Section V. Treatment of Drug-Resistant Tuberculosis

Home , Capreomycin, Ethionamide, Pyrazinamide

Tuberculosis Drug-Resistant of Treatment V. Section

Tuberculosis Section V. Treatment of Drug-Resistant Tuberculosis

• Patients must be treated with a regimen of at Principles of Treating least 3 to 5 anti-TB medications to which the Drug-Resistant Tuberculosis strain is likely to be susceptible.

Unlike the treatment of drug-susceptible • A single anti-TB medication should never be tuberculosis (TB), developing standardized added to a regimen that is failing (i.e., if the protocols for the treatment of known or suspected patient is not clinically improving or if the drug-resistant (DRTB) is not possible. Several cultures are still positive 4 months after start issues are involved: of therapy). At least 2, and preferably 3, new anti-TB medications to which the strain is • Any treatment recommendation must take likely to be susceptible should be added. into account the drug susceptibility results of the individual isolate and prior treatment history. • When an injectable agent is needed, begin with capreomycin as the injectable agent of • Good data are lacking on the efficacy of choice until drug susceptibilities are known. non-standard regimens. All strain W and strain W variants are streptomycin- and kanamycin-resistant (these • Adverse effects of second-line medications, strains are still seen in NYC patients). often serious and intolerable, may preclude the use of these drugs for the recommended • Switch to streptomycin if the organism period of time. is susceptible. Use kanamycin if strain is susceptible to it and amikacin, but resistant to Multidrug-resistant TB (MDRTB) refers to a streptomycin. (Laboratories usually test for strain of M. tuberculosis (M. tb) resistant to either kanamycin or amikacin susceptibility; at least isoniazid and rifampin. there is cross-resistance between these 2 agents and resistance to one predicts Treatment Principles resistance to the other.) • Patients with DRTB, particularly MDRTB, • Treatment for TB strains resistant to at least should be treated under a program of directly rifampin (mono-rifampin, or MDRTB) should observed therapy (DOT). If the patient is not be given for at least 18 months after culture given DOT, the compelling reason must be conversion to negative. Consider extending V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT documented in the medical record. Some therapy to 24 months after culture conversion patients will need DOT twice a day. to negative if:

• MDRTB treatment can be as complex as o There is cavitary or extensive disease cancer chemotherapy and should not be attempted without the consultation of a o The patient is HIV positive or has risk factors specialist in MDRTB. for HIV infection

• There are no fully intermittent regimens o The patient is immunosuppressed at present for MDRTB treatment. However, the injectable agents may be administered o Time to culture conversion is prolonged intermittently during part of the treatment, • In general, any level of resistance to an and certain drugs may be given intermittently anti-TB medication, documented by a reliable in patients with renal failure. mycobacteriology laboratory, indicates that the drug is unlikely to be effective. However, susceptibility testing for pyrazinamide,

New York City Department of Health and Mental Hygiene 83 ethionamide and capreomycin is often 1. If the patient is not acutely ill or clinically inconsistent among laboratories or even within deteriorating, the current or most recent the same laboratory. In cases of partial resistance anti-TB regimen may be continued until or inconsistent results, physicians should follow the new drug susceptibility results are the general dictum, “use the medication, but available. This regimen is often referred do not depend on it for success.” to as a “holding regimen”.

• If there is mono-resistance to pyrazinamide, 2. If the patient is acutely ill or clinically suspect Mycobacterium bovis, another member deteriorating, at least 2 new medications of the M. tb complex. should be started, based on an assessment of the other medications to which the strain • Because the continued administration of is likely to be susceptible. The original second-line drugs may be life saving, medications should be continued until the physicians should not discontinue an anti-TB new drug-susceptibility results are available. medication in a patient who has adverse reactions unless the reaction is severe or • If a regimen is not failing (i.e., the patient cannot be ameliorated by supportive treatment. shows clinical improvement and M. tb cultures have converted from positive to • Most of the medications used to treat MDRTB negative), but the MDRTB patient is having are known to cause fetal abnormalities or an adverse reaction to a specific, identifiable have not been studied adequately regarding medication (severe enough to preclude the their safety in pregnancy. Therefore, women further use of the medication, e.g., ototoxicity of child-bearing age who have MDRTB from streptomycin, gout from pyrazinamide, should be strongly encouraged to use birth etc.), the following treatment alternatives are control methods if they are sexually active. available, depending on the length and success Pregnant women with culture-proven of treatment before the adverse reaction: MDRTB on treatment should be offered abortion counseling. 1. The medication responsible for the adverse reaction may be omitted and the remainder • Children with MDRTB should be treated with of the anti-TB treatment regimen continued. the first- and second-line drugs to which their M. tb strain, or that of their source case, is sus- 2. A new, previously unused agent may be ceptible, including streptomycin, ethambutol substituted for the medication responsible. and pyrazinamide. Ethambutol is bactericidal (This alternative does not increase the at higher doses, so daily doses up to 25 mg/kg risk for drug resistance because the prior should be used in children being treated for anti-TB treatment regimen was not failing.) MDRTB. Some fluoroquinolones are not FDA- approved in children, and must be used after 3. If the cause for the adverse reaction (e.g.,

