From the WHO Collaborating Centre for STD and HIV, Pathology Department, The Prince of Wales Hospital, Sydney, Australia
Correspondence: Prof. John W. Tapsall, Microbiology Department, SEALS, The Prince of Wales Hospital, Randwick, Sydney, New South Wales, Australia 2031. E-mail: email@example.com.
Received for publication August 9, 2005, and accepted August 22, 2005.
THE SHEER NUMBER OF gonococcal infections estimated to occur each year—60 million globally—attests to the public health importance of Neisseria gonorrhoeae. This “success” as a pathogen is in no small part the result of its genetic adaptability and versatility that allows it to transmit then attach, adhere, and invade mucosal surfaces while simultaneously avoiding host defenses. This genetic flexibility has also provided the organism with a demonstrable capacity to develop resistance to antibiotics with resulting loss of efficacy of a number of formerly successful treatments.
Fluoroquinolones are one antibiotic group that has been used widely for treatment of gonorrhea for many years. In this issue, Herida et al1 describe a recent and sustained increase in fluoroquinolone resistance in N. gonorrhoeae isolated in France in the past 15 years. From 1989 on, a total of just under 2000 gonococci, obtained as part of a sentinel study throughout France, was examined. Only a single gonococcus with intermediate resistance to ciprofloxacin (minimum inhibitory concentration [MIC], 0.12–0.5 mg/L) was detected between 1989 and 1992, but the proportion of strains with intermediate or developed quinolone resistance (MIC, 1 mg/L or more) then rose progressively. Between 2001 and 2003, 70 gonococci (14.8% of those examined) displayed some level of fluoroquinolone resistance, and in 2003, 18 gonococci had even higher ciprofloxacin MICs in the range 4 to 32 mg/L.
These data are consistent with earlier descriptions of the emergence of quinolone-resistant N. gonorrhoeae (QRNG). The mechanisms of resistance in QRNG are multiple and thus far chromosomally mediated, but changes in the target sites for quinolones, gyrase, and topoisomerase intravenously are pivotal.2 GyrA is the primary target for quinolones in gonococci with ParC secondary with the latter associated with QRNG with high MICs. When increases in ciprofloxacin MICs first occur, they are associated with single point mutations in gyrA followed by additional gyrA and/or parC alterations as MICs rise. The increases in ciprofloxacin MICs described in the French study follow this sequence, although examination of the quinolone resistance-determining regions was not undertaken.
The pattern of spread of QRNG noted in France is also similar to that described previously in those parts of the United States3 and Australia2,4 on the Pacific rim and close to countries in South and East Asia where QRNG now represents 90% or more of all isolates.5 The appearance of QRNG in this region was documented a decade ago,6 and this focus has provided a reservoir for global spread of QRNG. The increase in QRNG reported in France has also been noted in other parts of Europe,7 and the QRNG are also often resistant to multiple antibiotics. As well as Europe, Asia, and Australia, QRNG are now widely distributed (reviewed in8) and more recently reported in numbers and proportions that warrant attention in the continental United States,9,10 Argentina,11 and South Africa.12,13
The implications of these findings are far reaching. Options for treatment of gonorrhea are increasingly limited after loss of efficacy of penicillins, tetracyclines and now, seemingly, fluoroquinolones also. Treatments for gonorrhea should be single dose (for compliance) and cure a high percentage (95% or more14) of cases if disease control and prevention of complications are to be achieved. Treatment options may be further restricted by drug cost and availability. It should be remembered that gonorrhea is a “disease of the disadvantaged”15 with the highest disease incidence in poorly resourced countries with limited capacity to provide expensive treatments.
What are the antibiotic treatment options available to deal with this inexorable global expansion of QRNG? It seems that the immediate future for antibiotic treatment of gonorrhea lies with third-generation cephalosporins. This group of antibiotics is in now use in many countries and most notably with the injectable and highly active ceftriaxone. However, there is already evidence of decreasing susceptibility to this and the other more established alternative agents such as the aminocyclitol spectinomycin and the macrolide azithromycin. Treatment failures are documented with oral third-generation cephalosporins such as cefixime and cefdinir16 (but not as yet with ceftriaxone) and also with azithromycin17 and spectinomycin.18 Some limited data suggest that aminoglycosides may also be efficacious agents.19–21 They have the advantage of a low cost and recognized side effects from toxicity are not a problem with single-dose treatments. Aminoglycosides must be given by injection and again resistance may develop with use.19 There is also “reserve capacity” insofar as the current dose of ceftriaxone (but not the oral equivalents) can be increased to accommodate the lowish increases in MICs observed thus far.16 (As an aside, it should perhaps be remembered that in most countries, a 250-mg intramuscular dose is used, in contrast to the 125-mg regimen recommended in the United States.) There are, however, issues of drug quality and potency emerging with some generic forms of this and other antibiotics, which may further compromise efficacy.22
Herida et al suggest a need for European recommendations for treatment of gonorrhea.1 Ideally, this should be based on an analysis of an active, continuous, and comprehensive program of surveillance of antimicrobial resistance in gonococci integrated with patient epidemiologic data that allows selection of appropriate population-based treatment.23 The French data suggest a concentration of QRNG in the men who have sex with men (MSM) population. The QRNG were found in nine regions in France predominated in men and were frequently encountered in male rectal and pharyngeal isolates. Recent U.S. data also noted QRNG in MSM9,10 and other patient subgroups as well.10 This clustering of QRNG provided a basis for targeted nonquinolone treatments in subgroups defined by analysis of epidemiologic and laboratory data.9
