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.

Metronidazole Neurotoxicity Is Real

SOURCE: Daneman N, Cheng Y, Gomes T, et al. Metronidazole-associated neurologic events: A nested-case control study. Clin Infect Dis 2020 Apr 18;ciaa395. [Online ahead of print].

For many years, in anecdotal reports and small series, metronidazole has been suspiciously related to the onset of encephalopathy, cerebellar findings with ataxia, tremor and nystagmus, and peripheral neuropathy but this association has never been proven. The central nervous system findings were thought to be largely reversible and did not appear to be dose-related, whereas the peripheral nervous system findings appeared to be possibly dose- and duration-related.

To examine the effects of metronidazole nervous system toxicity, the authors performed a large-scale, population-based, nested case-control study of adults ( 66 years of age) living in Ontario, Canada. Cases were defined as those with cerebellar dysfunction, encephalopathy, or peripheral neuropathy within 100 days of receipt of either metronidazole or clindamycin (but not both), sometime between 2003 and 2017. Every case was matched by at least 10 patients without such symptoms, who also received metronidazole or clindamycin within the preceding 100 days and who served as controls. The average age of the cases was 78 years.

A total of 1,212 cases were identified and compared with 12,098 controls. Both central and peripheral nervous system adverse effects remained significantly more frequent in those receiving metronidazole, even when the analysis was adjusted for age, demographics, comorbidities, and other medications. The overall incidence of metronidazole neurotoxicity was 0.25%. Central neurologic complications were more than four times more likely than the occurrence of peripheral neuropathy. No dose response was observed. The mechanism behind these effects has not been defined.

Although this frequency of neurotoxicity may seem relatively small, metronidazole is used increasingly for many serious anaerobic infections in the hospital, as well as for outpatient infections, such as trichomonas and orodental infections. In the United States alone in 2017, more than 12,657,000 prescriptions were written for metronidazole. These data suggest that up to 2.5 million people were possibly at risk for CNS toxicity and another 625,000 for peripheral neuropathy from their drug exposure. This is definitely something to keep in mind when evaluating patients with neurologic complaints on metronidazole.

2020 Updated LTBI Treatment Guidelines

SOURCE: Sterling TR, Njie G, Zenner D, et al. Guidelines for the treatment of latent tuberculosis infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020;69:1-11.

I like to explain to patients (with drawings) the risk of progression of their latent tuberculosis infection (LTBI) to active tuberculosis (TB) is about 7% or one in 13 people. Line up 13 people with LTBI, and one of them will develop active TB. And, as you age, or if you develop diabetes or kidney disease, or need chemotherapy for any reason, that risk goes up to one in five. You get their attention, it sounds like you know what you are talking about, and it is especially effective if you add that they may be contagious and infect their kids or coworkers. Somehow if you say the risk is 5% to 10%, it does not sound as bad. Maybe people do not understand percentages. And what they really may not understand is that despite all of our modern care, the risk of mortality from active TB in the United States is a surprising 4% worse than with COVID-19.

In the United States, 80% of active TB cases are due to progression of untreated LTBI. And at least 70% of active TB cases occur in foreign-born persons, many of whom do not want to believe they have been exposed to TB or understand the concept of latent TB. Capturing those individuals and treating them is important for controlling this infection in our communities.

The last official LTBI treatment guidelines were written in 2000. Since then, a nine-month course of isoniazid (INH) has been considered the standard of care for the treatment of LTBI in the United States, and was the comparator regimen for all others. New guidelines, published in February 2020, escaped most physicians’ notice coming just as COVID-19 hit. A committee formed by the Centers for Disease Control and Prevention (CDC) and the National Tuberculosis Controllers Association reviewed all available publications and treatment data, focusing on 63 publications with meaningful data on LTBI treatment. They systematically graded the outcomes, including the benefits, hepatotoxicity, adverse effects, patient preference, regimen complexity, and cost, as well as the quality of the published data.

The committee simmered down their findings to recommend three rifamycin-based regimens and two alternate six- or nine-month isoniazid monotherapy regimens for LTBI treatment. They gave priority to shorter-course regimens with similar efficacy, higher rates of completion, and favorable tolerability compared with the former standard nine-month regimen of INH. Benefits and disadvantages presented are relative to this previous standard:

1. Three months of INH and rifapentine:

  • Strongly recommended for adults and children > 2 years of age, including HIV-positive persons;
  • Benefits: Equivalent effectiveness, less hepatotoxicity, shorter course, higher rates of completion when administered through directly observed therapy (DOT);
  • Disadvantages: More adverse effects, higher cost, greater regimen complexity and higher pill burden, and lower rates of completion when not done through DOT.

