- Email: [email protected]
Ciprofloxacin therapy for typhoid fever needs reconsideration
J Infect Chemother (2006) 12:402–404 DOI 10.1007/s10156-006-0472-9
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2006
NOTE Sheetal Chitnis · Vikrant Chitnis · Nanda Hemvani Dhananjay Sadashiv Chitnis
Ciprofloxacin therapy for typhoid fever needs reconsideration
Received: April 4, 2006 / Accepted: August 1, 2006
Abstract Outbreaks of multidrug-resistant Salmonella enterica serotype Typhi in the Indian subcontinent in the late 1980s resulted in the failure of conventional drugs, and ciprofloxacin became the firstline drug to treat enteric fever. However, reduced susceptibility to ciprofloxacin, reported widely since 1994, has posed a therapeutic difficulty. The aim of the present work was to review the situation of drug resistance among S. enterica serotype Typhi in central India from 1988 to 2005. A minimum inhibitory concentration (MIC) study for ciprofloxacin was carried out by the agar dilution method on 314 stock cultures preserved since 1988. The MIC for ciprofloxacin was ≤0.125 mg/l for the 50 isolates isolated during 1989–1994, but during 1998–1999, 60% of the 50 isolates showed MIC > 0.125 mg/l, while in 2002– 2003, 82.5 % of the 97 isolates had MIC > 0.125 mg/l and 35% had MIC > 1 mg/l (high-level resistance). In 2004–2005, 88.2% of the 77 isolates had MIC > 0.125 mg/l and 15% had MIC > 1 mg/l (high-level resistance). Sixty-four isolates showing MIC > 1 mg/l with the agar dilution method were also checked by Epsilometer test (E-test, AB Biodisk, Solna, Sweden). Based on the data, it is suggested to withdraw ciprofloxacin as a therapeutic agent for enteric fever. Fortunately, multiple drug resistance, with concurrent resistance to chloramphenicol, cotrimoxazole, and ampicillin, which had reached more than 90% in 1990–1991, started declining over the years and was as low as 5.6% in 2004– 2005. According to these observations, older drugs such as chloramphenicol, cotrimoxazole, and ampicillin could be recalled to treat enteric fever. Key words Salmonella · Typhoid fever · Antibiotic resistance · Drug resistance
V. Chitnis Shri Aurobindo Institute of Medical Science Indore, India S. Chitnis · N. Hemvani · D. S. Chitnis (*) Microbiology and Immunology Department, Choithram Hospital and Research Centre, Indore 452014 (M.P.), India Tel. +91-0731-2124512; Fax +91-0731-2470068 email: [email protected]
Enteric fever remains endemic in the Indian subcontinent, and in several countries in Southeast Asia and Africa. Chloramphenicol had been the standard treatment since the 1950s.. Ampicillin and cotrimoxazole were subsequently considered as alternative therapeutic agents. However, since the late 1980s multidrug-resistant (MDR) strains of Salmonella enterica serotype Typhi were responsible for numerous outbreaks of enteric fever worldwide, including India.1,2 The multiple drug resistance included resistance to chloramphenicol, ampicillin, and cotrimoxazole. As a result, ciprofloxacin became the firstline drug used to treat enteric fever. However, reduced susceptibility to ciprofloxacin, reported widely since 19941–3 has resulted in therapeutic difficulty. We carried out a minimum inhibitory concentration (MIC) study for ciprofloxacin by the agar dilution method in a total of 314 isolates of S. enterica serotype Typhi (50 isolates isolated during the years 1991–1994, another 50 isolated during 1998–1999, 40 isolated in 2000–2001, 97 isolated during 2002–2003, and 77 isolated during 2004–2005). Ciprofloxacin powder with assayed potency was provided by Anusandhan Laboratory (Indore, India). The concentration of ciprofloxacin used in the plate was in the range of 0.0035 mg/l to 32 mg/l. Isolates showing MICs greater than 1 mg/l for ciprofloxacin by the agar dilution method were also confirmed by the Epsilometer method (E-test; AB Biodisk, Solna, Sweden). Escherichia coli ATCC 25922 was used for quality control of MIC checking both for the agar dilution and E test methods. The yearwise decrease in susceptibility to ciprofloxacin is shown in Fig. 1. All the cultures with ciprofloxacin MIC > 0.25 mg/l were also found to be resistant to nalidixic acid (Hi Media, Indore, India) by the disc diffusion method.4 The emerging situation is posing a serious therapeutic problem. The cephalosporin-like agent ceftriaxone remains an option for the treatment of typhoid caused by multidrug-resistant S. enterica serotype Typhi with decreased susceptibility to ciprofloxacin, but the increased therapeutic cost, together with difficulties in intravenous administration, can be a serious handicap in developing countries.
