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Potential Deleterious Effects of Promoting the Use of Ceftriaxone in the Treatment of Neisseria gonorrhoeae

Golden, Matthew R. MD, MPH*†; Barbee, Lindley A. MD, MPH*†; Kerani, Roxanne PhD*†; Dombrowski, Julia C. MD, MPH*†

doi: 10.1097/OLQ.0000000000000174
The Real World of STD Prevention
Free

Background US gonorrhea treatment guidelines recently changed to promote ceftriaxone as first-line therapy. Because ceftriaxone requires intramuscular administration, this could lead some patients to go untreated.

Methods We used an arithmetic model to compare the number of persons with gonorrhea who would be successfully treated with continued use of oral therapies versus exclusive use of ceftriaxone. Our base case scenario assumed the following: decreased cefixime susceptibility in 2% of heterosexuals and 5% of men who have sex with men, baseline oral therapy in 30% of heterosexuals and 15% of men who have sex with men, oral treatment failure in 10% of decreased susceptibility cases, and baseline patient-delivered partner therapy use in 30% of heterosexuals.

Results Considering only effects on index cases, universal ceftriaxone use would result in fewer cures if at least 5% of oral therapy recipients go untreated with the change in treatment practice. Exclusive ceftriaxone use consistently led to fewer infected persons being cured when the model incorporated partner treatment effects and assumed that the change in treatment practices eliminated the use of patient delivered partner therapy. If oral treatment were 75% effective against decreased susceptibility gonorrhea, exclusive ceftriaxone use would likely increase cure rates in persons with decreased susceptibility gonorrhea, but could diminish them in persons with gonorrhea overall.

Conclusions At least in the short term, eliminating oral therapy for gonorrhea will likely have small effects on decreased susceptibility treatment failures and could increase gonorrhea rates overall.

A mathematical model suggests that changes in US gonorrhea treatment guidelines to favor intramuscular therapy could decrease the proportion of gonorrhea cases that are cured if even a small number of persons go untreated because intramuscular therapy is more difficult to distribute.

From the *Center for AIDS and STD, University of Washington, Seattle, WA; and †Public Health–Seattle & King County, Seattle, WA.

Acknowledgment: The authors thank Dr Harrell Chesson for his helpful review of our model and manuscript.

Conflict of interest: None declared.

Correspondence: Matthew R. Golden MD, MPH, Harborview Medical Center Box 359777, 325 9th Ave, Seattle, WA 98104. E-mail: golden@u.washington.edu.

Received for publication October 21, 2013, and accepted July 07, 2014.

In 2012, the US Centers for Disease Control and Prevention (CDC) altered its guidelines for the treatment of Neisseria gonorrhoeae infections to increase clinicians’ use of intramuscular ceftriaxone and decrease their use of oral extended spectrum cephalosporins.1 This change was driven by both US and international data demonstrating an increase in the proportion of N. gonorrhoeae isolates with decreased susceptibility to oral cephalosporins2–5 and was designed to retard the transmission of these relatively resistant bacteria.

Ceftriaxone is substantially more active against N. gonorrhoeae than oral cephalosporins, like cefixime, and there is widespread consensus that clinicians should use ceftriaxone whenever possible. At the same time, some treating providers may not have ready access to ceftriaxone, and because the drug is administered intramuscularly, it cannot be used for patient-delivered partner therapy (PDPT), which has been shown to reduce the risk of recurrent gonorrhea in randomized controlled trials.6,7 Centers for Disease Control and Prevention guidelines continue to recommend that clinicians use oral therapies when ceftriaxone is not available and are not designed to diminish the use of PDPT. However, these recommendations are fairly nuanced and occur against a background of widespread popular and professional media attention emphasizing that oral cephalosporins are “no long a recommended treatment for gonococcal infections” and that ceftriaxone is a last line of antimicrobial defense.1 In the wake of the change in guidelines, the Oregon State Department of Health adopted a policy to discourage the use of PDPT for gonorrhea, and anecdotally, we have encountered several clinicians and large medical practices in Washington State that have ceased to use PDPT or considered such a change in practice because of concerns related to gonorrhea resistance and the new CDC guidelines.

