If we go along abusing antibiotics as we do now, we are faced with a return to a medical dark age, in which antibiotics no longer work against a vast range of infections, some created by antibiotics, some perhaps epidemic and deadly…. Idealists who seek to alert us to the damage done are opposed by an unholy alliance of those who supply and those who demand.
Prof. Graham Dukes [quoted in Lynch P, Omega, Dutton, 1997]
IN THIS ISSUE of Sexually Transmitted Diseases, Trees et al 1 report a multiclonal increase in ciprofloxacin resistance of Neisseria gonorrhoeae in Thailand over the last few years. Ciprofloxacin is a major member of the fluoroquinolone class of antimicrobials.
The Trees article is extremely important in signaling the need to reassess the criteria used to formulate the Center for Disease Control and Prevention's Sexually Transmitted Diseases (STDs) Treatment Guidelines in light of the way gonococcal resistance to the fluoroquinolone antimicrobials, ofloxacin and ciprofloxacin in particular, is emerging all over the world and compromising efficacy of treatment. 1–3
When the fluoroquinolones were first introduced, the prevailing view was that emergence of resistance to these antimicrobials was unlikely to be a significant clinical problem, because resistance would require two sequential step mutations. Nevertheless, various human pathogens, including N gonorrhoeae, have impudently gone on to become resistant to ciprofloxacin, ofloxacin, and other fluoroquinolones. 1,4,5
In the past, the strategy for choosing the antimicrobials to include in the CDC's STD Treatment Guidelines has been first, to look at the percent of strains of a target organism that remain susceptible to a candidate antimicrobial in the area where the Guidelines will be used, and then, if the percent of resistant strains is below some arbitrary norm (1 percent of gonococcal strains for ciprofloxacin 6), if the antimicrobial has been shown to be effective clinically with acceptable toxicity, and if it fills a useful niche, it is likely to be included in the Guidelines.
The Trees and colleagues data suggest that the time has come to revise the CDC's antimicrobial selection strategy to include a consideration of the rate of emergence of resistance to a single antimicrobial, or perhaps a class of antimicrobials, such as the fluoroquinolones. If the rate of emergence of resistance is high, consideration should be given to excluding that drug or its class from the Guidelines.
Whereas some individuals consider ciprofloxacin resistance of gonococci to be primarily a problem confined to Asia, that perspective is too limited. For instance, the resistance of gonococci to ciprofloxacin in Scotland increased from 0.5 percent in 1991 to 5 percent in 1999 (P < 0.001), an interval during which ciprofloxacin was recommended for the therapy of gonorrhea. 7
Such resistance of gonococci to the fluoroquinolones has been associated with failure of therapy. 1,2 Fluoroquinolone resistance and its associated failure of therapy was such a substantial problem in Hong Kong that the fluoroquinolone ofloxacin was removed from the list of approved therapy there. 2 The CDC's 1998 STD Treatment Guidelines for gonococcal infections included both ciprofloxacin and ofloxacin. 6 Whereas the overall percent of gonococcal strains resistant to ciprofloxacin was and still is relatively low (less than 1 percent in the United States), Forsyth et al, 7 in their study of fluoroquinolone resistance of gonococci in Scotland, question whether ciprofloxacin should remain the first-line therapy for gonorrhea if the rate of resistance increases at the current rate. An even more compelling example of the resistance problem comes from India where ciprofloxacin has been used as first-line treatment for gonorrhea. Ray et al 8 have shown that the resistance of gonococci to ciprofloxacin rose from zero percent in 1995 to 22 percent in 1999. As expected, resistance of the gonococcal isolates to ciprofloxacin was associated with treatment failure. 8 Ehret and Judson, 9 in reporting a patient who failed fluoroquinolone therapy of gonorrhea acquired in the Philippines asked/predicted, “Quinolone-resistant Neisseria gonorrhoeae: the beginning of the end?” Indeed, the rapid rate of emergence of resistance of gonococci to ciprofloxacin in Hawaii, to approximately 9% in 1999 10 justifies their concern.
