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By Carol A. Kemper, MD, FACP

Upgraded recommendations for gonorrhea: A reminder

In 2012, the CDC upgraded their recommendations for treatment of pharyngeal, anorectal, and urogenital gonorrhea to include ceftriaxone (CFTX) 250 mg IM plus either a single dose of azithromycin 1 gram orally or doxycycline 100 mg twice daily orally. This dose of ceftriaxone is believed to be effective for all anatomic sites of involvement, although personal experience with 1 individual as well as individual case reports document failure of treatment for pharyngeal disease, even for isolates with MICs below the resistant breakpoint (0.5 micrograms per mL). It is conceivable that gonorrhea (GC) involving the pharynx may be less responsive to treatment than urethral infection. In one report of 4 cases with oropharyngeal GC who failed single dose cephalosporin therapy, all 4 subsequently responded to CFTX 1 gram intramuscularly or CFTX 250 mg IM plus azithromycin 1 gram orally. Because most pharyngeal infections are asymptomatic, test of cure is essential.

In contrast to the United States, the European gonorrhea guidelines recommend CFTX 500 mg plus azithromycin 2 gram orally for uncomplicated GC. How rigorously these recommendations are being followed and dual treatment is being used in the U.S. and Europe is not known. But evolving resistance in GC isolates around the world continues to threaten our ability to treat this infection – and dual therapy should be mandated.

Also remember that revised CDC guidelines now recommend routine laboratory screening for GC and chlamydia of all genital and extra-genital sites for sexually active men who have sex with men (MSM) using the newer NAAT laboratory screening tests for all 3 anatomic sites. While earlier non-culture tests based on DNA or RNA sequences frequently failed to detect a good number of infections (especially chlamydia), the newer tests are much more sensitive and specific than earlier screening laboratory STD tests.

Treatment options for GC in cephalosporin allergic

Kirkclady RD, et al. The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. Clin Infect Dis 2014;doi10.10903/cid/ciu521.

There is an urgent need for a back-up regimen for the treatment of gonorrhea (GC), especially for patients allergic to cephalosporins or intolerant, or for patients with treatment failure from suspected resistant isolates.

The effectiveness of two different combination regimens for the treatment of uncomplicated GC in persons 15 to 60 years of age was determined in a non-comparative treatment trial at 5 clinical sites across the United States. The two regimens were either gentamicin 240 mg IM (or 5 mg/kg

for those < 45 kg body weight) plus azithromycin 2 gram orally, or gemifloxacin 320 mg orally plus azithromycin 2 grams orally. While it remains effective in the treatment of GC for most isolates, azithromycin is generally not recommended as monotherapy because of the risk of emergent macrolide resistance.

On the other hand, gentamicin is very effective in the treatment of GC, and has been used successfully as monotherapy in some countries, although infrequently used for this purpose in the United States. Gemifloxacin is an oral fourth-generation fluoroquinolone with in vitro activity against ciprofloxacin-resistant strains of GC.

A total of 614 patients were randomized to one of the two regimens; cultures were negative in 117 of these, and these individuals were excluded from the analysis. More than one-third (38%) reported sex between the initial and follow up study visits; 15% did not use a condom.

Microbiologic cure was achieved in 100% of the patients receiving gentamicin/azithromycin, and 97.6% of patients treated with gemifloxacin/azithromycin. All 25 patients with oropharyngeal GC and all 6 with rectal gonorrhea responded to treatment.

The single patient who failed therapy (with gemifloxacin/azithromycin) reported unprotected sex without a condom between visits. His initial isolate was sensitive to all agents tested with an MIC to gemifloxacin of .004; a post-therapy isolate was not available for testing.

Between the two regimens, 26% and 40% of participants reported nausea, and 17% and 22% experienced diarrhea; 7% vomited within an hour of receiving gemifloxacin and azithromycin combined.

Thus, these two regimens appear to be represent reasonable alternatives in patients intolerant/allergic to cephalosporins, although resulted in frequent gastrointestinal side-effects. A total of 421 isolates were available for susceptibility testing. None of the isolates were resistant to gentamicin.

