Multidrug-resistant tuberculosis (MDR-TB) rates are increasing in several parts of the world.1 Children have up to a 50% risk of becoming infected with TB after close contact with an infectious adult, particularly in the home and school setting.2 While the safety and efficacy for treatment of drug-susceptible latent TB infection (LTBI) and TB in children are well described,3 this information is not available for the treatment of MDR-TB and MDR-LTBI.
A teacher in California developed MDR-TB exposing dozens of children. This retrospective chart review describes our experience with the contact investigation and treatment of those child contacts. The index case was 4+ acid fast bacilli smear positive and culture grew M. tuberculosis resistant to isoniazid, rifampin and ethambutol but susceptible to pyrazinamide (PZA), levofloxacin (LEVO) and ethionamide. The case had contact with dozens of children at a school over a prolonged period within the classroom as well as in other group activities.
MATERIALS AND METHODS
The local health department initiated an extensive contact investigation at the school. A contact was defined as a child who spent ≥ 8 cumulative hours in either the same room as the case or the connected classroom. Contacts were screened with a tuberculin skin test (TST). Contacts who were initially TST negative had a second TST performed 8–10 weeks after contact with the case was broken. Contacts with a second negative TST were dismissed from further follow up.
All TST-positive children (TST ≥ 5 mm induration) were offered LEVO and PZA in liquid or tablet form for treatment of MDR-LTBI. Parents desiring therapy for their child were offered directly observed therapy (DOT) performed at the school by the health department. On weekends and holidays, parents were provided with the medications for self-administered therapy. During spring and summer vacations and for the subsequent school year, the directly observed therapy program was discontinued; the health department provided parents of child contacts with medication for self-administered therapy on a month-to-month basis. All TST-positive children had a chest X-ray to rule out active disease, and they were followed for 24 months. For the first year after exposure, those on treatment were evaluated monthly either by the local health department or by an Infectious Diseases clinician. Patients were questioned and examined for signs and symptoms of TB disease as well as medication adverse effects. All had monthly testing of transaminases with additional testing if clinically indicated. Chest X-rays were performed every 6 months. Families were advised to call immediately if their child had any possible medication adverse effects or symptoms of active TB disease. Completion of therapy was defined as taking at least 9 months of medication. This research study was approved by the Human Subject Review Committee of the health department.
Univariate analysis was performed using PASW Statistics 18 (SPSS, Inc. Quarry Bay, Hong Kong), and statistical significance was defined as P < 0.05. Median number of adverse effects of children who did not complete therapy compared with children who did complete therapy were analyzed using a Mann-Whitney U test for nonnormal data.
In the school setting, 118 children had significant contact with the case and were evaluated. No contact had active TB disease at the time of initial evaluation. Thirty-one children (26.3%) had a positive TST, 21 on initial testing and 10 on repeat testing (Fig. 1). Demographic and clinical characteristics of these 31 children are shown in the Table, Supplemental Digital Content 1, http://links.lww.com/INF/B801. Out of 31 children in the teacher’s classroom, where the case spent the majority time, 21 children (67.7%) had a positive TST. The other 10 children with a positive TST had exposures through homework club, daycare, circle time activities or were in an adjoining classroom that was separated from the case’s classroom by a loose, swinging door with a gap at the top. Five children’s parents refused treatment, 26 children (83.9%) started therapy with LEVO and PZA and 15 (57.7%) completed at least 9 months of therapy. Of these 26 children, 12 (46.2%) required an alteration in therapy due to medication adverse effects (Fig. 1). None of the children developed active TB during 24 months of follow up.
