In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

• Fecal Transplant for Recurrent C. diff Infection: A Systematic Review
• A Novel Hemoplasma Species Causes Human Fever and Anemia
• Antibiotic Resistance: Predating the Modern Antibiotic Era by 30,000 Years
• When to Start ART in HIV-Infected Adults on Pulmonary TB Therapy
• Appearance of HIV-1 Drug Resistance Across Africa: Time Is of the Essence

Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases.

Fecal Transplant for Recurrent C. diff Infection: A Systematic Review

Reviewed by George R. Thompson III, MD

Reduced clinical response rates and increased recurrence rates in patients with Clostridium difficile infection (CDI) have prompted an exploration of treatment alternatives. One potential, although seldom used, alternative is intestinal microbiota transplantation (IMT), or stool transplantation. Safety and acceptability concerns have limited its use. A recent systematic review on the use of IMT published in Clinical Infectious Diseases provides a summary of current practice and outcomes and suggests future research on this poorly understood intervention.

More than 2,000 publications and abstracts were reviewed, with 27 titles selected for final analysis, representing 317 patients. IMT was highly effective, showing resolution of disease in 92 percent of cases. Although a single treatment is often used, resolution was lowest in patients receiving only one treatment (87.5 percent). Those receiving <3 and >3 treatment courses had slightly higher response rates (95.7 percent and 90.0 percent, respectively).

The lowest resolution rates were in patients receiving IMT via gastroscope or nasojejunal infusion (76.4 percent) compared to patients treated via colonoscopy (88.7 percent), enema (95.4 percent), or rectal catheter (95.6 percent).

Donor-related factors also appear to play an important role. Stool from a related donor showed a slightly higher resolution rate (93 percent) compared to unrelated donor stool (84 percent). Interestingly, IMT from a spouse or partner was associated with the highest resolution rates (96 percent).

Stool prepared in saline showed a slightly lower response rate (86.2 percent) then that prepared in water (98.5 percent). Pre-IMT treatment with vancomycin or metronidazole also appeared helpful, with response rates of 91.5 percent in these groups. Adverse events were uncommon, and none could be directly attributed to IMT.

Although the authors are to be commended for their exhaustive summary of the published literature, multiple questions remain given the lack of comparative trials and heterogeneity treatment protocols. However, their findings are a helpful resource when more “palatable” options have been exhausted.

(Gough et al. Clin Infect Dis. 2011;53:994-1002.)

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A Novel Hemoplasma Species Causes Human Fever and Anemia

Reviewed by Rachel Simmons, MD

A recent case report published in Clinical Infectious Diseases describes a novel human pathogen and highlights the potential of molecular diagnostics for both diagnosis and monitoring of new and difficult to culture pathogens. Investigators from the United Kingdom described the case of a middle-aged woman with chronic moderate neutropenia who developed fever and hemolytic anemia shortly after returning from a trip to Australia and Singapore. She had persistent fever, hepatosplenomegaly (liver biopsy was unrevealing), and hemolysis.

The patient improved somewhat after empiric treatment with multiple antibiotics including piperacillin/tazobactam and doxycycline and prednisolone for possible autoimmune disorder. However, approximately three weeks after antibiotics were stopped, she presented with fever, anemia, and thrombocytopenia. Ultimately, bone marrow biopsy showed hemophagocytosis. Doxycycline was restarted, and she improved quickly. Bone marrow tissue was submitted for 16s ribosomal PCR, and the PCR product was found to be very similar to Mycoplasma haemomuris (a veterinary hemoplasma species) and Candidatus Mycoplasma turicensis. The woman was treated with doxycycline for three weeks, and shortly thereafter, suffered another clinical relapse. She improved rapidly with resumption of doxycycline.

Repeat bone marrow biopsy was positive for hemoplasma DNA by qPCR, but cultures for mycoplasma and ureaplasma species were negative. Sequencing, phylogeny, and PCR confirmed that her illness was caused by a novel hemoplasma (hemotropic mycoplasma) species that is now called Candidatus Mycoplasma haemohominis. The patient was monitored with serial blood panhemoplasma qPCR and ultimately treated with six months of doxycycline and moxifloxacin with clinical improvement and no additional relapses. It is unclear how she acquired the infection, and both her husband and her dog tested negative.

(Tasker et al. Clin Infect Dis. 2011;53(11): e147-e151.)

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Antibiotic Resistance: Predating the Modern Antibiotic Era by 30,000 Years
Reviewed by Christopher J. Graber, MD, MPH

A research letter recently published in Nature highlights the omnipresence of antibiotic resistance by finding homologues to modern antibiotic resistance genes in 30,000 year-old permafrost in the Yukon territory.

At the Bear Creek site east of Dawson City, Yukon, Canada, the authors recovered sediment cores from an area of permafrost immediately overlain by distinctive volcanic ash estimated by carbon dating to be 30,000 years old. After a thorough process to exclude contamination and to confirm the presence of DNA derived from flora and fauna of the late Pleistocene age, the authors amplified gene fragments corresponding to the tetracycline resistance gene tetM, the vancomycin resistance operon vanHAX (which contains the vanA gene typically found in vancomycin-resistant enterococci), and the beta-lactamase bla (a member of the TEM group of beta-lactamases).

