In the JournalsPerspective

Contact with MDR-TB led to latent infection in some children

After contact with a teacher diagnosed with multidrug-resistant pulmonary tuberculosis, 31 children developed latent infection, according to recent study results published in The Pediatric Infectious Disease Journal.

Felice C. Adler-Shohet, MD, of the department of infectious diseases at the Children’s Hospital of Orange County, and colleagues evaluated the treatment and diagnosis of children who had contact with the infected teacher (index case) to determine the best route of treatment.

Twenty-one children in the teacher’s classroom had a positive tuberculin skin test and the remaining 10 had exposures through homework club, day care, circle time activities, or were in an adjoining classroom separated by a loose, swinging door with a gap at the top.

Therapy with levofloxacin and pyrazinamide was started in 26 patients, and 58% completed at least 9 months of therapy. Treatment was refused by parents of five children with a positive test. Forty-six percent of the patients who started therapy needed an alteration of therapy due to adverse effects. At 24 months of follow-up, none of the patients developed active TB.

Adverse effects attributed to medication were reported by every patient. Arthralgias and myalgias, abdominal pain and elevated hepatic enzymes were the most common symptoms. Eleven of the 26 patients who started the two-drug therapy were switched to levofloxacin alone after adverse effects. All adverse effects resolved after drug withdrawal.

“Because of the toxicity associated with two drug fluoroquinolone containing regimens for MDR-[latent] TB [infection], patients should only be started on this regiment if they are highly likely to be infected with MDR-TB and if they are at high risk of progression to active disease, eg, young children, [tuberculin skin test] converters, and the immunocompromised,” the researchers wrote. “Children on these regimens should have transaminases checked monthly and be monitored for new gastrointestinal symptoms or toxicity. Alternate regimens should be considered based on susceptibilities. Several of the study children received fluoroquinolone monotherapy when they could not tolerate [levofloxacin] and [pyrazinamide], which may be a possible alternate regimen for MDR-[latent] TB [infection]. This regimen has been suggested by the Curry International Tuberculosis Center, though it is not endorsed by any national guidelines. This appears to be better tolerated; however, the effectiveness in preventing progression to active TB disease is unknown.”

Disclosure: The researchers report no relevant financial disclosures.

After contact with a teacher diagnosed with multidrug-resistant pulmonary tuberculosis, 31 children developed latent infection, according to recent study results published in The Pediatric Infectious Disease Journal.

Felice C. Adler-Shohet, MD, of the department of infectious diseases at the Children’s Hospital of Orange County, and colleagues evaluated the treatment and diagnosis of children who had contact with the infected teacher (index case) to determine the best route of treatment.

Twenty-one children in the teacher’s classroom had a positive tuberculin skin test and the remaining 10 had exposures through homework club, day care, circle time activities, or were in an adjoining classroom separated by a loose, swinging door with a gap at the top.

Therapy with levofloxacin and pyrazinamide was started in 26 patients, and 58% completed at least 9 months of therapy. Treatment was refused by parents of five children with a positive test. Forty-six percent of the patients who started therapy needed an alteration of therapy due to adverse effects. At 24 months of follow-up, none of the patients developed active TB.

Adverse effects attributed to medication were reported by every patient. Arthralgias and myalgias, abdominal pain and elevated hepatic enzymes were the most common symptoms. Eleven of the 26 patients who started the two-drug therapy were switched to levofloxacin alone after adverse effects. All adverse effects resolved after drug withdrawal.

“Because of the toxicity associated with two drug fluoroquinolone containing regimens for MDR-[latent] TB [infection], patients should only be started on this regiment if they are highly likely to be infected with MDR-TB and if they are at high risk of progression to active disease, eg, young children, [tuberculin skin test] converters, and the immunocompromised,” the researchers wrote. “Children on these regimens should have transaminases checked monthly and be monitored for new gastrointestinal symptoms or toxicity. Alternate regimens should be considered based on susceptibilities. Several of the study children received fluoroquinolone monotherapy when they could not tolerate [levofloxacin] and [pyrazinamide], which may be a possible alternate regimen for MDR-[latent] TB [infection]. This regimen has been suggested by the Curry International Tuberculosis Center, though it is not endorsed by any national guidelines. This appears to be better tolerated; however, the effectiveness in preventing progression to active TB disease is unknown.”