V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT careful consideration of the potential risks and hepatotoxicity, skin rash) cannot be readily benefits, which should be documented in the identified, all medications should be patient record. See p. 210, Appendix I-B for discontinued and retested by reintroduction dosages of second-line or reserve anti-TB singly into a regimen trial. In some instances drugs for treatment of MDRTB in children. of severe toxicity, hospitalization for rechallenge with multiple drugs may be needed. Monitoring Principles • Sputum AFB smear and cultures should be • For management of TB patients who are monitored monthly for patients with isoniazid HIV infected, treatment length and regimens and/or rifampin resistant isolates. are generally the same as for patients not infected with HIV. Nevertheless, HIV status • If a patient has a positive M. tb culture after should be determined for all TB patients, 4 months of treatment, the most recent as many providers recommend extended positive culture must be sent to the clinical treatment for these patients. In addition, laboratory for first- and second-line anti-TB if HIV infection is identified, patients can drug-susceptibility testing. There are at be referred for HIV treatment. least 2 treatment options while the drug- susceptibility results are pending:

84 Tuberculosis Clinical Policies and Protocols, 4th Edition e okCt eateto elhadMna Hygiene Mental and Health of Department City York New • • • • Drugs Selected for Principles • o-iapnbsdrgmn(82 months). a (18-24 for regimen as based same the non-rifampin the data, be clinical should of length lack treatment to due upon cannot relied rifabutin be the of effectiveness However, the outlined. since as agents agent oral injectable other an and with along regimen the to is there vitro When in rifabutin. to sensitive method, prove proportion will agar by resistant less 50% be than to reported those especially rifampin-resistant organisms, of rifabutin. minority to a resistant However, also are rifampin to all, not but Most, -;adifraino niiuldrugs.) individual Appendix on information 210, and p. I-B; I-A; Appendix 208, p. 101; p. (See guidelines. (BTBC) Tuberculosis Control of Bureau per as done be should monitoring laboratory and clinical needed, as Monthly, and mut fted n l-isomers). and d- the equal of of amounts consists (which against ofloxacin active of than more l-isomer is active and optically ofloxacin the in is It even children. treatment, TB for preferred the fluoroquinolone currently is Levofloxacin week. a times 3 to 2 be dosing can conversion, a culture days After initially. 5 week given be should agents Injectable and family. patient the the for consequences dire have may which under-treatment, than more preferable much is over-treatment documented MDRTB, With MDRTB. with patients survival in and conversion culture of strongest predictor the is medication with injectable treatment an of duration the BTBC that the indicate by analyzed Data of cultures. conversion sputum slow or drugs second-line to resistance extensive disease, extensive is there if after appropriate be months may 6 conversion culture than longer for capreomycin or aminoglycosides of continuation The develops. nephrotoxicity culture or after ototoxicity months unless 6 conversion least at for used be should capreomycin or Aminoglycosides estvt orfbtn tcnb added be can it rifabutin, to sensitivity .tb M. tan htaeresistant are that strains .tb M. rssetdMDRTB. suspected or confirmed with individuals for sought consultation be should Expert patient. use individual to an medications for best the on vary Furthermore, regimens. opinions previous to time added a at them one had the have of may some and of medications trials received patients already many have as will cut, clear seldom the reality, are In options V-1). Table 86, p. (see only guidelines are regimens suggested following The Patterns Resistance Drug Specific for Regimens Suggested o o o o o o o h eia record. medical in the documented be ben- should and this risks efits; the about educated be should caregiver and/or patient the and children, women pregnant in used When risk. potential the benefit justify potential must the children, in used When bactericidal. more be may since doses tolerated, higher as daily to once period mg 2-week 750-1,000 a which over daily, increased once be mg can 500 is dose initial The noeato te is-iedrugs. first-line other of intolerant are they unless organisms drug- susceptible with patients in treatment as first-line considered be not should Levofloxacin fluoroquinolones. newer the and ciprofloxacin ofloxacin, levofloxacin, among demonstrated been has Cross-resistance h oeta ikt h fetus. the to justifies risk mother potential the the to if benefit used potential be the only in should drug and C pregnancy category a is Levofloxacin fluoroquinolones. other is the profile to effects similar adverse the general, fluoroquinolones. In older the effects to adverse compared of incidence with decreased a associated been has Levofloxacin 85 V. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS Table V-1 Suggested Regimens for Treatment of Drug-Resistant Tuberculosis

