Date: January 23rd, 2015

Guest Skeptic: Nadia Awad is an assistant professor of emergency medicine at the Ernest Mario School of Pharmacy at Rutgers University, and the emergency medicine pharmacist at Robert Wood Johnson University Hospital Somerset.

She serves as associate editor and staff blogger of the blog, Emergency Medicine PharmD where she regularly contributes her thoughts, ideas, and clinical pearls related to her experiences in emergency medicine pharmacy and academia.

Nadia also is the co-host of the EMPOWER Podcast. She is actively involved in research in areas that include emergency medicine, toxicology, disaster preparedness, acute neurocritical care, and social media in pharmacy education. She is a strong supporter of all that Free Open Access Medical Education (FOAMed) has to offer, and she hopes to continue to have a fulfilling experience in both learning from and contributing to this outstanding and inspiring effort.

Screen Shot 2015-01-24 at 10.20.41 AMCase Senario: 28-year-old male who presents to your emergency department with a three-day history of urethral discharge and moderate to severe dysuria. He lives with his wife and denies, denies, denies any other sexual contacts. He reports experiencing a similar problem occurring shortly after his bachelor party last summer. On physical exam, you note the presence of a yellowish urethral discharge and bilateral inguinal adenopathy, which is moderately tender to palpation. A swab of the urethral discharge is collected, but the results of the gram stain will not be made available for a few days. You note that his chart states that he has an allergy to ceftriaxone, and when you question him further regarding the type of reaction that occurred, he states to you that the last time he was treated for this, he developed an anaphylactic reaction to the drug. You would like to empirically treat him for gonorrhea and chlamydia.

Question: What viable options do we have in the empiric treatment of gonorrhea in the patient who has a cephalosporin allergy or if there are concerns related to cephalosporin-resistant infections?

Background: For any clinician who really wants to get a good handle and better appreciation of how antimicrobial resistance has really affected the way we treat infections, look no further than the history and evolution of how we have managed gonococcal infections over the past century.

The evolution of treatment strategies for the management of gonorrhea over the past century is rather fascinating and disheartening. We have exhausted the use of penicllins, sulfonamides, tetracyclines, and fluoroquinolones for the treatment of this condition.

In 2011, due to treatment failures, decreased in vitro susceptibility, and greater demonstrated efficacy for pharyngeal infection, the Centers for Disease Control and Prevention (CDC) recommended higher doses of ceftriaxone to be used for gonococcal infection (250 mg from 125 mg administered parenterally as a one-time dose).

Concerns related to an increase in the number of isolates of gonorrhea that exhibited elevated minimum inhibitory concentrations (MICs) to cefixime prompted the CDC to no longer recommend the use of oral cephalosporins for the treatment of gonorrhoea. And just in 2013, the CDC named gonorrhoea as one of the top three diseases considered to be an urgent threat to the United States.

Actions recommended to address the increase in cephalosporin-resistant gonococcal infection included increased public awareness and preparedness by public health agencies and studies to be conducted related to alternative treatment regimens and combinations of therapy as well as the clinical development of novel agents to manage this condition.

Reference: Kirkcaldy et al. The Efficacy and Safety of Gentamicin Plus Azithromycin and Gemifloxacin Plus Azithromycin as Treatment of Uncomplicated Gonorrhea. Clinical Infectious Diseases 2014

  • Population: Patients between the ages of 15 to 60 years of age who were seen at outpatient sexually transmitted disease (STD) clinics within the United States with “suspected infection” of Neisseria gonorrhoeae of the urethra or cervix
    • Definition of “suspected infection”:
      • Untreated urethral or cervical infection with N. gonorrhoeae identified via gram stain
      • Laboratory testing from previous visit demonstrating gonococcal infection
      • Untreated patient with history of anal, oral, or vaginal sexual contact with someone with gonococcal infection within past 60 days
  • Intervention:
    • Single-dose combination of gentamicin 240 mg IM (or 5 mg/kg IM if ≤ 45 kg) and azithromycin 2 g PO OR
    • Single-dose combination of gemifloxacin 320 mg PO and azithromycin 2 g PO
      • Treatments were offered after ingestion of a small snack.
      • Participants were observed for a minimum of 30 minutes following administration of either intervention
      • Participants were instructed to contact study coordinator or return to clinic if vomiting occurred within 30 minutes of departure from the clinic
      • If vomiting occurred within 1 hour, patients were discontinued from the study and re-treated per standard of care at respective clinics
  • Control: None
  • Outcome:
    • Primary Outcome: Microbiological cure: defined as negative follow-up culture for urogenital N. gonorrhoeae at 10 to 17 days after receipt of study medication
    • Secondary Outcomes: Microbiological cure of pharyngeal and rectal infection, tolerability of each regimen, and antimicrobial susceptibility of enrollment isolates
  1. Exclusion Criteria:
    1. Patients under 15 years of age or greater than 60 years of age
    2. History of renal insufficiency
    3. History of hepatic insufficiency
    4. History of cardiac arrhythmia
    5. History of neuromuscular disorder
    6. History of rheumatoid arthritis
    7. History of tendon disorder
    8. Recipient of kidney, lung, or heart transplant
    9. Pregnancy or lactation
    10. Allergy or previously documented adverse reactions to macrolides, aminoglycosides or fluoroquinolones
    11. Concomitant infection requiring systemic antimicrobial therapy (besides chlamydia)
    12. Recipient of systemic or intravaginal antimicrobials within 30 days of study enrolment
    13. Current use of corticosteroids, immunosuppressive therapy, or medications for cardiac arrhythmias
    14. Clinically diagnosed abdominal pain related to pelvic inflammatory disease, testicular pain, epididymitis, disseminated gonococcal infection, or genital ulcer disease
    15. Females with bacterial vaginosis at enrollment who did not wish to defer treatment for BV until the follow-up visit