403
Fig. 2. Prevalence of multidrugresistant (MDR) Salmonella enterica serotype Typhi isolated at Choithram Hospital and Research Centre, Indore, Central India (1988–2005). Numbers above the bars show total numbers of isolates. Bars show percentages of MDR bacterial strains
% isolates of Salmonella enterica serotype Typhi
80
72.7
70 60 50
47.4
44 40
40
40 35.6 30
30 20
30
17
16
15.5 11
10 0 1998-1999(n=50)
2000-2001(n=40)
2002-2003 (n=97)
2004-2005 (n=77)
Years
100 421
90
75
80 70 60
% MDR
Fig. 1. Yearwise prevalence of low-level resistance and high level resistance for ciprofloxacin at Choithram Hospital and Research Centre, Indore, Central India (n = 314) among Salmonella enterica serotype Typhi. Empty bars represent minimum inhibitory concentration (MIC) values less than 0.125 mg/l. Dotted bars represent MIC values greater than 0.125 but less than 1 mg/l (values considered as low-level resistance, as per the criteria of Threlfall et al.2). Black bars represent MIC values greater than 1 mg/l (values considered as highlevel resistance as per the criteria of Threlfall et al.2)
50
34
48
17
40
74
103
30 20 10
124
107
2002-2003
2004-2005
0 1988-1989
1990-1991
1992-1993
1994-1995
1996-1997
1998-1999
2000-2001
Years Values on bar represent total number of isolates
Criteria suggested by Threlfall et al.2 in 2001 appear convenient to differentiate S. enterica serotype Typhi isolates as susceptible to ciprofloxacin (MIC ≤ 0.125 mg/l), MIC > 0.125 but ≤1.0 mg/l as low-level resistance and MIC > 1.0 mg/l as high-level resistance. With these criteria, only 11.6% of isolates in the present series were susceptible to ciprofloxacin in 2004–2005, while 72.7% exhibited low-level resistance and 15.5% had high-level resistance. MIC determination by agar dilution or broth dilution methods is cumbersome for ciprofloxacin, while the E test offers a convenient and precise alternative. However, the E-test strips are costly for use in economically developing countries and the present observations suggest that checking for resistance to nalidixic acid by disc diffusion test could be a convenient alternative to predict decreased susceptibility to ciprofloxacin; this method is practiced by some groups in India.5,6 Decreased susceptibility to ciprofloxacin among S. enterica serotype Typhi isolates has been reported by several workers.5–7 In the present study, data for clinical follow up were available for only 40 of the 77 patients receiving ciprofloxacin and 37 of these 40 patients showed delayed defervescence of greater than 6 days against an earlier average defervesence of 3.5 days noted in our hospital. Patients showing failure to respond to ciprofloxacin received
ceftriaxone and responded well. Ceftriaxone is now used as a drug of choice by the local clinicians. Follow-up reports on the use of chloramphenicol were available for only 8 patients and all responded well, with an average defervescence period of 4.75 days. The mechanism of resistance to ciprofloxacin was not examined in the present study, but could be due to mutation in the gyrA gene.8 Further, the fact needs to be emphasized that 88.2% of the isolates during 2004–2005 had reduced susceptibility to ciprofloxacin. This observation strongly suggests that ciprofloxacin should be withdrawn as a therapeutic agent in the treatment of typhoid. However, the most interesting observation in the present study has been the dramatic reduction in MDR S. enterica serotype Typhi isolates, from over 90% in 1990–1991 to 5.6% in 2004–2005 (Fig. 2) and this suggests that older drugs such as chloramphenicol, ampicillin, and cotrimoxazole could be recalled for the treatment of enteric fever. Acknowledgments We are thankful to the Choithram Hospital and Research Centre for institutional support and we thank the Council of Scientific and Industrial Research India for providing a Senior Research Fellowship (SRF) award to the first author.
