An evaluation of gentamicin susceptibility of Neisseria gonorrhoeae isolates in Europe

Nicholas

et al. 2012

577

549

Recently, the first Neisseria gonorrhoeae strain (H041) highly resistant to the expanded-spectrum cephalosporins (ESCs) ceftriaxone and cefixime, which are the last remaining options for first-line gonorrhea treatment, was isolated in Japan. Here, we confirm and characterize a second strain (F89) with high-level cefixime and ceftriaxone resistance which was isolated in France and most likely caused a treatment failure with cefixime. F89 was examined using six species-confirmatory tests, antibiograms (33 antimicrobials), porB sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of known gonococcal resistance determinants (penA, mtrR, penB, ponA, and pilQ). F89 was assigned to MLST sequence type 1901 (ST1901) and NG-MAST ST1407, which is a successful gonococcal clone that has spread globally. F89 has high-level resistance to cefixime (MIC ‫؍‬ 4 g/ml) and ceftriaxone (MIC ‫؍‬ 1 to 2 g/ml) and resistance to most other antimicrobials examined. A novel penA mosaic allele (penA-CI), which was penA-XXXIV with an additional A501P alteration in penicillin-binding protein 2, was the primary determinant for high-level ESC resistance, as determined by transformation into a set of recipient strains. N. gonorrhoeae appears to be emerging as a superbug, and in certain circumstances and settings, gonorrhea may become untreatable. Investigations of the biological fitness and enhanced understanding and monitoring of the ESCresistant clones and their international transmission are required. Enhanced disease control activities, antimicrobial resistance control and surveillance worldwide, and public health response plans for global (and national) perspectives are also crucial. Nevertheless, new treatment strategies and/or drugs and, ideally, a vaccine are essential to develop for efficacious gonorrhea management.

Section: Discussionmentioning

confidence: 97%

High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure

Unemo

Nicholas

et al. 2012

577

549

“…However, for future treatment of gonorrhea, there are few promising novel alternatives in sight (6,24,31,32,41,49,58). Nevertheless, gentamicin has been used as a first-line treatment in Malawi, Africa, for nearly 2 decades without any reported emergence of in vitro resistance, and in vitro susceptibility in the European Union appears high (10). Furthermore, a new fluoroketolide, solithromycin (CEM-101), has also been shown to have high in vitro activity against gonococci (15,36).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Activity of Ertapenem versus Ceftriaxone against Neisseria gonorrhoeae Isolates with Highly Diverse Ceftriaxone MIC Values and Effects of Ceftriaxone Resistance Determinants: Ertapenem for Treatment of Gonorrhea?

Unemo

Limnios

et al. 2012

dClinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining treatment options for gonorrhea, is being reported. Gonorrhea may become untreatable, and new treatment options are crucial. We investigated the in vitro activity of ertapenem, relative to ceftriaxone, against N. gonorrhoeae isolates and the effects of ESC resistance determinants on ertapenem. MICs were determined using agar dilution technique or Etest for international reference strains (n ‫؍‬ 17) and clinical N. gonorrhoeae isolates (n ‫؍‬ 257), which included the two extensively drug-resistant (XDR) strains H041 and F89 and additional isolates with high ESC MICs, clinical ESC resistance, and other types of clinical high-level and multidrug resistance (MDR). Genetic resistance determinants for ESCs (penA, mtrR, and penB) were sequenced. In general, the MICs of ertapenem (MIC 50 ‫؍‬ 0.032 g/ml; MIC 90 ‫؍‬ 0.064 g/ml) paralleled those of ceftriaxone (MIC 50 ‫؍‬ 0.032 g/ml; MIC 90 ‫؍‬ 0.125 g/ml). The ESC resistance determinants mainly increased the ertapenem MIC and ceftriaxone MIC at similar levels. However, the MIC ranges for ertapenem (0.002 to 0.125 g/ml) and ceftriaxone (<0.002 to 4 g/ml) differed, and the four (1.5%) ceftriaxone-resistant isolates (MIC ‫؍‬ 0.5 to 4 g/ml) had ertapenem MICs of 0.016 to 0.064 g/ml. Accordingly, ertapenem had in vitro advantages over ceftriaxone for isolates with ceftriaxone resistance. These in vitro results suggest that ertapenem might be an effective treatment option for gonorrhea, particularly for the currently identified ESC-resistant cases and possibly in a dual antimicrobial therapy regimen. However, further knowledge regarding the genetic determinants (and their evolution) conferring resistance to both antimicrobials, and clear correlates between genetic and phenotypic laboratory parameters and clinical treatment outcomes, is essential.

“…Furthermore, it is crucial to explore options, in industrialized settings as well as in less-resourced settings, for future treatment of ESC-resistant gonorrhea. This includes exploration of optimized dose regimens of presently used antimicrobials, new antimicrobials (or rediscovery of old drugs, such as gentamicin, ertapenem, and perhaps, piperacillin-tazobactam in emergent situations of ESC-resistant N. gonorrhoeae) or other substances, and combination therapy (6,7,19,20,22,31,36,37; M. Unemo and J. Tapsall, unpublished data).…”

Section: Vol 55 2011 N Gonorrhoeae: Soon a Superbug Causing Untreamentioning

confidence: 99%

Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone

Ohnishi

Shimuta

et al. 2011

612

624

Recently, the first Neisseria gonorrhoeae strain (H041) that is highly resistant to the extended-spectrum cephalosporin (ESC) ceftriaxone, the last remaining option for empirical first-line treatment, was isolated. We performed a detailed characterization of H041, phenotypically and genetically, to confirm the finding, examine its antimicrobial resistance (AMR), and elucidate the resistance mechanisms. H041 was examined using seven species-confirmatory tests, antibiograms (30 antimicrobials), porB sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of ESC resistance determinants (penA, mtrR, penB, ponA, and pilQ). Transformation, using appropriate recipient strains, was performed to confirm the ESC resistance determinants. H041 was assigned to serovar Bpyust, MLST sequence type (ST) ST7363, and the new NG-MAST ST4220. H041 proved highly resistant to ceftriaxone (2 to 4 g/ml, which is 4-to 8-fold higher than any previously described isolate) and all other cephalosporins, as well as most other antimicrobials tested. A new penA mosaic allele caused the ceftriaxone resistance. In conclusion, N. gonorrhoeae has now shown its ability to also develop ceftriaxone resistance. Although the biological fitness of ceftriaxone resistance in N. gonorrhoeae remains unknown, N. gonorrhoeae may soon become a true superbug, causing untreatable gonorrhea. A reduction in the global gonorrhea burden by enhanced disease control activities, combined with wider strategies for general AMR control and enhanced understanding of the mechanisms of emergence and spread of AMR, which need to be monitored globally, and public health response plans for global (and national) perspectives are important. Ultimately, the development of new drugs for efficacious gonorrhea treatment is necessary.