Initial Phase Continuation Phase Total Length Resistance Pattern Drugs Duration Drugs Duration Option A: Isoniazid ± Streptomycin Rifampin/Pyrazinamide/ 2 months Rifampin/Pyrazinamide/ 4-7 months 6-9 months. Ethambutol Ethambutol Extend to 9 months if still culture positive If extensive disease, consider at 2 months. Preferred adding a 4th agent such as regimen even in Fluoroquinolone or Injectable pregnancy Agent

Option B: Rifampin/Ethambutol/ 2 months Rifampin/Ethambutol 7 months 9 months Pyrazinamide

For Isoniazid/Pyrazinamide Option C: ± Streptomycin use option C Rifampin/Ethambutol 2 months Rifampin/Ethambutol 10 months 12 months + Fluoroquinolone or Injectable + Fluoroquinolone or Agent Injectable Agent

Option A: Rifampin ± Streptomycin Isoniazid/Pyrazinamide/ 2-3 months after Isoniazid/Pyrazinamide/ 12-14 months 18 months Ethambutol/Injectable Agent + culture conversion Ethambutol ± Fluoroqui- Preferred regimen Fluoroquinolone nolone

Option B: Isoniazid/Pyrazinamide/ 2-3 months after Isoniazid/Pyrazinamide/ 3-5 months 9 months Streptomycin (if no culture conversion Streptomycin ± Ethambutol Streptomycin resistance) ± Ethambutol

Pyrazinamide Isoniazid/Rifampin/ 2 months Isoniazid/Rifampin 7 months 9 months ± Streptomycin Ethambutol

Isoniazid/Ethambutol Rifampin/Pyrazinamide/ 2-3 months after Rifampin/Pyrazinamide/ 7-9 months 9-12 months or 6 months ± Streptomycin Fluoroquinolone ± Injectable culture conversion Fluoroquinolone after culture conversion, Agent whichever is longer

Isoniazid/Rifampin Pyrazinamide/Ethambutol/ 6 months after Pyrazinamide/Ethambutol/ 12-18 months 18-24 months after ± Streptomycin Fluoroquinolone/Injectable culture conversion Fluoroquinolone culture conversion Agent

Isoniazid/Rifampin/ Pyrazinamide/fluoroquinolone/ 6 months after Pyrazinamide/ 12-18 months 18-24 months after Ethambutol ± Streptomycin Injectable Agent plus at least culture conversion Fluoroquinolone plus at culture conversion

V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT 1-2 2nd line agents to which least 1-2 2nd line agents strain is susceptible to which strain is susceptible

Isoniazid/Rifampin/ Ethambutol/Fluoroquinolone/ 6 months after Ethambutol/ 12-18 months 18-24 months after Pyrazinamide ± Streptomycin Injectable Agent plus at least culture conversion Fluoroquinolone plus at culture conversion 1-2 2nd line agents to which least 1-2 2nd line agents strain is susceptible to which strain is susceptible

Isoniazid/Rifampin/ Fluoroquinolone/Injectable 6 months after Fluoroquinolone plus at 12-18 months 18-24 months after Pyrazinamide/Ethambutol Agent plus at least 2-3 2nd line culture conversion least 2-3 2nd line agents culture conversion ± Streptomycin agents to which strain is to which strain is susceptible susceptible

Isoniazid/Rifampin/Ethambutol/ Fluoroquinolone/Injectable 6 months after Fluoroquinolone plus at 12-18 months 18-24 months after Streptomycin/Kanamycin/ Agent plus at least 2-3 agents culture conversion least 2-3 2nd line agents culture conversion Ethionamide/Rifabutin ± to which strain is susceptible to which strain is Pyrazinamide (strain W and susceptible W variants)

Isoniazid/Rifampin/Ethambutol/ Any 3-4 drugs to which strain Until culture Any 3-4 drugs to which Unknown At least 24 months after Streptomycin/Fluoroquinolone is susceptible. Linezolid conversion strain is susceptible. culture conversion + second-line reserve injectable & Clofazimine may be Linezolid & Clofazimine agent ± Pyrazinamide (i.e. necessary. may be necessary. extreme drug resistant TB (XDRTB))

