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Brief Bactericidal Activity of Anti-Tuberculosis Drugs

Information source: Centers for Disease Control and Prevention
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Tuberculosis; Drug-resistant Tuberculosis; Multidrug-resistant Tuberculosis

Intervention: Capreomycin (Drug); High dose isoniazid (Drug); Rifampicin (Drug); Rifabutin (Drug); Moxifloxacin (Drug)

Phase: N/A

Status: Not yet recruiting

Sponsored by: Centers for Disease Control and Prevention

Official(s) and/or principal investigator(s):
J. Peter Cegielski, MD, MPH, Principal Investigator, Affiliation: U.S. Centers for Disease Control and Prevention

Overall contact:
J. Peter Cegielski, MD, MPH, Phone: +1-404-639-5329, Email: pcegielski@cdc.gov


Multidrug-resistant (MDR) tuberculosis (TB) must be treated with second-line drugs (SLD) that are less effective, more toxic, and more expensive. Treatment requires at least 20 months with 4 or more effective drugs based on timely drug susceptibility test (DST) results. However, there are many examples of closely related drugs with differing antimicrobial activities. Labs have found differences in DST results among the rifamycins, rifampin (RMP) and rifabutin (RBT); the fluoroquinolones, ofloxacin and moxifloxacin; and the second-line injectable agents, kanamycin, amikacin, and capreomycin. In a related finding, isolates resistant to 0. 2 mcg/ml INH may be susceptible to higher concentrations. In the Preserving Effective Tuberculosis Treatment Study (PETTS), 32% of RMP-resistant isolates were susceptible to RBT, 41% of kanamycin-resistant isolates were susceptible to capreomycin, and 45% of isolates resistant to 0. 2 mcg/ml INH were susceptible to 1. 0 or 5. 0 mcg/ml (1). Other studies have demonstrated differences in DST results between moxifloxacin and ofloxacin. Whether these in vitro results translate into clinical efficacy is completely unknown. Given the severely limited treatment options in MDR TB, it would be exceedingly useful to know whether these in vitro results translate into evidence for clinically meaningful treatment decisions. The investigators will determine the clinical bactericidal activity of certain antibiotics against M. tb that appear to be effective in vitro even though closely related drugs from the same class are ineffective in vitro. Further, the investigators propose to determine the molecular genetic determinants of these differences. Specifically, we plan to determine: 1. The bactericidal activity of RBT in patients whose baseline DST results demonstrate susceptibility to RBT and resistance to RMP. 2. The bactericidal activity of high-dose INH in patients whose baseline DST results demonstrate susceptibility to high concentrations of INH and resistance to low concentrations of INH. 3. The bactericidal activity of RMP when an approved molecular assay demonstrates genetic mutations associated with RMP resistance, but the phenotypic testing demonstrates susceptibility to RMP. 4. The bactericidal activity of moxifloxacin in patients whose baseline DST results demonstrate susceptibility to moxifloxacin and resistance to ofloxacin. 5. The bactericidal activity of amikacin and capreomycin in patients whose baseline DST results demonstrate susceptibility to either of these two drugs and resistance to kanamycin. 6. The genetic mutations associated with both in vivo and in vitro drug resistance and bactericidal activity. To achieve these objectives the investigators propose an innovative variation on early bactericidal activity (EBA) study methodology. Patients at risk for MDR TB will be screened for RMP resistance and INH resistance using molecular assays. In those with RMP-resistant or INH-resistant TB, the investigators will quickly perform phenotypic DSTs using the direct method in the Bactec Mycobacterium Growth Indicator Tube (MGIT) 960 system, so results will be available within 14-21 days. If the DST results show, for example, RMP resistance but susceptibility to RBT, consenting patients will be treated with RBT by itself for 10 days. The investigators will assess its effect with serial quantitative sputum cultures. If the concentration of viable bacteria decreases significantly, the investigators will interpret this to mean the drug is having an effect. If not, the drug is ineffective. After 10 days, the patients will resume individualized multidrug treatment based on the full set of DST results. In case the investigators identify drugs that are effective under these conditions, the investigators will sequence known and putative genes associated with the action of these drugs for the mycobacterial isolates from these patients. The results would have immediate implications for treatment of MDR TB and for diagnostic mycobacteriology.

Clinical Details

Official title: Brief Bactericidal Activity of Anti-Tuberculosis Drugs in Drug-Resistant Tuberculosis

Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Decrease in colony forming units per ml of sputum

Secondary outcome: Acquired drug resistance to the assigned drug


Minimum age: 8 Years. Maximum age: N/A. Gender(s): Both.


Inclusion Criteria:

- Written informed consent

- RMP and/or INH resistance by approved molecular genetic test

- Phenotypic drug susceptibility test results match one of the required patterns

- Sputum microscopy positive for acid fast bacilli

Exclusion Criteria:

- Ineligible for MDR TB treatment according to national guidelines

- HIV infection with CD4 count less than 50

- Pregnancy

- Incarceration

- Too sick to participate (Karnofsky score <60, arterial pO2<90, respiratory rate

repeatedly >25/min, clinician's judgment)

- Hepatic enzymes >3x normal

- Estimated glomerular filtration rate <60 mL/min/1. 73 m2

- Unable to provide adequate sputum specimen

Locations and Contacts

J. Peter Cegielski, MD, MPH, Phone: +1-404-639-5329, Email: pcegielski@cdc.gov

Kenya Medical Research Institute, Kisumu, Nyanza Province, Kenya; Not yet recruiting
Kevin P Cain, MD, Phone: +254-710-602-786, Email: kcain@cdc.gov
Additional Information

Related publications:

Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Erokhin VV, Ershova J, Gler MT, Kazennyy BY, Kim HJ, Kliiman K, Kurbatova E, Kvasnovsky C, Leimane V, van der Walt M, Via LE, Volchenkov GV, Yagui MA, Kang H; Global PETTS Investigators, Akksilp R, Sitti W, Wattanaamornkiet W, Andreevskaya SN, Chernousova LN, Demikhova OV, Larionova EE, Smirnova TG, Vasilieva IA, Vorobyeva AV, Barry CE 3rd, Cai Y, Shamputa IC, Bayona J, Contreras C, Bonilla C, Jave O, Brand J, Lancaster J, Odendaal R, Chen MP, Diem L, Metchock B, Tan K, Taylor A, Wolfgang M, Cho E, Eum SY, Kwak HK, Lee J, Lee J, Min S, Degtyareva I, Nemtsova ES, Khorosheva T, Kyryanova EV, Egos G, Perez MT, Tupasi T, Hwang SH, Kim CK, Kim SY, Lee HJ, Kuksa L, Norvaisha I, Skenders G, Sture I, Kummik T, Kuznetsova T, Somova T, Levina K, Pariona G, Yale G, Suarez C, Valencia E, Viiklepp P. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 2012 Oct 20;380(9851):1406-17. doi: 10.1016/S0140-6736(12)60734-X. Epub 2012 Aug 30. Erratum in: Lancet. 2012 Oct 20;380(9851):1386.

Starting date: September 2015
Last updated: July 28, 2015

Page last updated: August 23, 2015

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