404
References 1. Chande C, Shrikhande S, Kapale S, Agarwal S, Fule RP. Change in antimicrobial resistance pattern of Salmonella typhi in central India. Indian J. Med Res 2002;115:248–50. 2. Threlfall EJ, Skinner JA, Ward LR. Detection of decreased susceptibility to ciprofloxacin in serotypes Typhi and Paratyphi A. J Antimicrob Chemother 2001;48:735–48. 3. Chitnis V, Verma S, Hemwani N, Chitnis D. Multidrug-resistant Salmonella typhi in India. Lancet 1999;354:514. 4. Bauer AW, Kirby WM, Sherris JC, Truck M. Antibiotic susceptibility by standardized single disc method. Am J Clin Pathol 1966; 45:493–6.
5. Madhulika U, Harish BN, Parija SC. Current pattern in antimicrobial susceptibility of Salmonella Typhi isolates in Pondicherry. Indian J Med Res 2004;120:11–4. 6. Kariuki S, Rvathi G, Muyodi J, Mwituria J, Munyalo A, Mirza S, et al. Characterization of multidrug-resistant typhoid outbreaks in Kenya. J.Clin Microbiol 2004;42:1477–82. 7. Rodrigues C, Shenai S, Mehta A. Enteric fever in Mumbai, India: the good news and the bad news. Clin Infect Dis 2003;36:535. 8. Renuka K, Kapil A Kabra SK, Wig N, Das BK, Prasad VV, et al. Reduced susceptibility to ciprofloxacin and gyra gene mutations in North Indian strains of S. enterica serotype Typhi and serotype Paratyphi. Microb Drug Resist 2004;10:146–53.
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2006
NOTE Sheetal Chitnis · Vikrant Chitnis · Nanda Hemvani Dhananjay Sadashiv Chitnis
Ciprofloxacin therapy for typhoid fever needs reconsideration
Received: April 4, 2006 / Accepted: August 1, 2006
Abstract Outbreaks of multidrug-resistant Salmonella enterica serotype Typhi in the Indian subcontinent in the late 1980s resulted in the failure of conventional drugs, and ciprofloxacin became the firstline drug to treat enteric fever. However, reduced susceptibility to ciprofloxacin, reported widely since 1994, has posed a therapeutic difficulty. The aim of the present work was to review the situation of drug resistance among S. enterica serotype Typhi in central India from 1988 to 2005. A minimum inhibitory concentration (MIC) study for ciprofloxacin was carried out by the agar dilution method on 314 stock cultures preserved since 1988. The MIC for ciprofloxacin was ≤0.125 mg/l for the 50 isolates isolated during 1989–1994, but during 1998–1999, 60% of the 50 isolates showed MIC > 0.125 mg/l, while in 2002– 2003, 82.5 % of the 97 isolates had MIC > 0.125 mg/l and 35% had MIC > 1 mg/l (high-level resistance). In 2004–2005, 88.2% of the 77 isolates had MIC > 0.125 mg/l and 15% had MIC > 1 mg/l (high-level resistance). Sixty-four isolates showing MIC > 1 mg/l with the agar dilution method were also checked by Epsilometer test (E-test, AB Biodisk, Solna, Sweden). Based on the data, it is suggested to withdraw ciprofloxacin as a therapeutic agent for enteric fever. Fortunately, multiple drug resistance, with concurrent resistance to chloramphenicol, cotrimoxazole, and ampicillin, which had reached more than 90% in 1990–1991, started declining over the years and was as low as 5.6% in 2004– 2005. According to these observations, older drugs such as chloramphenicol, cotrimoxazole, and ampicillin could be recalled to treat enteric fever. Key words Salmonella · Typhoid fever · Antibiotic resistance · Drug resistance
V. Chitnis Shri Aurobindo Institute of Medical Science Indore, India S. Chitnis · N. Hemvani · D. S. Chitnis (*) Microbiology and Immunology Department, Choithram Hospital and Research Centre, Indore 452014 (M.P.), India Tel. +91-0731-2124512; Fax +91-0731-2470068 email: [email protected]
