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Research Letters |

Susceptibility to Fluoroquinolones of Vibrio cholerae O1 Isolated From Diarrheal Patients in Zimbabwe FREE

M. Sirajul Islam, PhD; Stanley M. Midzi, MD; Lincoln Charimari, MD; Alejandro Cravioto, MD, PhD; Hubert P. Endtz, MD, PhD
JAMA. 2009;302(21):2321-2322. doi:10.1001/jama.2009.1750.
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Published online

To the Editor: Cholera is endemic in many countries in Asia, Latin America, and Africa. Sub-Saharan African countries, particularly Angola, Congo, Mozambique, and Zimbabwe, have been strongly affected by cholera in recent years, with a large epidemic occurring in Zimbabwe in 2008. From August 2008 until February 2009, 70 640 patients were reported with cholera in Zimbabwe, of whom 3467 died.1 On request from the World Health Organization, a team from the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDRB), went to Zimbabwe to assess the cholera situation and provide assistance to control the outbreak. Preliminary data on the antibiotic resistance of Vibrio cholerae O1 strains that were isolated from the patients in Zimbabwe are reported.

Stool and rectal swab specimens were collected from randomly selected patients at 4 cholera treatment centers in Zimbabwe, including Beatrice Road Infectious Diseases Hospital and Budiriro in Harare province, Chinhoyi in Mashonaland West, and Binga in Matebeleland North provinces. V cholerae O1 was isolated and identified following standard procedures.2 The presence of virulence-associated genes (including genes encoding cholera toxin) and the major colonization factor (toxin coregulated pilus) were tested by specific polymerase chain reaction assays.2 The strains were also subjected to ribotyping to assess clonal relationship.3 The minimum inhibitory concentrations (MICs) of ciprofloxacin, tetracycline, and azithromycin were determined using Etest (AB bioMérieux, Solna, Sweden) following standard procedures. The measured MICs were rounded to the nearest higher 2-fold dilution. The strains were also tested for sensitivity using the disk diffusion method. Protocols were approved by the Ministry of Health and Child Welfare and the World Health Organization, Harare, Zimbabwe, and patients provided oral consent for participation.

A total of 64 stool and rectal swab samples were collected from January 16 to January 27, 2009. V cholerae O1 was isolated in 38 samples (59%). All isolates belonged to the El Tor biotype; 31 and 7 isolates belonged to Ogawa and Inaba serotypes, respectively. Of the 38 isolates, 31 strains were available for further testing. Two distinct ribotype patterns (A and B) were observed among the isolates.

All strains were susceptible to azithromycin and tetracycline, with MIC90 (MIC required to inhibit the growth of 90% of organisms) of 0.125 mg/L and 0.5 mg/L, respectively. The MIC90 of ciprofloxacin was 0.5 mg/L, with a distinction between the ciprofloxacin susceptibility of ribotype A and ribotype B. The ciprofloxacin MIC of ribotype A ranged from 0.125 to 0.5 mg/L. The ciprofloxacin MIC of type B was 0.004 mg/L (Figure). Thus, the ciprofloxacin MICs of clonal type A were 30 to 125 times higher than those of clonal type B and within 1 to 3 two-fold dilutions of the susceptibility breakpoint of 1 mg/L. The strains of clone B were susceptible to nalidixic acid by disk diffusion, but clone A strains were resistant. All strains were resistant to furazolidone and trimethoprim-sulfamethoxazole.

Place holder to copy figure label and caption
Figure. Ciprofloxacin Susceptibility of 31 Vibrio cholerae O1 Isolates From Zimbabwe
Graphic Jump Location

The measured minimum inhibitory concentrations were rounded to the nearest higher 2-fold dilution.

To our knowledge, this is the first description of an outbreak of cholera with reduced susceptibility against fluoroquinolones on the African continent. Nalidixic acid resistance has been reported in Ghana and Mozambique, but no quantitative susceptibility tests or MICs were performed and no resistance to fluoroquinolones was detected.4

Ciprofloxacin resistance may be associated with progressive multiple mutations in the gyrA gene5; nalidixic acid resistance may therefore have facilitated the emergence of resistance to the fluoroquinolones. Reduced susceptibility of V cholerae against ciprofloxacin (MIC, 0.25 mg/L) has been reported previously in patients hospitalized in Bangladesh and was associated with therapy failure in these patients.6 The reported reduced susceptibility is therefore reason for concern.

Antimicrobial susceptibility is often not determined in cholera, and qualitative antimicrobial susceptibility tests (eg, disk diffusion) may fail to detect strains with reduced susceptibility. Longitudinal surveillance of antimicrobial susceptibility of V cholerae O1 using quantitative (MIC) methods is therefore recommended for early detection of emergence of resistance.

Author Contributions: Dr Islam had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Midzi, Cravioto, Endtz.

Acquisition of data: Midzi, Charimari.

