Tanaka, M. et al. Analysis of mutations within multiple genes associated with resistance in a clinical isolate of Neisseria gonorrhoeae with reduced ceftriaxone susceptibility that shows a multidrug-resistant phenotype. Int. J. Antimicrob. Agents 27, 20-26

Department of Urology, School of Medicine, Fukuoka University, Jonan-ku, Japan.
International Journal of Antimicrobial Agents (Impact Factor: 4.3). 02/2006; 27(1):20-6. DOI: 10.1016/j.ijantimicag.2005.08.021
Source: PubMed


A Neisseria gonorrhoeae strain with a reduced susceptibility to ceftriaxone (minimum inhibitory concentration (MIC) = 0.5 microg/mL) was isolated among 398 clinical isolates obtained from 2000-2001 in Fukuoka City, Japan. The N. gonorrhoeae strain was negative for penicillinase production but it showed multidrug resistance against penicillin (MIC = 8 microg/mL), tetracycline (MIC = 4 microg/mL), azithromycin (MIC = 0.5 microg/mL) and ciprofloxacin (MIC = 16 microg/mL). The molecular mechanisms of the multidrug-resistant phenotype in this strain were analysed. Polymerase chain reaction and direct DNA sequencing were performed to identify mutations within the penA, ponA, mtrR, penB, gyrA and parC genes of the gonococcal strain, which thus explain the multidrug-resistant phenotype. The N. gonorrhoeae strain contained a significantly different sequence of the penA gene from that of the ceftriaxone-susceptible strains. Some regions of the transpeptidase domain within this penA gene were closely similar to those found in other Neisseria species such as Neisseria subflava, Neisseria flavescens or Neisseria perflava/sicca. This strain also included a ponA mutation that is associated with high-level resistance to penicillin, mtrR mutations that mediate overexpression of the MtrCDE efflux pump responsible for resistance to hydrophobic agents such as azithromycin, and penB mutations that reduce porin permeability to hydrophilic agents such as tetracycline. Moreover, this strain contained gyrA and parC mutations that confer high-level resistance to ciprofloxacin. These results indicate the emergence of a N. gonorrhoeae strain with reduced susceptibility to ceftriaxone, which also showed a multidrug-resistant phenotype that can be explained by the presence of multiple loci mutations associated with antibiotic resistance.

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    • "Penicillin-binding proteins are involved in the synthesis of peptidoglycan, a major component of bacterial cell walls. Mosaic sequences of PBP2, resulting from recombination events involving penA gene sequences from other Neisseria species, have been identified in clinical isolates that demonstrate reduced susceptibility to cefixime and ceftriaxone [24-26]. Options to treat gonorrhoea if cephalosporins become ineffective are severely limited. "
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    ABSTRACT: A high level of resistance in Neisseria gonorrhoeae has developed against penicillins, sulphonamides, tetracyclines and quinolones, and recent surveillance data have shown a gradual reduction in sensitivity to current first-line agents with an upward drift in the minimum inhibitory concentration of ceftriaxone. Laboratory sensitivity testing suggests that gentamicin, an aminoglycoside, may be an effective treatment option for gonorrhoea infection when used as a single intramuscular dose. A search of electronic reference databases and grey literature was used to identify randomised trials and well-conducted prospective studies with concurrent controls evaluating single-dose gentamicin against placebo or a comparator regimen in the treatment of uncomplicated gonorrhoea infection in men and women aged 16 years and over. The primary outcome was microbiological cure of N. gonorrhoeae. Eight hundred and thirty-nine studies were identified, of which five (1,063 total participants) were included. All five studies administered single-dose gentamicin via intramuscular injection to men with uncomplicated gonococcal urethritis. Three studies were randomised trials, one was quasi-randomised and one was non-randomised but included a comparator arm. Comparator antibiotics included an alternative aminoglycoside or antibiotic used in the syndromic management of male urethritis. Methodology was poorly described in all five included studies. The high risk of bias within studies and clinical heterogeneity between studies meant that it was inappropriate to pool data for meta-analysis. Cure rates of 62% to 98% were reported with gentamicin treatment. The relative risk of cure was comparable between gentamicin and comparator antibiotics. The studies identified provide insufficient data to support or refute the efficacy and safety of single-dose intramuscular gentamicin in the treatment of uncomplicated gonorrhoea infection. Additional randomised trials to evaluate gentamicin for this indication are therefore required. Systematic review registration PROSPERO CRD42012002490
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