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      Worldwide Susceptibility Rates of Neisseria gonorrhoeae Isolates to Cefixime and Cefpodoxime: A Systematic Review and Meta-Analysis

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          Abstract

          Background

          Neisseria gonorrhoeae (NG) infection is a serious public health problem. The third-generation extended-spectrum cephalosporins (ESCs) have been used as the first-line treatment for NG infection for almost three decades. However, in recent years, treatment failures with the oral third-generation ESCs have been reported worldwide. This study aimed to estimate worldwide susceptibility rates of NG to cefixime and cefpodoxime by analyzing data from all relevant published studies.

          Methodology/principal findings

          Two researchers independently searched five databases to identify studies on susceptibilities of NG to cefixime and cefpodoxime published between January 1, 1984 and October 15, 2012. A fixed-effect model was used to perform group analysis, and a χ2 test was employed to make subgroup comparison. Publication bias was assessed with the Begg rank correlation test. The pooled susceptibility rate of NG isolates to cefixime was 99.8% (95% CI: 99.7%–99.8%). The cefixime susceptibility rate of NG isolates from men was significantly lower than that from patients without information of gender or from men and women; the susceptibility rate of NG isolates from Asia was significantly lower than that from other continents; and the susceptibility rate of NG isolates collected before or during 2003 was significantly higher than that after 2003. The pooled susceptibility rate of NG isolates to cefpodoxime was 92.8% (95% CI: 89.0%–95.3%), which was lower than that to cefixime (92.8% vs. 99.8%, χ2 = 951.809, P<0.01).

          Conclusions

          The susceptibility rate of NG isolates to cefixime varied with the gender of patients and geographical location from which NG isolates were collected, and declined with time. The reported lower susceptibility rate of NG isolates to cefixime and associated treatment failures, as well as the emergence of NG strains with cephalosporin resistance call for the more effective control of NG infection and the development of new antibiotics.

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          Most cited references45

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          High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure.

          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 μg/ml) and ceftriaxone (MIC = 1 to 2 μg/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 ESC-resistant 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.
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            Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain.

            The aim of this study was to characterize the first two extended-spectrum cephalosporin-resistant and multidrug-resistant (MDR) Neisseria gonorrhoeae isolates collected from two sexually related patients (men who have sex with men) in Spain. Antimicrobial susceptibility was studied by Etest. Genes involved in quinolone, ceftriaxone and multidrug resistance were amplified by PCR and sequenced in both directions. The isolates were typed by N. gonorrhoeae multi-antigen sequence typing (NG-MAST). The two isolates had the same MDR profile, showing resistance to penicillin (MIC 0.094 mg/L; β-lactamase negative), ceftriaxone (MIC 1.5 mg/L), cefixime (MIC 1.5 mg/L), cefotaxime (MIC 1 mg/L), ciprofloxacin (MIC >32 mg/L) and tetracycline (MIC 1.5 mg/L). NG-MAST showed that both isolates belonged to sequence type (ST) 1407 (porB-908 and tbpB-110). Ciprofloxacin resistance was due to amino acid substitutions in GyrA (S91F and D95G) and ParC (S87R). An A deletion in the promoter of the MtrCDE efflux pump (mtrR) was detected. No changes were detected in the pilQ gene. The outer membrane protein PorB showed two substitutions at G120K and A121N. An L421P substitution was observed in the PBP1A (ponA) sequence. The sequence of PBP2 (penA) showed a mosaic structure related to genotype XXXIV with a single additional amino acid substitution (A501P). This genotype was identical to a recently described French isolate (F89). This is the first reported case of high-level extended-spectrum cephalosporin-resistant N. gonorrhoeae transmission. The molecular typing and MDR genotype suggest possible European spread of this strain, highlighting the need for surveillance and the importance of testing the susceptibility of N. gonorrhoeae to extended-spectrum cephalosporins.
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              Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae.

              Globally, antimicrobial resistance (AMR) in Neisseria gonorrhoeae is increasing in prevalence, both within and across antibiotic classes, including extended-spectrum cephalosporins, raising concerns that gonorrhea may become untreatable in certain circumstances. The AMR surveillance that is essential to optimize standard treatments is often lacking or of poor quality in countries with high disease rates. Recent initiatives by the WHO to enhance global AMR surveillance that focus on multidrug- and extensively drug-resistant N. gonorrhoeae through revision of surveillance standards and use of a new panel of N. gonorrhoeae control strains are described. Keys to meeting these new challenges posed by gonococcal AMR remain the reduction in global burden of gonorrhea combined with implementation of wider strategies for general AMR control, and better understanding of mechanisms of emergence and spread of AMR.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                31 January 2014
                : 9
                : 1
                : e87849
                Affiliations
                [1 ]Reference STD Lab, National Center for STD Control, Chinese CDC, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu Province, China
                [2 ]Department of STD, Anhui Provincial Institute of Dermatology, Hefei, Anhui Province, China
                California Department of Public Health, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YPY R-XY. Performed the experiments: R-XY G-QW QL. Analyzed the data: R-XY G-QW. Contributed reagents/materials/analysis tools: S-CC B-JZ X-QD. Wrote the paper: R-XY YPY. Edit the paper: YPY S-CC B-JZ X-QD YH G-YZ X-SC.

                Article
                PONE-D-13-29888
                10.1371/journal.pone.0087849
                3909252
                24498212
                d784e00e-8b2f-48e0-ab4a-517730080bb2
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 July 2013
                : 2 January 2014
                Page count
                Pages: 10
                Funding
                This work was supported by Natural Science Foundation of China (81101294). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Population Biology
                Epidemiology
                Infectious Disease Epidemiology
                Medicine
                Clinical Research Design
                Meta-Analyses
                Systematic Reviews
                Epidemiology
                Infectious Disease Epidemiology
                Infectious Diseases
                Sexually Transmitted Diseases
                Gonorrhea
                Obstetrics and Gynecology
                Genitourinary Infections
                Gonorrhea
                Urology
                Genitourinary Infections
                Gonorrhea

                Uncategorized
                Uncategorized

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