The net effect of changing the CDC guidelines and clinician practices will depend on the balance between the benefits of using a more effective drug and the possible deleterious effects of decreases in treatment that may result from promoting the use of a drug that is more difficult to deliver and administer. In this article, we estimate the potential impact of changes in gonorrhea treatment recommendations.

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METHODS

We developed an arithmetic model to estimate the number of persons with gonorrhea who would be untreated or ineffectively treated under different scenarios in which ceftriaxone replaces cefixime as a treatment of gonorrhea but, in some instances, results in fewer patients or infected sex partners receiving therapy. Like other models of this type,8–10 our approach was designed to assess effects only in persons diagnosed as having gonorrhea and their infected sex partners; the model does not provide information on second-generation partners (i.e., the sex partners of partners) or project long-term incidence or prevalence. We sought to separately estimate effects on treatment failure (defined here to include both ineffective therapy and the absence of any treatment) in persons infected with decreased susceptibility N. gonorrhoeae and all persons with gonorrhea. We also separately estimated effects including and not including the impact of eliminating the use of PDPT for gonorrhea. We examined the effects of a change in treatment practices from 3 different perspectives: (a) the effect on index cases (persons diagnosed as having gonorrhea) only; (b) the effect on index cases and their infected partners, but assuming that medical providers do not give patients PDPT; and (c) the effect on index cases and infected partners, assuming that PDPT is used at baseline, but that promotion of ceftriaxone use eliminates all use of PDPT.

Sample equations used in the model are presented in Table 1. The model used 4 identical sets of equations with different parameters to estimate treatment failures among heterosexuals infected with N. gonorrhoeae infections susceptible to cefixime, men who have sex with men (MSM) with N. gonorrhoeae infections susceptible to cefixime, heterosexuals infected with N. gonorrhoeae with decreased susceptibility to cefixime, and MSM infected with N. gonorrhoeae with decreased susceptibility to cefixime.

TABLE 1

TABLE 1

To assess the effect of a change in treatment guidelines, our model incorporated a term to reflect decreased treatment among index patients who previously received cefixime. We also sought to estimate the impact of eliminating cefixime use among sex partners and the elimination of PDPT. This included 3 components: (1) a change from cefixime to ceftriaxone in the treatment for sex partners, with some partners going untreated because of the need for intramuscular therapy; (2) increases in reinfection rates among index patients originally diagnosed as having gonorrhea who previously received PDPT for partner treatment; and (3) changes in the proportions of infected partners that receive treatment as a consequence of eliminating PDPT. Models assumed no use of PDPT in MSM and that the change in guidelines eliminated the use of PDPT in heterosexuals. Thus, when PDPT is eliminated, Phetpdpt and PRXCEFhet are equal to 0 and Phetnopdpt and PRXCTXhet are equal to 1.

Although our equations use a term (TOTGC) for the total number of cases of gonorrhea, all results are presented as percentages of cases cured.