Therefore, it was disappointing to find that the recently released CDC STD Treatment Guidelines 2002 11 still list ciprofloxacin and ofloxacin as first line therapy for gonococcal infections, albeit with the caveat that these fluoroquinolones should not be used in patients who have traveled in Asia. The assumption inherent in this recommendation is that a history of travel to Southeast Asia is predictive of fluoroquinolone resistance, and absence of such a history predicts fluoroquinolone susceptibility. However, such a strategy is flawed by the fact that the healthcare provider at the time of the selection of therapy seldom knows the travel history of the patient's sexual partner, and compelling evidence for the value of a travel history as reliably predictive of fluoroquinolone susceptibility is lacking in the Guidelines. Indeed, Bauer et al 4 found that in their study of ciprofloxacin-resistant gonococci in southern California, the travel history of the patient or the patient's contacts was not helpful in predicting the presence of ciprofloxacin-resistant gonococci. Surely at some point when the number of sites of high prevalence of ofloxacin- or ciprofloxacin-resistant N gonorrhoeae exceeds 5 or 10 as is approaching the case now, taking a patient's travel history to predict fluoroquinolone resistance or susceptibility of an infecting gonococcus is even more tenuous. It no longer seems reasonable to continue to recommend the fluoroquinolone antimicrobials for gonococcal infections, even if a history of travel by the patient or his or her contacts is considered.
The emergence of resistance to one drug in a class sometimes indicates the impending loss of susceptibility to others in that class, a phenomenon experienced by one of the authors, who watched Pseudomonas aeruginosa strains increase their resistance to the aminoglycosides and other antimicrobials at Vanderbilt University Hospital until some strains were resistant to all antibiotics commercially available at the time. 12 For a number of years methicillin-resistant Staphylococcusaureus were of only moderate concern when they seemingly remained confined to a few places in Europe, but geographic isolation of antimicrobial-resistant microbes is usually only temporary, and methicillin-resistant S aureus inevitably became a major problem in the United States. It is likely that fluoroquinolone resistance of gonococci will follow a similar path in the United States. Recently Davidson et al 3 reported the emergence of levofloxacin resistance of pneumococci and resultant treatment failure in Canada. However, the universality of this problem of emerging fluoroquinolone resistance is suggested by the experience of the authors, who have recently encountered a patient with community-acquired–pneumonia (CAP) who, failing therapy with levofloxacin, was unaccountably switched to moxifloxacin; the pneumococcal isolate proved resistant to both these fluoroquinolones. Ho et al 5 have also observed “within-class” cross-resistance of fluoroquinolone-resistant pneumococci. The mutations within the quinolone resistance-determining regions (QRDRs) of gyr A and par C that confer resistance to ciprofloxacin also confer resistance to the other fluoroquinolones, so that other fluoroquinolones, though they are on the first-line therapy list for gonococcal infections, are unlikely to provide effective alternative therapy of ciprofloxacin-resistant gonococcal infections. 1 This caveat should be made more clear in the Guidelines.
The unrestrained use of fluoroquinolones for the therapy of a variety of infectious diseases (and even in animal feed) virtually assures that these antimicrobials will be of little if any use in the future, thus making Dukes’ warning seem more imminent. As noted above, when there is resistance to or failure of one fluoroquinolone, switching to another fluoroquinolone seems unlikely to provide optimal therapy.
In all fairness to the expert committee that participated in the formulation of the STD Treatment Guidelines 2002, some of the most striking and compelling data on fluoroquinolone resistance of N gonorrhoeae cited above apparently were not available to the committee members at the time they met. Nonetheless, it is the nature of the CDC to respond to a changing database rapidly and in the interest of the common good. Thus, on the basis of the current widespread resistance and likely further emergence of fluoroquinolone resistance in N gonorrhoeae, it would seem prudent in the short term to limit the use of these antimicrobials in the therapy of gonococcal infections, and in the long term, to include the rate of emergence of resistance in the process of selecting the antimicrobial agents to be recommended in future Treatment Guidelines. If these modest course corrections fail to stem the rip tide of increasing antimicrobial resistance of gonococci, the Guidelines Committee will be faced with the specter of Graham Dukes’ dark age of a country (and world) without therapy for gonococcal infections. They will then be forced to consider a strategy involving narrowly focused antimicrobial therapy whereby one antimicrobial is reserved exclusively for the therapy of gonococcal infections. The antimicrobial chosen certainly should not be one previously squandered on animal feed. Such selective use of antimicrobials is conceptually sound, but will require tenacious adherence to the Hippocratic oath's third sentence: ‘The health and life of my patient will be my first consideration.”
