Updates

By Carol A. Kemper, MD, FACP

Outcomes in patients with XDR TB

Pietersen E, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: A cohort study. Lancet 2014: dx.doi.org/10.1016/S0140-6736 (13)62675-6.

The escalating presence of XDR TB in South Africa has created a public health crisis, squeezing already scarce public health dollars. While drug resistant TB represents a small percent of the total TB case load in South Africa, the cost of care for those patients soaked up nearly half of the government’s entire TB budget for 2010 (about $126 million USD). In 2011, more than 8000 cases of MDR TB were identified in South Africa, at least 500 of which were confirmed XDR by culture (defined as multi-drug resistance plus resistance to a fluoroquinolone and either capreomycin, amikacin or kanamycin). Current South African health policy dictates that persons with XDR TB should be admitted to one of 3 designated treatment facilities until culture conversion, death, or treatment failure.

To evaluate outcomes of patients with XDR TB, a cohort of 107 patients receiving medical treatment based on the results of extended susceptibility and genotypic testing, HIV treatment as needed, and hospital care were followed from 2008 to 2012. The median age was 33 years, 54% were male and 41% were HIV positive (median CD4 count 365 cells/ml). They received a median of 8 anti-tuberculous drugs, ranging from 6 to 10 agents. Agents most frequently used included Terizodone (a cycloserine derivative) (in 93%), capreomycin (in 92%), para-aminosalicylic acid (in 90%), pyrazinamide (in 78%), clarithromycin (in 75%), ethionamide (in 64%), and amoxicillin/clavulanate (in 61%). Clofazimine, for which we no longer have access in the United States, was used in 21%.

Isolates were obtained every month to determine smear and culture status, and phenotypic susceptibility testing to rifampicin, isoniazid, ofloxacin, amikacin and ethionamide was performed at the discretion of the treating physician. A subset of 56 isolates was genotyped, with spoligotyping and targeted DNA sequencing to identify mutations conferring resistance. Of these, 36 (64%) were resistant to 8 or more agents. Resistance to a greater number of agents was more commonly associated with the Beijing genotype.

At 24 months, nearly half (46%) of the patients had died, 23% were failing therapy, and 7% had interrupted therapy for 2 or more consecutive months. Only 17 (16%) were considered treatment cures and/or had completed therapy.

At 60 months, 73% had died, 10% were failing therapy, and only 12 (11%) were considered treatment cures and/or had completed therapy. Patients discharged from hospital died within an average of 19 months (range, 4 to 26 months).

Sputum culture conversion (defined as 2 negative sputums at least 30 days apart) was observed in 22 patients (21%), with a median time of 8.7 months (range, 5.6 to 26 months). Time to culture conversion was not associated with a better outcome. Mortality in patients with culture conversion was 27% (all 6 of whom had HIV). Predictors of response to therapy included no prior history of MDR TB, the use of clofazimine, and antiretroviral therapy in those with HIV.

Clusters of XDR cases were identified within families and communities. Many of these patients were younger, in the prime of their life, and had families they were supporting. The economic cost of drug resistant TB is enormous, and despite maximal care, the mortality is high. Countries with constrained resources may end up making tough choices, if they wish to continue to support their existing TB control programs.

Anti-NDM-1 compound found

King Am, et al. Aspergillomarasmine A overcomes metallo-beta-lactamase antibiotic resistance. Nature 2014;510:503-6. ProMED-mail post. June 25, 2014; Antibiotic resistance – new meatallo-beta-lactamase (NDM-1) inhibitor. www.promedmail.org

Researchers have discovered an inhibitor of NDM-1 enzyme, which may be useful in treating human infection due to these impossibly resistant organisms. The compound derives from a fungus found in soil samples from Nova Scotia. Original efforts to identify a compound that could effectively inhibit the actual bacteria itself from more than 10,000 soil compounds taken from across Canada and maintained in a library proved fruitless. But the investigators tried a different tack. They examined compounds that might inhibit the actual NDM-1 enzyme — and found one — called Aspergillomarasmine A (AMA for short), derived from Aspergillus versicolor.

In murine models infected with NDM-1-containing Klebsiella pneumoniae, 95% of the mice survived when treated with a carbapenem antibiotic plus AMA. The exact mechanism of action on the NDM-1 enzyme is not yet understood. It may be analogous to clavulanic acid, which has only weak antibacterial activity against most organisms, but is a potent inhibitor of many bacterial beta-lactamase enzymes. Beta-lactamases generally work in two different ways: metallo-beta-lactamases use zinc ions at the active site of the enzyme to hydrolyze beta-lactams – and serine beta-lactamases, such as the "KPC" and "OXA" carbapenemases, which attack serine at the active site of the enzyme. For example, clavulanate is considered a "suicide inhibitor" of many of the beta-lactamase enzymes by covalently bonding to this serine residue – this compound is then attacked by another amino acid molecule, which permanently deactivates the enzyme.

There is a long slog ahead to demonstrate the safety and efficacy of AMA in humans. But the mice fared well.

Yelp — a resource to public health departments

CDC Using online reviews by restaurant patrons to identify unreported cases of food borne illness – New York City, 2012-2013. MMWR 2014;63: 441-5.

New York being a mecca for restaurants, the New York City Department of Health and Mental Hygiene (DOHMH) maintains a telephone hot line and website for reporting possible food borne illness. They receive more than 3000 calls per year, approximately 1% of which prove to be related to an outbreak of food borne illness. It turns out that people more often report food borne illness on social media websites like Yelp than to their local public health departments. In fact, many people may not be aware that their local public health departments are interested in this information.

Recognizing this problem, the New York City DOHMH began a pilot project in conjunction with Yelp, the business review website, in 2012. The DOHMD reviewed data feed from Yelp restaurant reviews on a weekly basis containing the keywords sick, vomit, diarrhea and food poisoning. To select for reviews pointing to possible outbreaks and not just illness in one person, a narrower set of criteria were applied including reviews describing scombroid-like illness in one person or >2 people with similar complaints, incubation times > 10 hours, and reviews posted within 4 weeks of the meal.

Of 294,000 restaurant reviews posted during the 9-month period, possible food borne illness was described in 983. Close scrutiny of these reviews by a food-borne epidemiologist winnowed this number down to 499, 468 of which were reported in a timely manner. A total of 129 reviews described illness in 2 or more people. This amounted to close review of 23 reviews per week on average, with a weekly average of 13 requiring further investigation. Only 15 (3%) of these had also been reported to the public health department hot-line.

From these 129 reviews, investigators were able to contact 27 (21%) restaurant patrons for more information. From these, the DOHMH identified 3 food-borne outbreaks at 3 different restaurants accounting for 16 illnesses, not previously recognized. Likely food items involved house salads, a shrimp and lobster cannelloni special, and macaroni and cheese spring rolls. The reviews were posted within 2-5 days of the meal. Investigations of the 3 restaurants identified multiple violations of public food safety code (in fact, a routine inspection a week earlier had already identified problems with one of the restaurants). Only 22% of the reviewers indicated awareness of the automated telephone system for reporting food borne outbreaks.

Restaurant reviews may be an excellent resource for public health departments looking for cases of food borne illness. Responses to PHDs could be enhanced by linking PHD websites to business review websites.