Table 2 presents parameter values used in our base case model and ranges for these parameters used in analyses exploring different hypothetical scenarios. We estimated the proportion of cases occurring in MSM and the proportion of persons receiving ceftriaxone- and cefixime-based regimens before the 2012 change in the STD Treatment Guidelines based on US national data collected through the CDC STD Surveillance Network11 (M. Stenger, personal communication), and the proportion of partners infected with N. gonorrhoeae based on the mean of values reported in published studies.12–17 Our estimates for the proportion of infections caused by decreased susceptibility N. gonorrhoeae in the United States and Europe are based on data from the CDC Gonococcal Isolate Surveillance Project (R. Kirkcaldy, personal communication) and European gonococcal surveillance data18 (G. Spiteri, personal communication), respectively. For both areas, we defined decreased susceptibility to include infections causes by N. gonorrhoeae with minimum inhibitory concentrations (MICs) against cefixime of at least 0.125 μg/mL. Although this threshold is lower than that used in Europe (>0.125 μg/mL) or the United States (≥0.5 μg/mL), recent clinic data suggest an elevated risk of treatment failure at this MIC.19 A review undertaken as part of the development of the 2007 CDC STD treatment guidelines estimated that ceftriaxone 125 mg and cefixime 400 mg are 98.8% and 97.6% effective against N. gonorrhoeae, respectively.20 The studies that contributed to these estimates were undertaken in a time when the MICs needed to retard the growth of N. gonorrhoeae in vitro were somewhat lower, and these regimens may now be less effective, even against gonococcal isolates defined as being fully susceptible. On the other hand, the recommended dose of ceftriaxone is now 250 mg, and current US guidelines recommend that all patients treated with cephalosporins receive concurrent azithromycin or doxycycline; both of these factors should increase regimen efficacy. Data on the efficacy of cefixime-based regimens against decreased susceptibility N. gonorrhoeae are extremely limited.19 Thus, for our model, we estimated that ceftriaxone-based regimens would be 99% effective against both susceptible and decreased susceptibility N. gonorrhoeae, whereas cefixime-based regimens would be 96% effective against susceptible N. gonorrhoeae and 75% to 90% efficacious against gonorrhea with decreased susceptibility to cefixime. We used data from a previously published randomized controlled trial to estimate the impact of expedited partner therapy on the risk of reinfection and partner treatment6 and used Washington State surveillance data to estimate how often persons with gonorrhea receive PDPT. Because PDPT use among persons with gonorrhea varies nationally and probably internationally,21 we also present outcome estimates that assume that no medical providers use PDPT (panels B in all figures). Finally, because there are no published data on how promotion of ceftriaxone use might affect the proportion of persons with gonorrhea who receive treatment, we varied our assumptions about this parameter widely, from 0 to 15%.

TABLE 2

TABLE 2

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RESULTS

Figure 1 presents our base case findings considering the effects of a change in treatment guidelines. Panel A focuses exclusively on how a change in treatment guidelines might affect index cases and excludes consideration of any impacts on partner treatment. The net effect of a change in treatment toward the use of intramuscular therapy is small across the range of values considered. The initial bar in the figure assumes that the change in guidelines leads to no increase in the number of diagnosed persons who go untreated. As anticipated, if this is the case, the shift toward parenteral therapy leads to a small increase in the number of persons successfully treated for gonorrhea. The model suggests that if 5% or more of index cases who were treated with oral regimens when oral therapy was still recommended go without therapy after the change in treatment practices (i.e., 1% of all diagnosed infections go untreated), the net effect of the change will be a decline in the percentage of all gonorrhea cases that are effectively treated. If 10% or more of persons receiving oral therapy go untreated (2% of all diagnosed infections go untreated), the change would also lead to a small decline in the percentage of persons with decreased susceptibility N. gonorrhoeae infections that are successfully treated.

Figure 1

Figure 1

Panel B of Figure 1 incorporates estimates of partner treatment into the presented outcomes but assumes that providers do not use PDPT. This added consideration has no impact on the proportion of infections with decreased susceptibility N. gonorrhoeae that are cured and leads to a very slight increase in the proportion of all gonorrhea cases cured with the change in treatment practices relative to panel A, though the threshold at which the change in treatment recommendations becomes deleterious remains unchanged. In panel C, we assume that 30% of heterosexuals with gonorrhea would have received PDPT when cefixime was recommended and that promotion of ceftriaxone treatment eliminates all use of PDPT. Under this scenario, the net effect of the change in treatment to promote the exclusive use of ceftriaxone always leads to a decline in the total number of infected persons treated, although the number of persons with decreased susceptibility N. gonorrhoeae treated increases as long as the shift toward parenteral therapy does not lead to more than 2.5% of persons with diagnosed gonococcal infections going untreated.

Figures 2–4 explore model outcomes using different parameter values. In Figure 2, we assume that oral therapy cures only 75% of decreased susceptibility N. gonorrhoeae infections compared with 90% in our base case scenario. Here the effect of a change in treatment practices often produces divergent results on the success of gonorrhea treatment overall and among persons infected with N. gonorrhoeae with decreased susceptibility to oral cephalosporins. The change in treatment to ceftriaxone consistently leads to an improvement in effective treatment among index cases with decreased susceptibility N. gonorrhoeae. As in Figure 1, the incorporation of partner treatment effects has little impact in the absence of PDPT use. However, if a change in guidelines eliminates the use of PDPT (panel C), the change in treatment practices consistently leads to a decline in the total number of gonorrhea cases that are effectively treated.