Azithromycin MICs were elevated (breakpoint >2.0 micrograms/mL) in 0.5% of isolates, while gemifloxacin MICs were higher than the breakpoint (> 1.0 micrograms/mL) in 17% of isolates. Most of these MICs were similar or only 1-2 dilutions lower than those for ciprofloxacin.

Thus, gemifloxacin did not appear to provide a significant advantage for ciprofloxacin-resistant isolates as hoped.

Aggressive treatment of MDR TB worth the effort

Velasquez GE, et al. Improving outcomes for multidrug-resistant tuberculosis: aggressive regimens prevent treatment failure and death. Clin Infect Dis 2014;59(1):9-15.

Beginning in 2000, treatment of multidrug resistant (including XDR)-TB in Tomsk, Russia was assisted by the creation of a public-private partnership between the Tomsk public health, the Tomsk Penitentiary TB Hospital, and private funding sources, including the Bill & Melinda Gates Foundation.

A retrospective cohort analysis was performed for 614 patients with MDR/XDR TB who began treatment through this partnership between 2000 and 2004. A multivariate analysis, adjusting for XDR-resistance (resistance to fluoroquinolones plus resistant to an injectable agent) and other risk factors was performed.

Treatment regimens were based on standard algorithms, an assessment of prior treatment history, and the results of drug susceptibility testing, including testing for first- and second-line agents. Most of the patients were treated as inpatients during the first 6-9 months of treatment, and then continued treatment as outpatients for 18 months post culture-conversion. All treatment was administered as directly observed therapy.

A total of 614 patients with confirmed MDR TB were included in the analysis. All but 3 had received prior therapy. One-third had prior exposure to parenteral therapy and 15% had prior exposure to a fluoroquinolone. Half presented with bilateral and cavitary disease. Of these, 92% received what was considered an aggressive regimen, defined as 5 more likely effective agents for the first 6-9 months, followed by at least 4 effective drugs till completion of therapy. First-line drugs at maximal dosages were continued whenever feasible. Patients with resistance to fluoroquinolones nonetheless received treatment with ofloxacin or levofloxacin. The group had limited access to linezolid and imipenem.

The mean duration of treatment was 19 months, with 54 failures and 30 deaths. The median survival for treatment failures was 18 months (range, 11 – 28 months).

Treatment failure was associated with XDR-resistance, as well as a history of 2 or more previous treatment regimens, HIV disease, low BMI at baseline, and severe pulmonary disease at baseline. Extra-pulmonary disease was also a negative risk factor, and increased the risk of death by > 10%.

Monthly exposure to an aggressive regimen was significantly associated with treatment success (hazard ratio .52, p = .03). Although expensive and intensive to administer, and more likely to create problems in terms of compliance and side-effects, a treatment regimen with at least 5 likely effective agents seems to be well worth the effort and expense in these patients at high risk of mortality from their disease.

Screening for hepatocellular carcinoma — an empty proposition?

Kansagara D, et al. Screening for hepatocellular carcinoma in chronic liver disease: A systemic review. Ann Intern Med 2014;161(4):261-269.

Public health authorities report a trend in increasing numbers of cancers; one of these is hepatocellular carcinoma (HCC). Current guidelines recommend routine screening of persons at higher risk for HCC with periodic tumor markers and radiological studies.

These authors contend there is little evidence these measures have an affect on mortality from HCC. An extensive review of the literature was conducted, identifying 22 (English) studies that met criteria. Eighteen observational studies and 2 clinical trials provided little evidence in support of routine screening, using either tumor markers or periodic radiologic screening, in the reduction of mortality. One study of persons with chronic HBV infection found that routine periodic radiological screening was able to identify patients with HCC, with improved mortality rates, but the authors believe the study was flawed. One other study found that periodic alpha-fetoprotein screening was able to identify patients with earlier disease but found no survival benefit.

Perhaps the caveat to this argument is not that routine screening was unable to identify patients with earlier disease, potentially amenable to treatment, but that current treatments for HCC are woefully inadequate. But how are we to know which treatments may, in the future, be effective, if we fail to recognize patients who may be potentially salvageable. Because we don’t have uniformly effective therapies at present, should we stop looking?