The quinolones have proven useful in the treatment of gonococcal infections in penicillin- and cephalosporin-allergic patients during a period when spectinomycin, a useful alternative in such patients, was in limited supply. However, the manufacturer of spectinomycin has assured the authors that there are now and will continue to be adequate supplies of spectinomycin in distribution centers throughout the United States. This assurance has been validated in the STD clinic with which the authors are affiliated. The safety and efficacy of spectinomycin, especially its safety in pregnant patients (for whom the use of ciprofloxacin is not recommended 13) suggests that spectinomycin is a choice preferable to the fluoroquinolones for gonococcal infections in penicillin/cephalosporin-allergic as well as in pregnant patients.
A benefit-risk analysis of ciprofloxacin therapy of gonococcal infections provides further considerations for abandoning ciprofloxacin as recommended therapy. Although the rather high cure rates of gonorrhea with ciprofloxacin indicate the potential benefit to patients whose gonococcal strain is not fluoroquinolone resistant, there are potential adverse reactions to ciprofloxacin therapy that can be life threatening. Lee et al 14 have reported a series of patients receiving ciprofloxacin for upper respiratory tract infections who developed pneumococcal bacteremia, pneumococcal meningitis, or both. One patient died. Apparently ciprofloxacin, because of its broad-spectrum activity eradicated the normal flora and because it has little activity against pneumococci, allowed pneumococcal overgrowth and bloodstream invasion. 14 Ciprofloxacin has also been reported to cause eosinophilic meningitis, probably via another mechanism. 15 Moreover, Chiba et al 16 have cautioned about the proarrhythmic effects of some of the fluoroquinolones, which have sometimes been associated with Torsades de Pointes and sudden death from ventricular arrhythmias. Ofloxacin has been associated with pseudomembranous colitis, 17 which can result in toxic megacolon, 18 a condition, which if not lethal, may necessitate surgical removal of the colon. 18 Because gonococcal infections per se are seldom lethal, subjecting patients to such risks does not seem justified, even though the likelihood of the risks materializing may be small, especially when there are alternative antimicrobials with less dire adverse reactions and comparable or superior efficacy. Thus, it would seem prudent to remove ciprofloxacin and the other fluoroquinolones from the list of recommended therapy for gonococcal infections to help limit the potential harm to patients and to minimize the medicolegal vulnerability of STD clinic staff as well.
There are undoubtedly those who will point to the currently low overall rate of gonococcal resistance to ciprofloxacin of less than 1 percent who will advocate leaving ciprofloxacin on the Recommended Therapy list with a ‘let sleeping dogs lie‘ philosophy. However, the trouble with sleeping dogs is that they are not dead, and many patients may suffer treatment failure or unnecessary adverse effects of fluoroquinolone therapy before the adverse benefit:risk ratio is appreciated and acted on. In view of the foregoing considerations, the authors recommend four immediate or long-term actions: (1) that the STD Treatment Guidelines Committee, in consideration of the worldwide burgeoning fluoroquinolone resistance, remove these antimicrobials from the list of first-line therapies for gonococcal infections; (2) that antimicrobials to which there is a rapid rate of emergence of resistance be avoided in formulating guidelines; (3) that more intensive surveillance by the Gonococcal Isolate Susceptibility Project (GISP) be performed and that the results be made rapidly available to the Guidelines Committee members; and (4) when further development of multiple foci of gonococcal resistance to an antimicrobial or class of antimicrobials is documented, those antimicrobials should be promptly removed from first-line recommendations; and (5) if antimicrobial resistance of N gonorrhoeae continues to increase despite the above measures, consideration should be given to selecting a single antimicrobial to be used exclusively for gonococcal infections.
It is unfortunate that many patients will have to suffer failure of therapy before these almost certainly inevitable steps are taken. So why wait?
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