Authors’ Conclusions: “The results of this trial indicate that the combinations of azithromycin plus gentamicin or gemifloxacin exhibit excellent efficacy for treatment of uncomplicated urogenital gonorrhea. Cephalosporin resistance in N. gonorrhoeae is expected to emerge, and these combinations may be helpful for patients infected with ceftriaxone-resistant gonococci or patients with severe cephalosporin allergy. This trial provides much-needed data in the short term, but additional treatment options for gonorrhea are urgently needed.”

checklist-cartoonQuality Check List for Randomized Control Trials: 

  1. The study population included or focused on those in the emergency department. No
    • Comment: Although the study population represented those patients who may typically present to the emergency department with suspected signs and symptoms of uncomplicated gonococcal infection, the study was conducted in outpatient clinics across five cities within the United States.
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. No
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results:

  • Primary Outcome:
    • 100% microbiological cure achieved in those patients treated with gentamicin and azithromycin (lower 1-sided exact 95% CI bound, 98.5%) of 202 patients in per protocol analysis
    • 99.5% microbiological cure achieved in those patients treated with gemifloxacin and azithromycin (per protocol analysis, lower 1-sided exact 95% CI bound, 97.6%) of 199 patients in per protocol  analysis
  • Secondary Outcome:
    • All patients included in the study with pharyngeal gonorrhea and rectal gonorrhea were microbiologically cured

Screen Shot 2015-01-24 at 9.16.24 AM

  • Tolerability: Mostly gastrointestinal adverse events in safety analysis:
    • Mild to moderate nausea: 25.9% gentamicin/azithromycin versus 40.3% gemifloxacin/azithromycin
    • Diarrhea: 17.4% gentamicin/azithromycin versus 22.1% gemifloxacin/azithromycin
    • Vomiting within 1 hour: 3.3% gentamicin/azithromycin versus 7.7% gemifloxacin/azithromycin
  • Antimicrobial susceptibility: Percentage of isolates with elevated minimum inhibitory concentrations at or above breakpoint prior to treatment for N. gonorrhoea.
    • Azithromycin: 0.5%
    • Gentamicin: 0%
    • Gemifloxacin: 17.1%

Screen Shot 2015-04-25 at 3.11.12 PM

  • Nadia Awad PharmD

    Dr. Nadia Awad

    Male to Female Ratio: Compared to the male population, a large proportion of females who were randomized and treated were excluded from analysis in the study due to negative bacterial cultures upon enrollment (48.7% female versus 11.8%). However, this may be representative of the fact that gram-stain may not be as reliable for diagnosis of gonorrhea in females compared to males (D’Angelo LJ, Mohla C, Sneed J et al. J Adolesc Health Care 1987; 4:344-348).