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

In Figure 3, we model a scenario based on European data in which 40% of gonorrhea cases occur in MSM, and 12% of MSM cases and 26% of heterosexual cases have decreased susceptibility to oral cephaolosporins (MIC ≥ 0.125).18 The overall pattern of effect on the total number of persons with gonorrhea effectively treated is similar to that observed in Figure 1, although in the absence of PDPT, the beneficial effects of a change in guidelines on decreased susceptibility N. gonorrhoeae are somewhat greater if the change is associated with no decrement in the percentage of persons treated and are somewhat more deleterious if the change in guidelines leads to a decline in the number of persons treated or elimination of PDPT.

Finally, in Figure 4, we model European data assuming that oral therapy is only 75% curative in persons infected with N. gonorrhoeae with decreased susceptibility to oral cephalosporins. The pattern observed is similar to Figure 2, which models US parameters, but the beneficial effects of eliminating the use of oral therapy, particularly on decreased susceptibility N. gonorrhoeae, are greater. This difference reflects the fact that decreased susceptibility N. gonorrhoeae in Europe is concentrated in heterosexuals, whereas in the United States, decreased susceptibility N. gonorrhoeae is more common in MSM. Our model assumes that oral therapy is more frequently used in heterosexuals, meaning that the change toward ceftriaxone has a greater impact on the treatment for heterosexuals than in MSM. The effect of eliminating PDPT is less in the European scenario because of the higher proportion of all cases occurring in MSM, a population in which the model assumes PDPT is not used.

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DISCUSSION

We found that a change in gonorrhea treatment guidelines to promote the universal use of intramuscular ceftriaxone therapy in place of oral medications could lead to a decline in the effective treatment of gonorrhea under some circumstances, at least in the short-term. When our model incorporated epidemiologic and treatment parameters from the United States, the net effect of the change was that fewer people were effectively treated if 5% or more of persons who previously received oral therapy went untreated (i.e., 1% of all diagnosed cases), or if the change in guidelines resulted in the elimination of PDPT. Perhaps surprisingly, promoting the exclusive use of ceftriaxone could also result in a decline in the effective treatment decreased susceptibility N. gonorrhoeae. However, this effect is dependent on assumptions regarding the efficacy of oral regimens. If therapy with cefixime and azithromycin, the most widely used oral regimen, is associated with a high risk of treatment failure (i.e., 25%), changing treatment practices may lead to mixed effects, with an improvement in the successful treatment of decreased susceptibility N. gonorrhoeae, but a decline in the proportion of all gonococcal infections that are cured.

Our findings draw attention to 2 critical areas of uncertainty: the efficacy of oral regimens against decreased susceptibility N. gonorrhoeae and the potential for guideline recommendations favoring intramuscular regimens to lead to fewer infected persons receiving treatment. There are few data on the efficacy of cefixime and azithromycin for N. gonorrhoeae with MICs of 0.12 to 0.25 μg/mL, the MIC range typically observed in the United States and Europe among gonoccocal isolates with decreased susceptibility to oral cephalosporins. Allen and colleagues19 reported that 7 (25%) of 28 cefixime-treated persons infected with gonococci with a cefixime MIC of 0.12 μg/mL failed therapy. However, only 1 of the persons who failed treatment received concurrent azithromycin, an agent that is active against approximately 95% of gonoccocal isolates in both the United States and Europe.18,22 Although a 1-g dose of azithromycin is not a recommended therapy for gonorrhea and azithromycin single-agent treatment has been associated with the development of resistance, small observational studies suggest that the 1-g dose is usually effective when treating susceptible gonococcal isolates.23–26 More data on the efficacy of cefixime and azithromycin combination therapy when treating N. gonorrhoeae with decreased susceptibility to oral cephalosporins are needed.