It has been suggested, however, that narrow guidelines may “railroad prescribing and its contingent selection pressure in single directions.”24 This hypothesis argued that the recent concentration of ciprofloxacin treatment for gonorrhea in England was responsible for the upsurge of quinolone resistance observed there. However, other data does not confirm this viewpoint, and additional and alternative explanations for this phenomenon exist. It is highly unlikely that use, in appropriate doses, of quinolones as single-dose treatment for gonorrhea in the United Kingdom, United States, or Australia was responsible for emergence of resistance determinants.4,25 Rather, emergence of antibiotic resistance in gonococci, with subsequent global spread, has been repeatedly documented in countries where overuse and misuse of antibiotics is rife.21,26
Alternatively, it may be held that overuse of quinolones may have contributed to the subsequent selection and spread of QRNG in the United Kingdom following repeated importation from external sources. Again, other evidence also negates this argument. Longitudinal data on QRNG obtained over 20 years in Sydney,4,27–30 for example, indicate that gonococci with intermediate quinolone resistance existed there only in low proportions for a decade. Despite use of ciprofloxacin as the standard treatment, multiple gonococcal subtypes, mostly imported and with low-level resistance, waxed and waned over a low and narrow prevalence range for many years. A significant expansion and then contraction of a particular subtype with low-level resistance then occurred within a defined MSM cohort. Before this, however, a similar expansion followed by the disappearance of a different quinolone-resistant gonococcal subtype with MICs in the “resistant” range and in a subgroup of heterosexual patients had been reported. The largest upsurge in QRNG in Sydney30 then occurred in MSM quite some time after quinolone treatment was discontinued as the standard treatment. The recent California data10 also illustrated differences in the geographic and temporal distribution of QRNG and noted “the role that different sexual networks play in the spread of STDs at different times and in different places.” These phenomena also suggest that factors other than antibiotic resistance alone such as the intrinsic ability of a gonococcal subtype to expand within a patient population have a substantial influence on QRNG prevalence. This interpretation is consistent with the known characteristics of gonococci31 and provides some reassurance regarding the concerns expressed in regard to the use of standard or programmatic treatments.24
One recurrent approach to the problem of antimicrobial resistance has always been to simply await the discovery and introduction of new antibiotics, but this solution can no longer be relied on either in the short or longer term.25 Thus, the answer to the problem of multiresistant gonococci may need to be found elsewhere and in wider approaches to disease and antimicrobial resistance control.25 There are no easy solutions here. The complexity and interplay of different patient subgroups and gonococcal subtypes mean that the targeted treatment approach requires the ongoing provision of significant resources that are not available in many countries with high rates of gonorrhea. Indeed, even the less complicated systems recommended for surveillance, antimicrobial resistance in gonococci is wanting. For more than 25 years, there have been repeated recommendations for a coherent surveillance system.22,26 Because of the recognized problem of international dispersal of resistant gonococci, there have also been recommendations for the last 25 years for a coherent global surveillance system.22,26 However, not only has this has failed to materialize, but those elements that do exist are also now under threat. Resource restraints limit the generation of those high-quality data on which decisions for treatment change are based.29
One other possible solution is the use of combination of antibiotic treatments for gonorrhea. This supposes that simultaneous and multiple mutations would then be required for the gonococcus to develop resistance and that these are less likely to occur. This strategy too has been mooted for more than 25 years26 and is in place already insofar as dual therapy for both N. gonorrhoeae and Chlamydia trachomatis is recommended because infection with both agents is common. Some caution, however, needs to be exercised regarding this approach. This recommendation may have contributed to the emergence of azithromycin resistance,7 albeit with a 1-g dose not wholly suited for treatment of gonorrhea,17 and its implementation may be limited in resource-poor settings where availability of even one effective agent is restricted by cost.22 In the absence of proper regulation of antibiotic use in areas of high disease prevalence, inappropriate use of two agents, rather than one, may compound rather than relieve existing problems.26
A more comprehensive solution has been advocated for the containment of antibiotic resistance in general.25 This requires that antibiotic use should be both reduced in total as well as being properly targeted.25 Antibiotic resistance occurs in a wide number of organisms in those situations in which overuse of antimicrobials is generally common. Thus, gonococci may exist in an “antibiotic soup” irrespective of use or misuse of specific treatments for gonorrhea. Nevertheless, a reduction in the total burden gonococcal disease itself would considerably decrease antibiotic use and pressure on existing treatments. Although difficult to achieve, the control of gonorrhea, and indeed all sexually transmitted infections, relies on an integrated, multidisciplinary approach.22 Judicious use of appropriately selected treatments within this wider context of active sexually transmitted disease control, rather than continuing use of antibiotic treatment in isolation, may yet avert a situation in which the disease becomes potentially untreatable.
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