  • Pregnancy: The elimination of pregnant patients within this study makes it difficult to apply these results to the general population. The current standard of treatment with ceftriaxone is pregnancy category B, as is azithromycin. However, gemifloxacin and gentamicin are pregnancy category C and D, respectively, although these categories will be removed by the FDA in the future and replaced with alternative labeling, and it will be interesting to see the implications of these labeling changes with respect to recommended regimens in the management of all disease, including gonorrhea.
  • Diagnostic Testing: Results from gram stain and culture may be limited and inadequate for detecting infection in specimens obtained from the endocervical canal, urethra, or urine. Nucleic acid amplification tests (NAATs) obtained from these specimens may be necessary for detection of gonococcal infection (MMWR Recomm Rep. 2014; 63(RR-02):1-19).
  • Synergy: As per the CDC guidelines, azithromycin 2 g orally as a single dose can be offered as an alternative in those patients with a documented cephalosporin allergy. This study incorporated the use of this treatment option along with either gentamicin IM or gemifloxacin PO. Future studies with these regimens may entail the evaluation to determine if efficacy and safety were associated with synergy between the combination of azithromycin with either agent or due to one drug alone.
  • Patient History: The management of STIs is heavily dependent on patient history in addition to clinical signs and symptoms. In this study, pharyngeal and rectal specimens were only obtained if patients reported exposure, which may lead to an underestimation of the actual number of patients infected in these areas. The types of questions asked by clinicians of patients related to sexual history were not described. This may also be problematic since a period of 10 to 17 days elapsed before a follow up visit was conducted, which may have allowed for possibility for additional sexual activity and/or re-exposure.
  • Tolerability: The incidence of gastrointestinal adverse events across both treatment arms in this study was not insignificant, but did occur less frequently in those patients who received gentamicin in combination with azithromycin compared to those who received gemifloxacin in combination with azithromycin. Is it warranted and/or practical to provide suspected infected patients with a prophylactic antiemetic and/or small snack in the ED prior to treatment with either combination of agents?
  • Susceptibility Patterns: The authors do note that interpretation of the number of isolates demonstrating an elevated MIC breakpoint with gemifloxacin is not well defined. While this may require further analysis for determination of clinical relevance in in relation to treatment for gonococcal infection, interpretation of these values may not reasonably occur within the ED setting.
  • Implications with Antimicrobial Stewardship for STIs in the Emergency Department: Although antimicrobial stewardship is becoming a common practice for culture follow up in patients who are discharged from the emergency department, more often than not, these patients are often empirically treated prior to being discharged following the collection of gram-stains and/or Nucleic Acid Amplification Tests. For most EDs, nearly all culture results for gonorrhea and other STIs will return negative or positive with no further results provided related to antimicrobial susceptibility. Since resistance is becoming a growing issue related to this condition, additional mechanisms may need to be in place to allow for reported susceptibility patterns, which may lead to additional resources and costs associated with treatment.

Our Conclusions Compared to Authors’: Overall, this was a well-intentioned study aimed to evaluate the efficacy and safety of viable alternative treatment options in the era of increased resistance in gonococcal infection.

Although the authors did demonstrate similar rates of microbiological cure with combination treatment regimens consisting of gentamicin and azithromycin as well as gemifloxacin and azithromycin, due to better tolerability and superior antimicrobial susceptibility patterns, it may be reasonable to prefer the combination treatment regimen of azithromycin with gentamicin versus azithromycin with gemifloxacin.

However, it may be reasonable to conduct future studies evaluating the feasibility of these treatment regimens within the ED setting, since many practical factors associated with this study as pointed out above may need to be further delineated to determine overall applicability of the findings of this study to our patient population.

The Bottom Line: Azithromycin in combination with either gentamicin or gemifloxacin administered as one-time dose are highly effective and generally tolerable in managing otherwise healthy patients with suspected uncomplicated gonococcal infection.

Case Resolution: You offer your 28-year-old patient empiric treatment for his gonococcal infection, and highlight that two antimicrobial regimens may be used as a potential cure for his infection: two oral agents as a single dose or one parenteral and one oral agent as one-time doses.

You discuss with him that although the combination of these agents have not had widespread utilization for the treatment of this condition, they have been shown in small populations to be associated with cure of his infection, which may be especially helpful in his case given his previous history of infection as well as his allergy to cephalosporins, the standard treatment of this condition.

You counsel him related to the potential for adverse effects, mainly gastrointestinal in nature, and he decides to choose the combination of parenteral gentamicin and oral azithromycin for empiric therapy. He receives treatment with no adverse effects noted, and prior to discharge, you advise him related to safe sexual practices.

You also inform him that it is essential that he notify his sexual partner regarding the need for evaluation and treatment for the same infection.

Clinical Application: This study provides us with potential alternative options that may be used for the management of suspected uncomplicated gonococcal infection in patients who may be at increased risk for resistance or in those patients who have a cephalosporin allergy.

What Do I Tell Patients? The combination of azithromycin with either gentamicin or gemifloxacin administered as one-time doses will likely cure your suspected gonococcal infection, as the combination of agents has been found to be safe and effective in otherwise healthy patients.

Keener Kontest: Last weeks winner was Matthew Marschall from the Philadelphia College of Osteopathic Medicine. Matt knew that in addition to decreasing the rate of COPD, quitting smoking has the FIVE following benefits:five+fingers

  1. Lower risk of lung cancer, and other types of cancer
  2. Reduced risk for coronary heart disease, stroke, and peripheral vascular disease.
  3. Reduced coronary heart disease risk within 1 to 2 years of quitting
  4. Reduced respiratory symptoms, such as coughing, wheezing, and shortness of breath. The rate of decline in lung function is slower among people who quit smoking than among those who continue to smoke
  5. Reduced risk for infertility in women of reproductive age. Women who stop smoking during pregnancy also reduce their risk of having a low birth weight baby.

Listen to the SGEM podcast for this weeks question. If you think you know the answer send me an email to TheSGEM@gmail.com with “keener/gunner” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

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