Delayed Culture Conversion, Low Serum Drug Levels

 

 

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Case History

Our patient is a 54 year-old male who presented to his physician for follow up of a right upper lobe carcinoma which was ressected in 1979. He complained of shortness of breath, weight loss, fatigue, chest pain and a productive cough but no hemoptysis. A chest x-ray on June 20, 2006 revealed new bilateral alveolar infiltrates. He was referred to a pulmonologist and admitted to his hometown hospital on June 20, 2006. Smears were positive for acid fast bacilli and a CT scan June 22nd showed cavitation in the left upper lobe, bilateral infiltrates and mediastinal adenopathy. He was placed on anti-tuberculosis therapy—isoniazid (INH) 300 mgs, rifampin(RIF) 600 mgs, pyrazinamide (PZA) 1500 mgs and ethambutol (EMB) 1600 mgs daily with vitamin B6 50 mgs. Directly Observed Therapy(DOT) was started on July 7, 2006; given Monday through Friday with self-administration on the weekends. His culture grew Mycobacterium tuberculosis and was susceptible to INH, RIF and EMB.

The patient’s past history included long term tobacco and alcohol abuse. He reported marijuana use in the past but denied intravenous drug abuse. He received medical disability since his lung resection in 1979. He had chronic obstructive pulmonary disease(COPD). He also was positive for Hepatitis C.

His PZA and EMB were discontinued on August 31, 2006 at the normal 2 month mark. The patient’s sputum smears and cultures remained consistently positive through September 15, 2006. His sputum cultures remained positive for pansensitive pulmonary TB. While there was slight clinical improvement, the positive cultures nearly 4 months into therapy made him a possible treatment failure. He was referred to the Texas Center for Infectious Disease (TCID) for evaluation and management.

He was admitted to TCID on November 21, 2006. He weighed 149 pounds (5’9”), blood pressure was 177/100, respirations were 26 and irregular, and his pulse was 99. His films showed a stable right upper lobe nodular opacity compatible with tuberculosis. His laboratory findings on admission were: WB C 10.4, hemoglobin 12.9, hematocrit 40.4, platelets 271, metabolic panel was normal except for an albumin of 3.5. Urinalysis was significant for positive nitrate and trace leucocytes however no WBC were seen and there was no growth at 48 hours. Serum INH level was low at 1.29 (3-6 adequate) on 300 mg per day and serum RIF was low at 4.29 (8-24 adequate) on 600 mg per day.

The patient’s treatment at TCIDwas augmented with reinstitution of PZA, EMB, and additional treatment with levofloxacin and amikacin. These were continued for 4 weeks. Based on the low serum levels, INH was increased to 600 mg and RIF was increased to 900mg daily. His course at TCID was unremarkable; his last positive culture was obtained October 5, 2006. This isolate remained susceptible to all drugs. His sputum cultures converted to negative as of October 7, 2007 although his sputum smears remained AFB positive (less than 1 organism per field) through April 4, 2007. His LFTs remained stable throughout treatment.

The patient was discharged December 18, 2006 back to his home with DOT Monday through Friday and self-administered therapy on the weekends to completion of 6 months post-culture negativity. Patient completed DOT on April 19, 2007.

Teaching Points

Treatment Failure

  • Patients with continued or recurrently positive cultures after three months should be evaluated critically to ascertain the reason for delay. Possible reasons include:
    • Nonadherence
    • Drug resistance
    • Malabsorption
    • Laboratory error
    • Extreme biological variation in response
    • Unrecognized vomiting
  • Patients with persistently positive cultures after four months are considered treatment failures.
    • The patient in this case study had positive cultures from July 7, 2006 (his treatment start date) through October 5, 2006. Although there were no specific risk factors for malabsorption noted in his health history (e.g. severe gastrointestinal or metabolic abnormality), serum drug level results confirmed subtherapeutic absorption of isoniazid and rifampin.
  • Serum drug level monitoring enabled the treating physician to:
    1. appropriately identify the cause of treatment failure,
    2. safely increase isoniazid and rifampin daily doses by 100 and 50 percent, respectively, without inducing hepatotoxicity, and
    3. achieve treatment completion and cure.
  • There are several situations where serum drug level monitoring may be helpful:
    • Evaluating cause of treatment failure
    • Persons with a medical condition that may result in abnormal pharmacokinetics of first line drugs
    • Management of MDR or XDR TB (Refer to PDF document for chart)
  • Protocols for obtaining serum drug levels are available through the Heartland National TB Center or National Jewish Medical Center

Never add a single drug to a failing regimen

  • In patients diagnosed with treatment failure until drug resistance is ruled out through repeat susceptibility testing, patients should be treated with at least two and preferably three new drugs to which they are susceptible:
    • In this case, PZA and EMB were reinstituted, and levofloxacin and amikacin were added for four weeks until drug susceptibilities were known. Had the patient beendrug resistant, the levofloxacin and amikacin would have been an effective start in progressing the patient towards cure and would have protected against the amplification of drug resistance

Tobacco abuse and TB

  • Although not historically considered syndemic, several recent studies out of India have found that smoking may be a significant risk factor for TB disease and TB deaths
  • Meta-analysis of TB disease and tobacco abuse in India suggest that smoking may double or triple the risk for TB disease
  • TB deaths may be doubled in any smokers and tripled in “bidi” or homemade cigarette smokers
  • There is some biological plausibility to increased TB disease and death due to the following smoking related effects:
    • Diminished immune response
    • CD4 lymphopenia
    • Defects in macrophage immune response
    • Mechanical disruption of the cilia function in airways
  • The authors of these studies suggest that potentially modifiable risk factors that lead to TB infection, disease and death, such as tobacco smoking, should be targeted for prevention

Request consultation

  • Treatment failure is rare and difficult to manage. Managing treatment failure should be in close consultation with an expert
  • For state by state expert TB consultation in the Heartland region, use the following web link http://www.heartlandntbc.org/medical.asp or contact the HNTC Medical Consultation Service directly at 1-800-TEX LUNG (1-800-839-5864)

References

Bates, M. N. et al. Risk of TB from Exposure to Tobacco Smoke: A systemic review and meta-analysis [Review Article]. Archives of Internal Medicine. Vol 167(4), 26 Feb 2007 pp. 335-342.

CDC. Treatment of Tuberculosis. Morbidity and Mortality Weekly Report. June 20, 2003. Vol 52 (RR11); pp. 1-77.

Khan, A. E. and Kimerling, M. E. “Chemotherapy of Tuberculosis” in Tuberculosis and Nontuberculous Mycobacterial Infections, fifth edition. Schlossberg, D., editor. McGraw-Hill, Medical Publishing Division. 2006. p. 87

Pendakar, M. S. et al. Prospective study of smoking and TB in India. Preventive Medicine. Vol 44(6), June 2007 pp. 496-498.

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