Enteric fever remains endemic in the Indian subcontinent, and in several countries in Southeast Asia and Africa. Chloramphenicol had been the standard treatment since the 1950s.. Ampicillin and cotrimoxazole were subsequently considered as alternative therapeutic agents. However, since the late 1980s multidrug-resistant (MDR) strains of Salmonella enterica serotype Typhi were responsible for numerous outbreaks of enteric fever worldwide, including India.1,2 The multiple drug resistance included resistance to chloramphenicol, ampicillin, and cotrimoxazole. As a result, ciprofloxacin became the firstline drug used to treat enteric fever. However, reduced susceptibility to ciprofloxacin, reported widely since 19941–3 has resulted in therapeutic difficulty. We carried out a minimum inhibitory concentration (MIC) study for ciprofloxacin by the agar dilution method in a total of 314 isolates of S. enterica serotype Typhi (50 isolates isolated during the years 1991–1994, another 50 isolated during 1998–1999, 40 isolated in 2000–2001, 97 isolated during 2002–2003, and 77 isolated during 2004–2005). Ciprofloxacin powder with assayed potency was provided by Anusandhan Laboratory (Indore, India). The concentration of ciprofloxacin used in the plate was in the range of 0.0035 mg/l to 32 mg/l. Isolates showing MICs greater than 1 mg/l for ciprofloxacin by the agar dilution method were also confirmed by the Epsilometer method (E-test; AB Biodisk, Solna, Sweden). Escherichia coli ATCC 25922 was used for quality control of MIC checking both for the agar dilution and E test methods. The yearwise decrease in susceptibility to ciprofloxacin is shown in Fig. 1. All the cultures with ciprofloxacin MIC > 0.25 mg/l were also found to be resistant to nalidixic acid (Hi Media, Indore, India) by the disc diffusion method.4 The emerging situation is posing a serious therapeutic problem. The cephalosporin-like agent ceftriaxone remains an option for the treatment of typhoid caused by multidrug-resistant S. enterica serotype Typhi with decreased susceptibility to ciprofloxacin, but the increased therapeutic cost, together with difficulties in intravenous administration, can be a serious handicap in developing countries.
403
Fig. 2. Prevalence of multidrugresistant (MDR) Salmonella enterica serotype Typhi isolated at Choithram Hospital and Research Centre, Indore, Central India (1988–2005). Numbers above the bars show total numbers of isolates. Bars show percentages of MDR bacterial strains
% isolates of Salmonella enterica serotype Typhi
80
72.7
70 60 50
47.4
44 40
40
40 35.6 30
30 20
30
17
16
15.5 11
10 0 1998-1999(n=50)
2000-2001(n=40)
2002-2003 (n=97)
2004-2005 (n=77)
Years
100 421
90
75
80 70 60
% MDR
Fig. 1. Yearwise prevalence of low-level resistance and high level resistance for ciprofloxacin at Choithram Hospital and Research Centre, Indore, Central India (n = 314) among Salmonella enterica serotype Typhi. Empty bars represent minimum inhibitory concentration (MIC) values less than 0.125 mg/l. Dotted bars represent MIC values greater than 0.125 but less than 1 mg/l (values considered as low-level resistance, as per the criteria of Threlfall et al.2). Black bars represent MIC values greater than 1 mg/l (values considered as highlevel resistance as per the criteria of Threlfall et al.2)
50
34
48
17
40
74
103
30 20 10
124
107
2002-2003
2004-2005
0 1988-1989
1990-1991
1992-1993
1994-1995
1996-1997
1998-1999
2000-2001
Years Values on bar represent total number of isolates
