By Carol A. Kemper, MD, FACP

Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center

Dr. Kemper reports no financial relationships relevant to this field of study.

Intestinal Yeast Revisited — With a New Angle

SOURCE: Malik F, Wickremesinghe P, Saverimuttu J. Case report and literature review of auto-brewery syndrome: Probably an underdiagnosed medical condition. BMJ Open Gastroenterol 2019;6:e000325.

Although auto-brewery syndrome (ABS) may be a little-recognized medical condition, it has provided a theoretical defense for cases of driving under the influence (DUI). ABS occurs when selected yeasts and fungi in the small intestine and cecum ferment carbohydrates to alcohol, leading to occult intoxication. While some yeast naturally colonize the colon of healthy individuals, certain strains of Candida and Saccharomyces cerevisiae (brewer’s yeast) can abnormally colonize the small intestine and cecum, where they can convert carbohydrates to endogenous alcohol. In an earlier study of teetotalers in the Middle East, researchers detected low levels of blood alcohol in some individuals simply from endogenous gut production. Patients with disturbances in gut flora from prior antibiotic use or inflammatory bowel disease may be more likely to develop ABS.

The authors report the saga of a previously healthy 46-year-old man whose life was virtually ruined by ABS. He had been arrested for DUI, had several traumatic falls when inebriated (including an intracerebral hemorrhage), despite protestations that he had not been drinking, and ended up being cared for in a nursing facility. He claimed he had been fine until he was treated with three weeks of Keflex for a traumatic injury, after which he developed intermittent periods of confusion, mental deterioration, aggression, and depression. Blood alcohol levels were measured at various times from 50 to 400 mg/dL.

During an investigation by curious physicians, his blood alcohol level was observed to increase by ~57 mg/dL following a carbohydrate challenge. Both S. cerevisiae and Saccharomyces boulardii were isolated in stool cultures; cultures obtained from the upper small gut and cecum grew C. albicans and C. parapsilosis. He was treated sequentially with a carbohydrate-free diet, fluconazole 150 mg daily for 14 days, nystatin three times daily for 10 days, and then increasing doses of itraconazole, without much success. He then received micafungin 150 mg daily for six weeks — and it worked. Carbohydrates were re-introduced gradually into his diet, he received probiotics, and resumed a fairly normal, inebriate-free life.

To establish the diagnosis, the authors suggest standardization of the procedures, with a standardized carbohydrate challenge, e.g., 200 g glucose, following overnight fasting, with serial blood alcohol levels obtained between 0 to 24 hours. Delayed blood draws may be necessary since some yeasts are slow fermenters.

Patients feasibly could monitor their own blood alcohol levels using an over-the-counter breathalyzer — although these devices require regular calibration with fresh reagents and careful maintenance or they may provide false readings. A recent New York Times exposé suggested that many professional breathalyzers are not properly calibrated or maintained and are potentially inaccurate.

Preemptive Steroids for TB/HIV Treatment

SOURCE: Meintjes G, Stek C, Blumenthal L, et al. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS. N Engl J Med 2018;379:1915-1925.

Immune reconstitution inflammatory syndrome (IRIS) during tuberculosis (TB) treatment occurs in 18-54% of HIV-infected patients and carries significant morbidity, frequently resulting in high-dose steroid use and prolonged hospitalization. Despite the survival benefit of antiretroviral therapy (ART), earlier initiation of HIV medications has been shown to significantly increase the risk of IRIS in patients being treated for TB. Patients with newly diagnosed TB and HIV infection, therefore, often are started on TB medications first, with delayed initiation of ART for one to two months, depending on their CD4 count.

This research team examined whether the addition of modest doses of prednisone for four weeks could reduce the risk of TB IRIS in patients who had started TB treatment within 30 days and who were just beginning ART. A total of 240 patients were randomly assigned to receive ART plus prednisone 40 mg daily for two weeks and then 20 mg daily for two weeks, or ART plus identical-looking placebo. Most patients were male (60%); their median CD4 count was 49 cells per microliter (range, 24-86 cells per microliter), and their median viral load was 5.5 logs. Patients had received anti-tuberculous medications for a median of 17 days before beginning ART. Patients with uncontrolled diabetes, Kaposi sarcoma, neurological or pericardial TB, or those who received non-standard TB therapy were excluded.