Every child on medication reported at least 1 adverse effect thought to be drug related. Most common symptoms included arthralgias and myalgias (8), abdominal pain (8) and elevated hepatic enzymes (8). Seven children had photosensitivity and 6 each had ankle/Achilles pain, rash, vomiting and/or red eyes. Of the 26 children that started 2-drug therapy, 11 were switched to LEVO alone due to adverse effects of rash (5), hepatotoxicity (5), red eyes (2) and immediate flushing reaction after the first dose of PZA (2). One child was changed to PZA and ethionamide due to a non-urticarial, erythematous rash that developed on LEVO. Eleven children were unable to complete treatment due to medication adverse effects. Children unable to complete treatment were more likely to experience myalgias, arthralgias, Achilles pain or abdominal pain, whereas those who completed treatment were more likely to have elevated transaminases though none of these differences reached statistical significance. Only 1 child had a rise in transaminases >5 times the upper limit of normal; 3 children had transaminases rise 2–4 times the upper limit of normal. One child had night terrors and hallucinations while on LEVO monotherapy requiring discontinuation of treatment. All children had complete resolution of their adverse effects following drug withdrawal. Children who did not complete treatment had a median of 3 (range 1–5) adverse effects versus 2 (range 1–6) in those who did complete treatment (U = 80.0, P = 0.894).
To our knowledge, this is the first report to evaluate LEVO and PZA as treatment for MDR-LTBI in children. Such treatment is controversial due to lack of controlled trials.4,5 Centers for Disease Control and Prevention guidelines recommend using 2 drugs to which the organism is susceptible but caution against the long-term use of fluoroquinolones in children.6 The American Academy of Pediatrics suggests considering a multidrug regimen that may include PZA and a fluoroquinolone.3 It is unclear how large a role treatment of LTBI played in preventing disease in our patients, most of whom were healthy children between 6 and 13 years of age, when early progression to active TB disease following infection is relatively low.7
Our adverse effects rate of 100% is much higher than that seen in 2 previous reports of treatment for MDR-LTBI in children (with no fluoroquinolone use), which ranged from 24% to 49%,5,8 but similar to the 82% rate of adverse effects from another school exposure in California where only 8/26 (31%) were able to complete at least 9 months of therapy with ofloxacin and PZA.9 One study evaluating PZA and LEVO as treatment for MDR-LTBI in adults had equally poor outcomes with all participants having at least 1 adverse effect, and all had to be taken off the medication regimen.10
Despite limited data in children, fluoroquinolones are now recommended as part of a multidrug regimen for treatment of MDR-TB and MDR-LTBI.11 There is no evidence for sustained bone and joint injury in children who receive these drugs though there is a suggestion of increased musculoskeletal adverse events.12 In our cohort, 14 of 26 children had musculoskeletal complaints, in 1 case leading to treatment discontinuation; however, complaints were mild and all symptoms resolved once off therapy. Several pediatric treatment studies that used long-term fluoroquinolones did not report any musculoskeletal adverse effects.5,8 Our rate may have been higher because our patients were older and more active. Parents were also given extensive information regarding possible musculoskeletal adverse effects of LEVO, which may have prompted more reports.
Our study had several limitations. Because it was retrospective and multiple clinicians were evaluating patients, we could not grade the severity of complaints. It was difficult to prove that the medications were responsible for all the adverse effects as many of the symptoms such as abdominal pain are common in pediatrics. However, symptoms all resolved when medication was stopped. Finally, several of the parents were very anxious about the use of these medications. This may have led to over reporting of otherwise common pediatric complaints which may or may not have been medication related.
Because of the toxicity associated with 2-drug fluoroquinolone containing regimens for MDR-LTBI, patients should only be started on this regimen if they are highly likely to be infected with MDR-TB and if they are at high risk of progression to active disease, for example, young children, TST converters and the immunocompromised. Children on these regimens should have transaminases checked monthly and be monitored for new gastrointestinal symptoms or other toxicity. Alternate regimens should be considered based on susceptibilities. Several of the study children received fluoroquinolone monotherapy when they could not tolerate LEVO and PZA, which may be a possible alternate regimen for MDR-LTBI. This regimen has been suggested by the Curry International Tuberculosis Center though it is not endorsed by any national guidelines.13 This appears to be better tolerated; however, the effectiveness in preventing progression to active TB disease is unknown.
The authors thank the following individuals for their contributions to this study: Gisela Schecter, MD, MPH and Lisa True, RN, MSN, California Department of Public Health, Tuberculosis Control Branch, Richmond, CA; Susan Sawley, RN, SPHN, Roseanne Tayag, RN, PHN and Valerie Brooks, RN, County of Orange Health Care Agency, Santa Ana, CA; Lauri Thrupp, MD, University of California, Irvine and Jeffrey R. Starke, MD, Baylor College of Medicine, Houston, TX.
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