Disclosure: The researchers report no relevant financial disclosures.

    Perspective
    Andrea T. Cruz

    Andrea T. Cruz

    WHO and the AAP have been recommending treatment of at-risk children for latent tuberculosis infection (LTBI) for decades. Isoniazid monotherapy, when taken as prescribed, is very efficacious to prevent progression to disease caused by drug-susceptible isolates. Management of children infected with MDR-LTBI isolates is less clear. Second-line medications for TB tend to be less efficacious and more toxic than first-line medications. As there are no clinical trials comparing efficacy of different regimens for MDR-LTBI, one approach is to use a first-line drug (eg, ethambutol or pyrazinamide) to which the isolate is susceptible, often combined with a fluoroquinolone.

    The article by Adler-Shohet and colleagues in The Pediatric Infectious Disease Journal describes this approach when caring for a cohort of elementary school children with MDR-LTBI after contact with a teacher. Almost one-half of children required a change from the initial regimen of pyrazinamide and levofloxacin due to adverse events that resolved after cessation of therapy. Despite how well children tolerate first-line TB medications, abdominal complaints, transaminitis, and musculoskeletal complaints were very common with this regimen. This article raises several important issues. One issue is the need for more data to determine the optimal number of drugs to include in an MDR-LTBI regimen. Is fluoroquinolone monotherapy sufficient? Some studies have indicated that potentially ethambutol combined with a fluoroquinolone may be better tolerated than pyrazinamide-containing regimens. Another issue is the frequency of adverse events. Children receiving LTBI regimens containing drugs other than isoniazid and rifampicin may require frequent clinical and biochemical monitoring, as well as more comprehensive anticipatory guidance for the children and their caregivers.

    • Andrea T. Cruz, MD
    • Department of Pediatrics Sections of Infectious Diseases and Emergency Medicine at Baylor College of Medicine

    Disclosures: Cruz reports no relevant financial disclosures.

    Perspective
    Jeffrey R. Starke

    Jeffrey R. Starke

     This study by Adler-Shohet et al. describes the effort to treat 31 children – though only 26 took treatment - with tuberculosis (TB) infection likely caused by a multidrug-resistant (MDR) strain of M. tuberculosis (Mtb) after exposure to a teacher who had pulmonary TB that was resistant to isoniazid (INH), rifampin (RIF) and ethambutol (Trecator, Wyeth; EMB) but susceptible to pyrazinamide (PZA) and levofloxacin (LEVO). The children, who ranged in age from 6 to 13 years, were treated initially with LEVO and PZA for a planned course of 9 months, as recommended by the CDC. The good news is that none of the children developed TB disease. The bad news is that every child developed at least one significant adverse reaction, and only 14 children completed 9 months of LEVO with or without PZA. Many of the adverse reactions, particularly arthralgias and myalgias, abdominal pain, and elevated serum hepatic enzymes, likely were caused by PZA. Photosensitivity could have been caused by either PZA or LEVO. These results mirror those found with the short-lived CDC recommended regimen of 2 months of PZA and RIF to treat drug-susceptible latent tuberculosis infection, a regimen that was effective but was not tolerated by a large proportion of adults to whom it was administered. PZA is a difficult drug and patients who are otherwise healthy often have a low tolerance for it.

    The truth is that we have no idea how to treat TB infection that is resistant to INH and RIF because there have been no clinical trials. It is important to remember that the vast majority of children of school age who become infected with Mtb will not develop TB disease even without treatment. We are used to the excellent risk:benefit ratio afforded by INH; we know the risk of using other drugs like LEVO and PZA but we do not know the benefit yet. Most experts think that treatment of MDR TB infection should be attempted and a fluoroquinolone antibiotic should be the mainstay of treatment. It is unclear if a second drug adds any positive effect. If the organism is susceptible to EMB, it is probably a better choice than PZA because it is tolerated better. In Houston, we have tended to use LEVO as a single drug but the majority of adolescents who have received it have experienced at least one adverse reaction similar to those described in this paper. The bar for stopping therapy when significant adverse reactions occur should be pretty low.

    • Jeffrey R. Starke, MD
    • Professor of pediatrics at Baylor College of Medicine and infection control officer at Texas Children's Hospital, Houston.

    Disclosures: Starke reports no relevant financial disclosures.