalidixic acid resistance is a marker for predicting low level resistance to ciprofloxacin and also an indicator of treatment failure to ciprofloxacin (10). This is due to the fact that mutations in DNA gyrase, a mechanism for ciprofloxacin resistance, also correlates with resistance to nalidixic acid, the first generation of quinolones (11). In the present study resistance to nalidixic acid was associated with decreased susceptibility to ciprofloxacin (MIC 0.125-1.0 [micro]g/ml). Treatment failures have been reported in patients infected with strains having MIC between 0.12-1 [micro]g/ml (12). Nalidixic acid resistant Salmonella isolates are endemic in the Indian subcontinent. There is unpredictable response to treatment with ciprofloxacin in patients infected with these kinds of strains. This resistance is however not detected by disc diffusion method using the recommended breakpoints in diagnostic laboratories, resulting in ciprofloxacin being administered as the drug of choice to treat typhoid fever. This may delay the decision to switch over to third generation cephalosporins or other appropriate antibiotics. Hence, nalidixic acid susceptibility testing must be included with ciprofloxacin susceptibility testing in routine microbiological laboratory. Treatment with ciprofloxacin must be avoided in nalidixic acid resistant isolates although higher doses may be helpful in a few cases.

However, chloramphenicol susceptibility reemerged. 36 (90%) isolates were susceptible to chloramphenicol with MIC [less than or equal to] 8 [micro]g/ml, 3 (7.5%) were intermediate susceptible with MIC of 16 [micro]g/ml and only one was resistant with MIC >32 [micro]g/ml (Table III) as against chloramphenicol susceptibility seen in 2004 where 50 per cent of the isolates were resistant. Studies in Rourkela (6) and Calicut (1) reported 91.48 and 96.49 per cent susceptibility to chloramphenicol respectively. Replacement of chloramphenicol by ciprofloxacin as the drug of choice for the treatment of enteric fever would have led to withdrawal of selective pressure resulting in re-emergence of chloramphenicol susceptibility. Sensitivity to ampicillin has decreased compared to previous years. Only 29 of the 40 (72.5%) isolates were sensitive to ampicillin during 20062007. Sensitivity to ampicillin was 57.1 per cent in Pune (13) and 66.7 per cent in Nagpur (4) whereas a study conducted at Kasturba Hospital, a rural hospital at Sevagram (5), reported a sensitivity of 96.49 per cent to ampicillin. This probably reflects indiscriminate use of antibiotics in urban areas in contrast to rural.

Plasmid mediated multi-drug resistance is known to be increasing in Salmonella serotypes. However, in the present study only lof the 40 isolates was multi-drug resistant showing resistance to ampicillin, co-trimoxazole, and chloramphenicol simultaneously. Though multi-drug resistance among Salmonella Paratyphi A is not yet a problem at our institution, its emergence in other parts of the country warrants judicious use of antibiotics. Incidence of multi-drug resistance was 11.1 per cent in Nagpur (4) and 13 per cent in New Delhi (3).

The present study endorses the observation of Salmonella Paratyphi A as rapidly emerging pathogen of enteric fever. With increasing resistance to fluoroquinolones (as indicated by increased MIC) and possibility of re-emergence of sensitivity to chloramphenicol, the policy of empirical treatment of enteric fever needs to be rationalized. Third generation cephalosporins are gaining importance in the treatment of enteric fever due to nalidixic acid resistant isolates with high MIC to fluoroquinolones. However, high cost and need for parenteral administration are the disadvantages of cephalosporin therapy. So, continued surveillance on antimicrobial susceptibility pattern and study of multi-drug resistance of S. Paratyphi A from different parts of the country will help in up-dating the knowledge to use proper antibiotics for therapeutic cure.

Received August 14, 2007

References

(1.) Lathi N, Sudarsana J, Pushpa KK. Epidemic of Salmonella enterica serotype Paratyphi A in Calicut. Calicut MedJ2004; 2;e2.

(2.) Chandel DS, Chaudhry R, Dhawan R, Pandey A, Dey AB. Drug resistant Salmonella enterica serotype Paratyphi A in India. Emerg Infect Dis 2000; 6 : 420-1.

(3.) Sood S, Kapil A, Dash N, Das BK,Goel V, Seth P. Paratyphoid fever in India. Emerg Infect Dis 1999; 5: 483-4.

(4.) Tankhiwale SS, Agrawal G, Jalgaonkar SV. An unusually high occurrence of Salmonella enterica serotype Paratyphi A in patients with enteric fever. Indian JMed Res 2003; 117 : 10-2.

(5.) Mendiratta DK, Deotale V, Thamke D, Narang R, Narang P. Enteric fever due to Salmonella Paratyphi A-an emerging problem. Indian J Med Microbiol 2004; 22 : 196.

