A common explanation for the rise in QRNG is repeated importation (9,19
); some evidence that importation played a role in the initial growth of resistance in the United Kingdom can be seen in data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (20
). However, genetic evidence for a combination of importation, followed by internal proliferation of fluoroquinolone resistance in N. gonorrhoeae,
has been reported (21,22
). Similarly, GISP data suggest that whereas importation may play a substantial role when resistance levels are relatively low, the prevalence of resistance for certain types increases further for certain types without the aid of importation. Indeed, for heterosexual men, for whom levels of ciprofloxacin resistance were relatively low, resistance of the GISP gonococcal isolates was positively associated with patient’s recent travel. Nevertheless, prevalence of QRNG was much higher in MSM, with the triply resistant type being the most prominent component in the rise of ciprofloxacin resistance in GISP isolates. Starting at the end of 2002, when GISP travel data became available and 7% of GISP isolates from MSM were triply resistant, prevalence levels for that type of isolate from MSM further increased along with negative association with recent travel. Given the lack of travel data before mid-2002, we cannot, however, exclude the possibility that the initial growth in the prevalence of the triply resistant type in MSM was aided by importation.
In addition, using ciprofloxacin for gonorrhea treatment may have contributed to the increase in ciprofloxacin resistance. Indeed, ciprofloxacin resistance has declined significantly since 2007 when CDC indicated that fluoroquinolones were no longer a recommended treatment for gonorrhea (23
). At the same time, although CDC stopped recommending fluoroquinolones for gonorrhea treatment in California and Hawaii in 2002 and nationally for MSM in 2004, ciprofloxacin resistance continued to increase in California and among MSM for years after those recommendations were made. However, adherence to these recommendations might have been poor in non-GISP settings because the oral cephalosporins recommended for gonorrhea treatment were not marketed in the United States during the study period (12
). Community usage of fluoroquinolones for other indications might have also contributed to the rise in ciprofloxacin resistance in N. gonorrhoeae
. Fluoroquinolones were the most commonly prescribed class of antimicrobial agents in the United States around the study period (24
The prominence of multidrug resistance, particularly among MSM, combined with the negative association with recent travel in MSM starting in late 2002, suggests that this type has proliferated without the aid of repeated importation. Resistance to a variety of antimicrobial agents for that type raises the possibility that usage of nonfluoroquinolone antimicrobial drugs could have played a role in propagation of multidrug resistance. Data reported by Kent et al. (25
) show high rates of asymptomatic N. gonorrhoeae
infection among MSM attending STD clinics in San Francisco. Some of those patients likely received antimicrobial drugs to treat conditions other than gonorrhea. For such persons, multidrug resistant N. gonorrhoeae
strains are more likely to survive the antimicrobial drug treatment, giving the multidrug-resistant type a selective advantage over other N. gonorrhoeae
types. Further studies are needed to assess the scope of antimicrobial drug use for various indications, including STD treatment, in asymptomatic N. gonorrhoeae
infections and the magnitude of the possible selective advantage.
The presence of bisexual men in the GISP data suggests a possibility for passage of resistant strains between the MSM and heterosexual communities. To address this question, we explored whether associations could be shown between the time of first appearance of ciprofloxacin resistance in heterosexual men and in MSM at different GISP sites. The timing of first appearance is highly correlated between heterosexual men and MSM, with a median delay (in either direction) of 5.5 months, despite a 5-year range of times of first appearance across different sites. Moreover, this correlation was observed in different geographic regions at different times, suggesting that resistant strains spread from 1 group to the other within each city. Given that heterosexual men are much more numerous than MSM among the GISP patients, the fact that resistance was detected first in MSM in half of the cities may reflect the more rapid rate of increase in MSM than in heterosexual men (described previously) and possibly also that the resistant type truly appeared first in MSM in most cities but was first recorded in heterosexual men in some places; our data do not enable us to disentangle these 2 contributions.
Our study had several limitations. The use of travel data to infer the role of out-of-site acquisition of resistance is complicated by several factors: travel data go back only to mid-2002; until 2004 “travel” signified the presence of travel abroad or to Hawaii within the past 60 days, and later it was changed to include any out-of-state travel. Moreover, during the periods for which our logistic regression analysis was performed, travel data were missing for many GISP patients. For periods when travel data were missing, we note that our regression analysis included only clinics that had travel information available for >50% of patients of the selected sexual orientation. Moreover, multiple imputations were used to deal with the missing travel data (18
). Of course, many gonorrhea cases are not captured by GISP, and travel by these infected persons may have been critical in the introduction of the resistant strains.
Although gonorrhea patients with recent travel history may not have acquired their infection during travel, the negative association between recent travel history and triple resistance argues against acquisition through travel as a driver of increasing prevalence of that type among MSM. Positive association with recent travel for other types argues that acquisition through travel played a role in the increase in resistance level of the corresponding type, although travel data do not enable us to quantify the extent of that role.
Our study on the rise of ciprofloxacin resistance sheds some light on the possible mechanisms that might contribute to the emergence of cephalosporin resistance. Importation of resistance and acquisition through domestic travel are likely to play a substantial role in the initial rise in resistance levels. Analysis of the rise in triple resistance levels in isolates infecting MSM suggests that resistance levels for some types, particularly the multidrug resistant type, may increase through selective advantage in domestic transmission. This increase is probably associated with antimicrobial drug usage; repeated importation is not required. Several studies (13,14,26
) have shown that decreased N. gonorrhoeae
susceptibility to cephalosporins such as cefotaxime is associated with resistance to other antimicrobial agents. This finding suggests that proliferation of multidrug resistance is also possible for cephalosporin-resistant N. gonorrhoeae.
Correlation between appearance times in persons of the 2 sexual orientations further strengthens the argument that prevention efforts should be geared toward both groups, particularly when the appearance of resistance is detected in either population.