The preemptive addition of prednisone when beginning ART therapy reduced the risk of TB-associated IRIS by ~30%. IRIS symptoms occurred in 32.5% of those in the prednisone group compared to 46.7% of the placebo group (relative risk [RR] 0.7, P = 0.03). Open label steroids were prescribed for IRIS signs and/or symptoms in 13% of the prednisone group vs. 28.3% of the placebo group. Hospitalization was required in 14% of the prednisone group vs. 22.5% of the placebo group. Nine patients died, including five in the prednisone group. Interestingly, the risk of invasive bacterial infection and AIDS-defining infection was not dissimilar between the two groups (11 patients in the prednisone group vs. 18 patients in the placebo group, P = NS). The onset of IRIS symptoms was similar between the two groups, occurring within a median of 10 days in the prednisone group and eight days in the placebo group.

Modest doses of preemptive steroids administered for four weeks in patients being treated for TB, along with their ART therapy, reduced the risk of IRIS by about 30%, and fewer such patients required high-dose glucocorticoids to control IRIS symptoms. Side effects were minimal, and investigators did not observe an increased risk of invasive bacterial infection or AIDS-related infections. The dose of prednisone used for preemptive therapy was fairly low compared to that recommended for actual treatment of IRIS symptoms (1 to 1.5 mg/kg body weight) — and was not dose-adjusted for concurrent use with rifampin (which may have further lowered the prednisone dose).

Fluoroquinolone for Exposure to Drug-Resistant Tuberculosis

SOURCE: Malik AA, Fuad J, Siddiqui S, et al. TB preventive therapy for individuals exposed to drug-resistant tuberculosis: Feasibility and safety of a community-based delivery of fluoroquinolone-containing preventive regimen. Clin Infect Dis 2019 Jun 12. pii: ciz502. doi: 10.1093/cid/ciz502. [Epub ahead of print].

For household contacts of persons with drug-resistant tuberculosis (DR-TB), the risk of acquiring tuberculosis (TB) is approximately 20-47%, and the risk of developing active TB disease may be as high as 10-20%. As a result, in 2018, the World Health Organization recommended that high-risk contacts of persons with DR-TB receive preemptive treatment for TB.

In Karachi, Pakistan, at least 400 cases of DR-TB occur annually. The authors of this study prospectively examined the use of oral fluoroquinolone therapy in high-risk household contacts of such patients. From 2016 to 2017, researchers contacted 800 contacts from 100 households of patients with DR-TB for evaluation and possible study participation. Only household contacts of patients with DR-TB were considered (including those with fluoroquinolone-resistant strains, but not those with extensively drug-resistant TB).

Community health workers evaluated household contacts within two to four weeks of the index case enrollment in a treatment facility. A total of 737 household contacts were screened, 11 of whom were already being treated for TB, and three were found to have active TB. Those who were eligible for study treatment included all children younger than 5 years of age; any child between 5 and 17 years of age with a positive skin test or HIV, diabetes, or malnutrition; or any adult 18 years of age or older with diabetes, HIV, or malnutrition.

Two-hundred fifteen contacts were eligible for study; 172 initiated therapy and 121 completed the course of treatment (70.3% completion rate). Participants received one of four different regimens for six months, including either levofloxacin (weight-based, maximum dose 1,000 mg daily) plus either ethambutol or ethionamide, or moxifloxacin (weight-based, maximum dose 400 mg daily) plus either ethambutol or ethionamide. During the study, researchers monitored the participants every two months by either a telephone call or home visit, and then for a year following the completion of treatment. About 20% reported one or more side effects from the medications, and dose-limiting side effects were the main reason for premature treatment discontinuation. Side effects were less frequent with the combination fluoroquinolone plus ethambutol compared to the combination of fluoroquinolone plus ethionamide (14.2% vs. 33.5%, respectively).

This completion rate of 70.3% for six months of preventive TB therapy is tremendous — and for those who completed therapy, 96% completed 12 months of additional follow-up. (For each study visit, the participants received a small stipend ~$6 US for travel time and expenses.) None of the household contacts developed TB disease during study or the 12 months of follow-up. The authors recommended the combination of fluoroquinolone plus ethambutol for chemoprophylaxis of high-risk household contacts of DR-TB, since it seemed to be tolerated better.