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By Carol A. Kemper, MD, FACP
Failure of treatment: M. genitalium and macrolides
Salado Rasmussen K, et al. Mycoplasma genitalium testing pattern and macrolide resistance: A Danish Nationwide retrospective survey. CID 2014;59:24-30.
Manhart, LE. Diagnostic and resistance testing for Mycoplasma genitalium: What will it take? CID July 2014; 59:31-32.
Declining rates of response to standard treatment for non-gonococcal urethritis (NGU) may prompt changes in accepted treatment strategies. Current guidelines recommend the use of either single dose azithromycin 1 gram or doxycycline 100 mg twice daily x 7 days for patients with NGU, as defined by mucupurulent or purulent urethral discharge or a urethral swab with > 5 white blood cells per HPF in the absence of gonorrhea; or a positive nucleic acid amplification test (NAAT) for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU) or Trichomanas vaginalis (TV).
However, rates of response to these standard first-line regimens are declining, especially those infections due to M. genitalium. Response rates to single dose azithromycin in 3 recent U.S. studies ranged from a high of 77% in New Orleans to as low as 40% in Seattle. While there remains a significant debate regarding the potential of Mycoplasma genitalium to cause symptomatic infection in both men and women, it is apparent that current treatment protocols do not adequately cover this organism and that many failures of treatment for symptomatic urethritis are likely due to M. genitalium. Doxycycline is also now widely ineffective against this organism.
Unlike the United States, testing for M. genitalium has been performed on a routine basis in Denmark since 2003, allowing a retrospective epidemiologic analysis and survey of resistance patterns. From 2006 to 2010, a total of 31, 600 specimens from 28,958 persons were submitted for testing for M. genitalium by PCR. The number of positive specimens increased from 3858 in 2006 to 7,361 in 2010 — with an observed increase of 2.4% to 3.8% in women, and an increase of 7.9% to 10.3% in men during this period.
More than half of the specimens were submitted by general practitioners, with positive results in 5.7% of specimens, and 40% of the patients were men. In contrast, gynecologists submitted one-third of the specimens, most of whom were women, and rates of infection were lower at 2.0%. STD clinics tested 11% of the patients, with 10.4% being positive.
Beginning in 2007, specimens were tested for macrolide resistance using a rapid pyrosequence assay testing for mutations in the 23S rRNA gene. Macrolide resistance was detected in 38% of specimens — but was highest in patients being seen at STD clinics (43%).
It is anticipated that newer CDC STD guidelines will provide, for the first time, recommendations on testing for M. genitalium — although many of the commercially available tests have not yet been approved by the FDA, and resistance testing is not incorporated.
PET-CT for fever of unknown origin
Gafter-Gvili A, et al. FDG-PET/CT for the diagnosis of patients with fever of unknown origin. QJM September 9th, 2014. Advance Access.
FUO remains often — by definition — a puzzle. While I love a good puzzle as much as the next ID doc, I especially enjoy one I can solve. When discussing the work up with patients and their families, I often liken it to peeling an onion — take away one layer, and then another, until the problem is finally revealed. But the process can be frustrating and stressful for patients and their families, with prolonged work ups and multiple studies. Now, consider adding one more study for use in the work up of FUO. PET/CT scanning may help to target and characterize an area of inflammation, infection, or malignancy.
These authors performed a 4-year retrospective analysis of the utility of FDG — PET/CT scanning in patients hospitalized for the evaluation of FUO at the Rabin Medical Center in Tel Aviv. From 2008 to 2012, PET/CT scan was performed in 112 adults (> 18 years of age) with FUO. FUO was defined as fever lasting 3 or more weeks without a diagnosis following a minimum one-week work up (either inpatient or outpatient). Patients with HIV infection and neutropenia were excluded from study. All of the patients underwent a standard battery of tests, including cell counts, chemistries, sed rates, blood cultures and various serologies, but specific studies, including CT scans, MRIs, echocardiograms, etc. were at the discretion of the treating physicians.
PET/CT scans were considered positive when they led to the confirmation or localization of a disease process, either by culture or pathology. A negative study was defined as one in which no disease process was identified, and the fever resolved without a diagnosis, and the patient remained well for the next 6 months of follow up.
Nearly three-fourths (74%) of the patients received a final diagnosis, which included infection (43%), non-infectious inflammatory disease (16%), malignancy (14%) or other (2%). FUO resolved in 20% of patients without a diagnosis and the patients remained afebrile for 6 months of follow-up. Six patients (5%) died with fever and no diagnosis.
PET Scans in 69 patients were abnormal — and were useful in helping to solve the diagnosis in 52 patients (true-positives). Abnormal scans in the remaining 17 patients were considered falsely-positive, either because no disease was identified and the fever resolved with no sequelae for the next 6 months; or because an alternate diagnosis was made, and the scan proved non-contributory. PET scans were negative in 43 of the cases. Based on these findings, the sensitivity of PET scanning in the work up of FUO was 72% and specificity was 57%. Overall, PET scanning was felt to be useful in 66% of cases. Of those scans that were true-positives, 31 infections were diagnosed (60%), including pneumonia (in 7 cases), endovascular infections, including infections of aortic graft material, femoral graft material, endocarditis, infected pacemakers x 2, infected stents x 2); but also included hepatic abscess, septic arthritis, occult osteomyelitis, occult pyelonephritis, epidural abscess, as well as one case each of CMV colitis, TB and nocardia.
Fourteen of the true-positive PET scans led to diagnosis of malignancy (meaning that PETs were useful in diagnosing 14 of 15 cases of malignancy), including 9 cases of lymphoma, 2 cases of non-Hodgkin’s lymphoma, 2 cases of lung cancer, and a sarcoma. Nine of these cases presented an initial diagnosis of malignancy, and six were relapses of an earlier malignancy.
Twenty-three scans were considered true negatives — but 6 cases were eventually diagnosed with infections based on other means, including three cases of Q fever, 2 cases of mononucleosis, and one case of urosepsis — but the scans were considered true negatives because PET scanning would not be considered useful in these conditions.
While these results are limited to patients hospitalized for FUO, and only retrospective in design, this is the largest collection of FUO patients studied to date. These data are consistent with other studies of PET scanning as a diagnostic tool — although the authors believe that FDG PET/CT may be more useful than PET alone — and the addition of FDG contrast may provide even better results. When considering the next step in your FUO work up, it is best to keep in mind that PET scanning remains inherently limited by the anatomic nature of its results — and is therefore not useful in certain infections, like those based on serologic results, or inflammatory disorders, such as vasculitis. But I can immediately see the utility, especially in patients with occult graft infection, where nuclear studies have been negative.