2. Four months of rifampin:

  • Strongly recommended for HIV-negative adults and children of all ages;
  • Benefits: Similar effectiveness, less hepatotoxicity, fewer adverse effects, shorter course;
  • Disadvantages: Numerous drug interactions; difficult to give in HIV infection; medication costs are higher (although offset by shorter course/fewer visits, may be more cost-effective on the whole).1

3. Three months of daily INH and rifampin:

  • Conditionally recommended for adults and children of all ages, including HIV-positive persons when their regimen allows;
  • Benefits: Similar effectiveness, lower risk of hepatotoxicity, and shorter course;
  • Disadvantages: Higher rate of discontinuation for other adverse effects; risk for hepatotoxicity may be greater when both drugs given together; and numerous drug interactions.

4. Six months of INH:

  • Strongly recommended for HIV-negative adults and children of all ages; conditionally recommended for HIV-positive adults and children;
  • Benefits: Highly effective, but perhaps not quite as effective as nine or 12 months of INH (controlled data are lacking), inexpensive, shorter than nine months of INH;
  • Disadvantages: Hepatotoxicity, longer treatment duration than the other proposed regimens, lower completion rates.

5. Nine months of INH:

  • Conditionally recommended for adults and children of all ages, regardless of HIV status;
  • Benefits: Highly effective, inexpensive;
  • Disadvantages: Hepatotoxicity, longer treatment duration, lower completion rates.

It is important to keep in mind these guidelines are for patients with LTBI presumed sensitive to therapy. Recommendations for treatment of exposure to drug-resistant strains of TB were published separately in 2019. However, even in our northern California county, the risk of INH resistance among those with culture-positive TB with no prior history of TB who were born in the United States is 5%, and among those who are foreign-born it is 13%. INH resistance is highest in those born in Vietnam (18%), the Philippines (17%), and India (11%). Approximately 3% of all culture-positive TB cases in Santa Clara County were resistant to rifampin. Perhaps this is another reason to consider a rifamycin-based regimen.


  1. Bastos ML, Campbell JR, Oxlade O, et al. Health system costs of treating latent tuberculosis infection with four months of rifampin versus nine months of isoniazid in different settings. Ann intern Med 2020; June 16. doi: 10.7326/M19-3741 [Online ahead of print].

Risks of Hookah Smoking

SOURCE: International Society for Infectious Diseases. ProMED-Mail. Tuberculosis — Switzerland: Hookah usage. Dec. 27, 2019.

Smoking a hookah pipe is a centuries-old social custom in some societies. A pipe filled with “shisha” or flavored tobacco is passed around in a group, sometimes for hours, often at a hookah cafe. The same mouthpiece is shared, and the device may or may not be cleaned well between uses. Dried tobacco is combined with fruit pulp, molasses, and/or honey or other flavorings like coconut, mint, or coffee. This lends a sweet quality to the smoke which when drawn through a water bath gives the impression to many that smoking a hookah is safer than smoking cigarettes. Apparently, this is not the case: The tar from charcoal-burned tobacco in a hookah may be diminished by the water bath, but many of the cancer-causing chemicals, hydrocarbons, and metals found in today’s tobacco are not filtered out by the water bath. But it is not just the chemicals: An average hookah contains as much tobacco as 20 filtered cigarettes. The nicotine hit from a hookah is every bit as real and as addictive as smoking cigarettes. Further, the temperature of the smoke when heated electronically in newer hookahs, rather than by older charcoal versions, may be cidal to lung cells.

A recent University of California study found that one good draw on a hookah was similar to smoking one filtered cigarette, in terms of hazardous chemicals and metals. Further, the amount of carbon monoxide inhaled during one hookah session was similar to smoking 12 cigarettes.

Another adverse effect from sharing a hookah is the spread of oral and respiratory infections, such as herpes simplex, syphilis, and tuberculosis. While the water bath may filter out larger particles, it actually creates ultra-fine particles that can pass directly to the deeper parts of the lungs. Some extra-fine particles (< 0.1 micron) may pass directly through lung tissue into the bloodstream.

This Pro-MED-Mail report identified a 20-year-old man with cavitary tuberculosis (TB). He was a regular hookah smoker, and smoked at least five times per week with friends. The authors theorize that regular hookah smoking increased his risk for TB, with close, high-level contact, and spread of microparticles from the mouthpiece. Alternately, frequenting hookah cafés, crowded with people smoking and coughing, also could increase the risk for TB exposure. One wonders if the hot smoke may increase the risk of more severe bacterial or viral lung infection via repeated damage or inflammation to the tissues, similar to vaping.