These findings confirm that antibiotic resistance is an ancient, naturally occurring phenomenon that significantly predates our use of antibiotics. The presence of pre-existing resistance determinants that have been present in the microbial pangenome for thousands of years may help to explain why resistance to newly developed antibiotics can occur so quickly and further emphasizes the importance of antimicrobial stewardship in resistance avoidance.

(D’Costa et al. Nature 2011;477:457-61.)


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When to Start ART in HIV-Infected Adults on Pulmonary TB Therapy
Reviewed by Ed Dominguez, MD

The most common infectious cause of death in HIV-infected individuals is tuberculosis (TB). The optimal time to integrate antiretroviral therapy (ART) with pulmonary TB therapy is unknown. Three studies in the Oct. 20 issue of The New England Journal of Medicine investigated this issue.

In South Africa, 642 patients with CD4+ T-cell counts less than 500/cu mm were randomized to one of three different treatment sequences for commencing ART. Two sequences were analyzed: earlier integrated-ART (within four weeks after initiation of TB treatment) and later integrated-ART (within four weeks after completion of the intensive phase of TB treatment). While there were no differences in the rate of AIDS-defining illness or death, the 72 patients with a baseline CD4+ count of less than 50/cu mm experienced a lower rate of  AIDS illness and death but a higher rate of immune reconstitution inflammatory syndrome (IRIS), with two attributable deaths.

A second study randomized 809 patients with CD4+ counts less than 250/cu mm to ART within two weeks after initiation of TB treatment or ART between eight and 12 weeks after initiating TB treatment. As in the first trial, the rate of AIDS-defining illness or death was reduced in the 285 patients with CD4+ counts below 50/cu mm, but the rate of IRIS was increased.

Finally, a Cambodian study of 661 HIV-infected patients with TB and CD4+ counts of less than 200/cu mm randomized patients to one of two treatment groups: ART initiated two weeks or eight weeks after the start of TB treatment. Unlike the previous studies, this study showed a reduction in mortality in the early-ART group, but with an increased frequency of IRIS, including six fatalities. Taking the different study designs into consideration, an accompanying editorial suggests initiating ART two to four weeks after TB therapy may be beneficial for patients with lower CD4+ counts. For those with higher counts, deferring therapy until patients are on a two-drug regimen may be more practical. Unfortunately, when to initiate ART in patients with extra-pulmonary TB remains unanswered.

(Blanc et al. N Engl J Med. 2011; 365:1471-1481; Havlir et al. N Engl J Med. 2011; 365:1482-1491; Karim et al. N Engl J Med. 2011; 365:1492-1501; and Török and Farrar. N Engl J Med. 2011; 365:1538-1540.)

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Appearance of HIV-1 Drug Resistance Across Africa: Time Is of the Essence

Reviewed by Christian B. Ramers, MD, MPH

Wherever antimicrobial therapy is introduced, drug resistance almost uniformly follows. In the United States, an estimated 16 percent of newly acquired HIV infections harbor important resistance mutations, a steady rise since the introduction of anti-retroviral therapy. These rates make pre-treatment genotype testing an important and cost-effective intervention. Because the large-scale introduction of antiretroviral therapy (ART) began in Africa only in 2004, resistance has not generally been an immediate concern. A study in the October issue of Lancet Infectious Diseases investigating resistance rates across Sub-Saharan Africa shows some surprising heterogeneity.

This large, cross-sectional study across six countries (Kenya, Nigeria, South Africa, Uganda, Zambia, and Zimbabwe) included 2,436 treatment naïve individuals from 2007 to 2009. The authors performed population-based sequencing of the pol gene on all plasma specimens with more than 1,000 copies per mL of HIV RNA. They identified known resistance mutations, calculated the prevalence of mutations by site, and using logistic regression, determined risk factors for resistance.

Overall prevalence of HIV-1 drug resistance was 5.6 percent (95 percent CI 4.6-6.7 percent), but varied widely by sites. Uganda, the nation with the longest ART history, had the highest rates of resistance (11.6 percent overall and 12.3 percent in urban Kampala). The most common mutations (in decreasing order of prevalence) were: K103N, TAM’s, M184V, and Y181C. The authors calculated an odds ratio for the appearance of drug resistance of 1.38 (95 percent CI 1.13-1.68) for each additional year of ART availability. Despite the use of single-dose nevirapine for the prevention of mother-to-child transmission in some settings, women did not seem more likely than men to harbor resistance.

These results have important implications for deciding how best to allocate limited resources in HIV-related care. While individualized genotypic testing is not currently available in Africa, perhaps national HIV-1 resistance surveillance should be considered. In addition, routine virologic monitoring and potency of first- and second-line regimens are important factors in the struggle against these rising rates of drug resistance.

(Hamers et al. Lancet Infect Dis. 2011; 11(10):750-59.)

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