Analysis and interpretation of data: Islam, Cravioto.

Drafting of the manuscript: Midzi, Charimari.

Critical revision of the manuscript for important intellectual content: Islam, Cravioto, Endtz.

Obtained funding: Cravioto.

Administrative, technical, or material support: Islam, Midzi, Charimari, Cravioto, Endtz.

Study supervision: Cravioto.

Financial Disclosures: None reported.

Funding/Support: Financial and material support was provided by the International Centre for Diarrhoeal Disease Research, Bangladesh; the World Health Organization, Zimbabwe; Communicable Disease Control, Zimbabwe; and the Ministry of Health and Child Welfare, Zimbabwe.

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: The ICDDRB cholera working group comprised Siraj U. Ahmed, MBBS, MPH; Munirul Alam, PhD; Mohammad Ansaruzzaman, MSc; Pradip K. Bardhan, MD; Shah M. Faruque, PhD; Anwarul Iqbal, MBBS, MSc; M. Shafiqul Islam, MSc; Azharul I. Khan, MBBS, PhD; Zahid H. Mahmud, PhD; Ramendra N. Mazumder, MBBS, MD; Firdausi Qadri, PhD; and Kaisar A. Talukder, PhD. All are affiliated with the ICDDRB, and none received compensation for their contributions. James Mudzori, MSc, and Owen Chitsatso, MSc (Ministry of Health and Child Welfare, Zimbabwe), and Sheetal Patel, MSc (Communicable Disease Control, Zimbabwe), helped in collecting samples, for which they did not receive compensation.

Bhattacharya S, Black R, Bourgeois L,  et al.  Public health: the cholera crisis in Africa.  Science. 2009;324(5929):885
PubMed   |  Link to Article
Islam MS, Jahid IK, Rahman MM,  et al.  Biofilm acts as a microenvironment for plankton associated Vibrio cholerae in the aquatic environment of Bangladesh.  Microbiol Immunol. 2007;51(4):369-379
PubMed
Faruque SM, Roy SK, Alim AR, Siddique AK, Albert MJ. Molecular epidemiology of toxigenic Vibrio cholerae in Bangladesh studied by numerical analysis of rRNA gene restriction patterns.  J Clin Microbiol. 1995;33(11):2833-2838
PubMed
Opintan JA, Newman MJ, Nsiah-Poodoh OA, Okeke IN. Vibrio cholerae O1 from Accra, Ghana carrying a class 2 integron and the SXT element.  J Antimicrob Chemother. 2008;62(5):929-933
PubMed   |  Link to Article
Garg P, Sinha S, Chakraborty R,  et al.  Emergence of fluoroquinolone-resistant strains of Vibrio cholerae O1 biotype El Tor among hospitalized patients with cholera in Calcutta, India.  Antimicrob Agents Chemother. 2001;45(5):1605-1606
PubMed   |  Link to Article
Saha D, Karim MM, Khan WA, Ahmed S, Salam MA, Bennish ML. Single-dose azithromycin for the treatment of cholera in adults.  N Engl J Med. 2006;354(23):2452-2462
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Ciprofloxacin Susceptibility of 31 Vibrio cholerae O1 Isolates From Zimbabwe
Graphic Jump Location

The measured minimum inhibitory concentrations were rounded to the nearest higher 2-fold dilution.

Tables

References

Bhattacharya S, Black R, Bourgeois L,  et al.  Public health: the cholera crisis in Africa.  Science. 2009;324(5929):885
PubMed   |  Link to Article
Islam MS, Jahid IK, Rahman MM,  et al.  Biofilm acts as a microenvironment for plankton associated Vibrio cholerae in the aquatic environment of Bangladesh.  Microbiol Immunol. 2007;51(4):369-379
PubMed
Faruque SM, Roy SK, Alim AR, Siddique AK, Albert MJ. Molecular epidemiology of toxigenic Vibrio cholerae in Bangladesh studied by numerical analysis of rRNA gene restriction patterns.  J Clin Microbiol. 1995;33(11):2833-2838
PubMed
Opintan JA, Newman MJ, Nsiah-Poodoh OA, Okeke IN. Vibrio cholerae O1 from Accra, Ghana carrying a class 2 integron and the SXT element.  J Antimicrob Chemother. 2008;62(5):929-933
PubMed   |  Link to Article
Garg P, Sinha S, Chakraborty R,  et al.  Emergence of fluoroquinolone-resistant strains of Vibrio cholerae O1 biotype El Tor among hospitalized patients with cholera in Calcutta, India.  Antimicrob Agents Chemother. 2001;45(5):1605-1606
PubMed   |  Link to Article
Saha D, Karim MM, Khan WA, Ahmed S, Salam MA, Bennish ML. Single-dose azithromycin for the treatment of cholera in adults.  N Engl J Med. 2006;354(23):2452-2462
PubMed   |  Link to Article
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