(6.) Bhattacharya SS, Dash U. A sudden rise in occurrence of Salmonella Paratyphi A infection in Rourkela, Orissa. Indian J Med Microbiol 2007; 25 : 78-9.

(7.) Old DC. Salmonella. In: Colle JG, Fraser AG, Marimon BP, Simmon A, editors. MacMe and McCartney practical medical microbiology. 14th ed., Vol. II. London: Churchill Livingstone; 1996. p. 385-404.

(8.) Bauer AW, Kirby WMM, Sheris JC, Turck M. Antibiotic susceptibility testing by a standardized single disc method. Am J Clin Pathol 1966; 45 : 493-6.

(9.) Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Sixteenth International Supplement. Wayne, Pennsylvania, USA. National Committee for Clinical Laboratory Standards. 2006 (M100-S16).

(10.) Ray P, Sharma J, Marak RSK, Garg RK. Predictive efficacy of nalidixic acid resistance as a marker of fluoroquinolones resistance in Salmonella enterica var Typhi. Indian J Med Res 2006; 124: 105-8.

(11.) Ruiz J, Castro D, Goni P, Santamaria JA, Borrego JJ, Vila J. Analysis of mechanism of quinolone resistance in nalidixic acid resistant clinical isolates of Salmonella serotype Typhimurium. J Med Microbiol 1997; 46: 623-8.

(12.) Crump JA, Kretsinger K, Gay K, Hoekstra RM, Vugia DJ, Hurd S, et al. Clinical response and outcome of infection with Salmonella Typhi with decreased susceptibility to fluoroquinolones: a United States Food Net multi-center retrospective cohort study. Antimicrob Agents Chemother 2008; 52: 1278-84.

(13.) Sanghvi SK, Nane MP, Nipadhkar KB. Multidrug resistance in Salmonella serotypes. Indian J Med Microbiol 1999; 17 : 88-90.

Reprint requests: Dr Varsha Gupta, Professor, Department of Microbiology, Government Medical College & Hospital Sector 32, Chandigarh 160 030, India e-mail: varshagupta_99@yahoo.com

Varsha Gupta, Jaspal Kaur & Jagdish Chander

Department of Microbiology, Government Medical College & Hospital, Chandigarh, India
Table I. Salmonella isolates among enteric fever patients from
January 2003-April 2007

Time period Total no. of S. Typhi S. Paratyphi A
January to Salmonella
December isolates

2003 49 42 (85.71) 7 (14.29)
2004 85 71 (83.53) 14 (16.47)
2005 60 47 (78.33) 13 (21.67)
2006 79 52 (65.82) 27 (34.18)
2007 * 32 19 (59.37) 13 (40.63)
Total 305 231 84

Figures in parenthesis indicate percentages
* January to April 2007

Table II. Antimicrobial sensitivity pattern of Salmonella Paratyphi A
isolates

Time period No. of A Co C
January to December isolates

2003 7 7 (100) 7 (85.71) 6 (85.71)
2004 14 13 (92.85) 11 (78.57) 7 (50)
2005 13 13 (100) 10 (76.92) 11 (84.61)
2006 27 20 (74.07) 24 (88.89) 24 (88.89)
2007 ([dagger]) 13 9 (69.2) 11 (84.61) 12 (92.31)

Time period Cf Ct N
January to December

2003 7 (100) 7 (100) *
2004 14 (100) 14 (100) *
2005 13 (100) 13 (100) *
2006 27 (100) 27 (100) 2 (7.40)
2007 ([dagger]) 13 (100) 13 (100) 1 (7.69)

* Nalidixic susceptibility was not performed routinely before 2006
Figures in parenthesis indicate percentages
A, ampicillin; Co, co-trimoxazole; C, chloramphenicol;
Cf, ciprofloxacin; Ct, cefotaxime; N, nalidixic acid;

([dagger]) January to April 2007

Table III. MIC values of ciprofloxacin and chloramphenicol for
Salmonella Paratyphi A

Antimicrobial No. of isolates showing MIC ([micro]g/ml) values of

 0.0625 0.125 0.25 0.5 1
 (n=40)

Cpprofloxacin 0 9 26 3 2
Chloramphenicol * * * * 5

Antimicrobial No. of isolates showing MIC ([micro]g/ml) values of

 2 4 8 16 32 64

Cpprofloxacin 0 0 * * * *
Chloramphenicol 18 8 5 3 0 1

* Not performed
For ciprofloxacin: MIC <1 [micro]g/ml sensitive; >4 [micro]g/ml
resistant
For chloramphenicol MIC [less than or equal to] 8 [micro]g/ml
sensitive; [greater than or equal to] 32 [micro]g/ml resistant
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Author:Gupta, Varsha; Kaur, Jaspal; Chander, Jagdish
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:Jan 1, 2009
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