Criteria suggested by Threlfall et al.2 in 2001 appear convenient to differentiate S. enterica serotype Typhi isolates as susceptible to ciprofloxacin (MIC ≤ 0.125 mg/l), MIC > 0.125 but ≤1.0 mg/l as low-level resistance and MIC > 1.0 mg/l as high-level resistance. With these criteria, only 11.6% of isolates in the present series were susceptible to ciprofloxacin in 2004–2005, while 72.7% exhibited low-level resistance and 15.5% had high-level resistance. MIC determination by agar dilution or broth dilution methods is cumbersome for ciprofloxacin, while the E test offers a convenient and precise alternative. However, the E-test strips are costly for use in economically developing countries and the present observations suggest that checking for resistance to nalidixic acid by disc diffusion test could be a convenient alternative to predict decreased susceptibility to ciprofloxacin; this method is practiced by some groups in India.5,6 Decreased susceptibility to ciprofloxacin among S. enterica serotype Typhi isolates has been reported by several workers.5–7 In the present study, data for clinical follow up were available for only 40 of the 77 patients receiving ciprofloxacin and 37 of these 40 patients showed delayed defervescence of greater than 6 days against an earlier average defervesence of 3.5 days noted in our hospital. Patients showing failure to respond to ciprofloxacin received
ceftriaxone and responded well. Ceftriaxone is now used as a drug of choice by the local clinicians. Follow-up reports on the use of chloramphenicol were available for only 8 patients and all responded well, with an average defervescence period of 4.75 days. The mechanism of resistance to ciprofloxacin was not examined in the present study, but could be due to mutation in the gyrA gene.8 Further, the fact needs to be emphasized that 88.2% of the isolates during 2004–2005 had reduced susceptibility to ciprofloxacin. This observation strongly suggests that ciprofloxacin should be withdrawn as a therapeutic agent in the treatment of typhoid. However, the most interesting observation in the present study has been the dramatic reduction in MDR S. enterica serotype Typhi isolates, from over 90% in 1990–1991 to 5.6% in 2004–2005 (Fig. 2) and this suggests that older drugs such as chloramphenicol, ampicillin, and cotrimoxazole could be recalled for the treatment of enteric fever. Acknowledgments We are thankful to the Choithram Hospital and Research Centre for institutional support and we thank the Council of Scientific and Industrial Research India for providing a Senior Research Fellowship (SRF) award to the first author.
404
References 1. Chande C, Shrikhande S, Kapale S, Agarwal S, Fule RP. Change in antimicrobial resistance pattern of Salmonella typhi in central India. Indian J. Med Res 2002;115:248–50. 2. Threlfall EJ, Skinner JA, Ward LR. Detection of decreased susceptibility to ciprofloxacin in serotypes Typhi and Paratyphi A. J Antimicrob Chemother 2001;48:735–48. 3. Chitnis V, Verma S, Hemwani N, Chitnis D. Multidrug-resistant Salmonella typhi in India. Lancet 1999;354:514. 4. Bauer AW, Kirby WM, Sherris JC, Truck M. Antibiotic susceptibility by standardized single disc method. Am J Clin Pathol 1966; 45:493–6.
5. Madhulika U, Harish BN, Parija SC. Current pattern in antimicrobial susceptibility of Salmonella Typhi isolates in Pondicherry. Indian J Med Res 2004;120:11–4. 6. Kariuki S, Rvathi G, Muyodi J, Mwituria J, Munyalo A, Mirza S, et al. Characterization of multidrug-resistant typhoid outbreaks in Kenya. J.Clin Microbiol 2004;42:1477–82. 7. Rodrigues C, Shenai S, Mehta A. Enteric fever in Mumbai, India: the good news and the bad news. Clin Infect Dis 2003;36:535. 8. Renuka K, Kapil A Kabra SK, Wig N, Das BK, Prasad VV, et al. Reduced susceptibility to ciprofloxacin and gyra gene mutations in North Indian strains of S. enterica serotype Typhi and serotype Paratyphi. Microb Drug Resist 2004;10:146–53.