Fluoroquinolone resistance in Haemophilus influenzae

Eugenne Elliott1, Deon Oosthuizen2, Maggie M Johnson3 and Laura J. V. Piddock3,*

1 Medunsa Microbicide Division, P.O. Box 211, Medunsa, 0204; 2 Medical Microbiology, Institute for Pathology, P.O. Box 2034, Pretoria, 0001, South Africa; 3 Antimicrobial Agents Research Group, Division of Immunity and Infection, The Medical School, University of Birmingham, Birmingham B15 2TT, UK

Keywords: fluoroquinolones, fluoroquinolone-resistant, H. influenzae

Sir,

Resistance to the fluoroquinolone class of antimicrobials is considered extremely rare in Haemophilus species.1 In addition, according to the British Society for Antimicrobial Chemotherapy surveillance of respiratory tract infections of 958 clinical isolates of Haemophilus influenzae examined in 2000/01, only for three isolates were the MICs of ciprofloxacin >0.12 mg/L, and no MICs were >0.5 mg/L.

In November 2001, two fluoroquinolone-resistant Haemophilus species were isolated at the clinical microbiology laboratory of the Pretoria Academic Hospital. One isolate was an H. parainfluenzae (N16) and the other an H. influenzae type B (N15). Upon testing by the Kirby Bauer disc diffusion method with a 5 µg gatifloxacin disc, neither isolate had a zone of inhibition. MIC testing confirmed that both isolates were resistant to gatifloxacin and the MIC of this agent was 8 mg/L. Both isolates were also resistant to the other fluoroquinolones tested (Table 1). DNA sequencing of gyrA and gyrB revealed that N15 contained two mutations within gyrA, resulting in substitution of serine-84 with leucine and aspartate-88 with tyrosine. Beidenbach & Jones1 and Georgiou et al.2 have described similar strains. Despite having similar susceptibility to fluoroquinolones, N16 only possessed a single mutation in gyrA, resulting in substitution of serine-84 with leucine. Neither isolate had a mutation in the quinolone resistance determining region of gyrB, parC or parE. These data suggest that N16 may possess additional mechanisms contributing to resistance.


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Table 1. MICs (mg/L) of five fluoroquinolones
 
The clinical impact of the resistance of these two isolates is difficult to determine. N15 came from patient 1, a 51-year-old male admitted for secondary bacterial pneumonia superimposed on a presumed recurrent TB infection. He was treated with co-amoxiclav, and an intercostal drain was inserted to reduce the concomitant pleural effusion. He responded well to therapy, and an acid-fast smear of his sputum confirmed TB; TB therapy (rifampicin, isoniazid, ethambutol and pyrazinamide), as recommended by the South African Department of Health, was commenced. The patient was unable to recall prior fluoroquinolone use. N16 was isolated from a 55-year-old female, with previous renal impairment, admitted with pneumonia. She was treated with cefuroxime and responded well. She had received ciprofloxacin for a urinary tract infection within the previous 10 months of admission.

Emergence of these highly resistant Haemophilus species may be the result of several factors. Firstly, in the South African community, there is considered to be a relatively high use of fluoroquinolone antibiotics for the treatment—among other infections—of sexually transmitted diseases and urinary tract infections. Secondly, during the winter of 2001, two new fluoroquinolones (moxifloxacin and gatifloxacin) were licensed for use, widely advertised and recommended in the treatment of community-acquired pneumonia. It should be noted that both of the isolates described in this report were resistant to these new agents. Previous use of a fluoroquinolone has been associated with fluoroquinolone resistance in H. influenzae,3 and it is suggested that prior exposure to a quinolone selected the bacteria described. However, the high-level resistance of both these isolates has been considered previously to be extremely rare, and such strains have not been isolated easily in the laboratory after exposure to the older fluoroquinolones, such as ciprofloxacin and ofloxacin. Therefore, we caution the use of these newer fluoroquinolones, and emphasize the importance of vigilance and surveillance of bacterial species considered previously to be exquisitely susceptible to these agents, so that any changes in the population can be identified quickly and policies put in place to prevent transmission.

Footnotes

* Corresponding author. Tel: +44-121-414-6966; Fax: +44-121-414-3599; E-mail: l.j.v.piddock{at}bham.ac.uk Back

References

1 . Biedenbach, D. J. & Jones, R. N. (2000). Fluoroquinolone-resistant Haemophilus influenzae: frequency of occurrence and analysis of confirmed strains in the SENTRY antimicrobial surveillance program (North and Latin America). Diagnostic Microbiology and Infectious Disease 36, 255–9.[CrossRef][ISI][Medline]

2 . Georgiou, M., Munoz, R., Roman, F. et al. (1996) Ciprofloxacin-resistant Haemophilus influenzae strains possess mutations in analogous positions of GyrA and ParC. Antimicrobial Agents and Chemotherapy 40, 1741–4.[Abstract]

3 . Vila, J., Ruiz, J., Sanchez, F. et al. (1999). Increase in quinolone resistance in a Haemophilus influenzae strain from a patient with recurrent respiratory infections treated with ofloxacin. Antimicrobial Agents and Chemotherapy 43, 161–2.[Abstract/Free Full Text]