In building our model, we explored the possibility that the promotion of intramuscular therapy might come at a cost and that some infected persons who would have received oral therapies when they were previously recommended would go untreated because they could not access an intramuscular drug. Prior studies have highlighted how, in at least some instances, substantial numbers of patients with positive STD screening test results go untreated,27 and in general, each step in a medical care continuum is associated with attrition.28 In other words, each new potential impediment to successful care leads to some patients going untreated. We believe that the promotion of parenteral therapy represents a new potential impediment to care. The extent, if any, to which the increased emphasis on providing ceftriaxone will lead some patients to go untreated is unknown. At present, most Americans with gonorrhea receive ceftriaxone.11 However, persons treated in medical practices that do not stock ceftriaxone on-site, such as many smaller medical practices, may face significant barriers to treatment. Our findings highlight how even a small decrement in treatment among these persons could result in a population-level decline in the effective therapy for gonorrhea. It should be noted that current CDC guidelines are not meant to eliminate all use of oral cephalosporins in the treatment of gonorrhea or to eliminate the use of PDPT. However, at least one state health department in the United States has elected to discourage the use of PDPT because of concerns related to antimicrobial resistance, and anecdotally, we have observed medical providers in Washington State who stopped using PDPT because of concerns related to resistant N. gonorrhoeae. This occurred despite the fact that less than 2% of all N. gonorrhoeae isolates obtained from heterosexuals in King County, WA, in 2011 had a cefixime MIC of at least 0.12 μg/mL. Efforts to monitor how changes in STD treatment guidelines affect the proportion of persons who go untreated are needed. Also, at least in the United States, public health communications designed to educate medical providers on the threat of resistant gonorrhea need to better delineate the scale of the current problem from the longer-term threat.

The effect of changing treatment guidelines could be different in Europe and the United States, reflecting differences in the current epidemiology of gonorrhea in the 2 areas. Based on the definition used for our model (i.e., cefixime MIC ≥0.125 μg/mL), decreased susceptibility N. gonorrhoeae was over 4 times as common in Europe as in the United States in 2011. Also, at least in 2011, relatively resistant organisms in the United States were highly concentrated in MSM, whereas in Europe, they were more common in heterosexuals. Because of these differences, as well as our model parameterization in which oral therapy use is more common in heterosexuals than in MSM, we found that the beneficial effects of increasing ceftriaxone use on the successful treatment of decreased susceptibility N. gonorrhoeae would likely be greater in Europe than in the United States, although there is still some risk that the change would decrease the number of infected persons treated overall.

Our findings are subject to a number of limitations. First, as indicated above, we do not have precise estimates for several of the parameters used in our model. Also, in some instances, such as our estimate of the effect of PDPT on partner treatment, the parameters used in our model came from results of a randomized trial; the effect of PDPT in actual practice may be different from those seen in the trial. Second, our findings are based on a simple instantaneous model of gonorrhea treatment that evaluates the effects of different treatment scenarios among index cases and their sex partners. The model does not assess longer-term effects on transmission, and it ignores network effects and provides no information on how different treatment scenarios might affect the prevalence of antimicrobial resistant gonorrhea over time. A dynamic mathematical model would be useful in evaluating these longer-term outcomes, although it would also be more speculative because many parameters related to the natural history and transmission dynamics of gonorrhea are unknown, and the patterns of sexual mixing among persons within the population are not well defined. Finally, although we examined how our results changed when we varied key assumptions in our model, our sensitivity analyses were not exhaustive. We have made our excel spreadsheet model available online for readers who wish to explore how changing other parameters might alter our findings.

In conclusion, our findings highlight how efforts to promote the use of intramuscular therapy for gonorrhea could potentially backfire, leading to increased gonococcal transmission. There is widespread consensus that ceftriaxone-based regimens should be the preferred therapy for gonococcal infections, and our model findings should not be interpreted as a challenge to that consensus. At the same time, at least at present, clinicians in the United States and perhaps in some parts of Europe should remain mindful that a regimen of cefixime and azithromycin is likely to be effective for most patients infected with N. gonorrhoeae and that ensuring the treatment for patients and exposed sex partners is a higher priority than ensuring that every patient receives ceftriaxone. Over the longer term, our findings highlight the need to develop new oral gonorrhea treatment regimens.

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