86 Tuberculosis Clinical Policies and Protocols, 4th Edition e okCt eateto elhadMna Hygiene Mental and Health of Department City York New • • • and negative positive: HIV HIV are who patients both For Treatment of Length • regimen.” failing a to drug single a add acid-fast for negative bacilli. smear responded is has and patient treatment the to if medica- added single be a can agent, tion fourth a of requiring addition disease the extensive has months, patient 3 the to and 1 for ethambutol rifampin, and isoniazid, pyrazinamide taking been has patient the after discovered is without resistance) or streptomycin (with isoniazid to resistance If • • • Regimens Resistance) Streptomycin without or (with Resistance Isoniazid ihds snai is isoniazid dose High pinC. Option B. Option patients. is all week for a preferred times 3 can intermittently; that given regimen be only the is starting This after treatment. months 2 are positive who culture those still to given be should regimen A. Option regimen. this high on of rates because relapse recommended ethambutol not and is rifampin alone of 12-month use a The for period. used be injectable should an agent, or fluoroquinolone along a ethambutol, with and a rifampin intolerance, of or regimen resistance drug of because C. months. Option 7 additional an for rifampin ethambutol with the and treat and discontinued, months was 2 drug least at for pyrazinamide B. Option conversion. culture after months be 2 may discontinued it cultures), sputum of conversion or slow disease extensive with patients (in used been a has If agent injectable months. or 2 fluoroquinolone at positive culture the still if is months patient 9 to Extend high. are and ethambutol rifampin with rates relapse as pregnant patients, for even regimen preferred the Thisis treatment. of duration the for ethambutol A. Option hsde o ilt h ueo d not “do of rule the violate not does This -ot regimen 9-month s iapn yaiaieand pyrazinamide rifampin, Use 2mnhregimen 12-month 9-month the regimen; 6-9-month faptetwstetdwith treated was patient a If fprznmd antb used be cannot pyrazinamide If not recommended. • • Regimens Resistance) Streptomycin without or (with Resistance Ethambutol and Isoniazid • • Regimens Resistance) Streptomycin without or (with Resistance Rifampin conversion. culture after months used 6 be for should injectable the of cultures, conversion sputum slow or disease extensive patients with in culture However, after negative. to months conversion 3 to be 2 may discontinued capreomycin or aminoglycoside An • Treatment of Length loounln oteregimen. the a to add of fluoroquinolone alone, more rifampin or and the days If isoniazid 10 treatment. received of has start patient the at known is resistance streptomycin if other streptomycin than aminoglycoside an or Use capreomycin capreomycin. with or appropriate aminoglycoside an with along ethambutol, A. Option glycoside. amino- appropriate an or capreomycin as such agent injectable fluoro- an possibly a and quinolone least at adding and pyrazinamide, rifampin Continue isoniazid ethambutol. discontinue and months, 1-3 for butol etham- taking been and pyrazinamide has rifampin, isoniazid, patient the is after resistance) discovered streptomycin without ethambutol or and (with isoniazid to resistance If treatment. of start the at known is resistance streptomycin if streptomycin than other aminoglycoside an or capreomycin Use capreomycin. with or aminoglycoside appropriate an with a along and fluoroquinolone, pyrazinamide rifampin, Use fiaywe sdfrls hn1year. 1 than less high for have used to when shown efficacy been has that regimen non-rifamyacin–containing only the HIV- is negative, are who patients in studied regimen, This streptomycin. and pyrazinamide isoniazid, use B. Option longer. is whichever conversion, culture regimen after 6-month or regimen, 12-month to Nine fteei osrpoyi resistance, streptomycin no is there If s snai,prznmd and pyrazinamide isoniazid, Use 87 V. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS Streptomycin was administered daily or Isoniazid and Rifampin Resistance intermittently for the entire 9 months in one study. (with or without Streptomycin It can be used in patients who are HIV positive Resistance) with tuberculosis, who are on any antiretroviral treatment, without dose adjustments of anti-TB Regimens meds or HIV medications. • Use pyrazinamide, ethambutol and a fluoroquinolone, along with an appropriate Some experts recommend an 18-month aminoglycoside or capreomycin. Use regimen of isoniazid/ethambutol as an option, in capreomycin or an aminoglycoside other which streptomycin is used for 2 to 3 months post than streptomycin if streptomycin resistance culture conversion. In NYC, most rifampin-resist- is known at the start of treatment. ant TB is seen in persons infected with HIV in whom this regimen has not been studied. Use • If resistance to isoniazid and rifampin (with pyrazinamide throughout the entire treatment or without streptomycin resistance) is if this regimen is used. discovered after the patient has been taking isoniazid, rifampin, pyrazinamide and • Isoniazid, pyrazinamide, ethambutol and a ethambutol for 1 to 3 months, discontinue fluoroquinolone in a 12-month regimen, while isoniazid and rifampin. Continue pyrazinamide recommended in the new American Thoracic and ethambutol, and add at least 2 drugs — Society/Centers for Disease Control and a fluoroquinolone along with an appropriate Prevention (CDC)/Infectious Diseases Society aminoglycoside or capreomycin to the regimen. of America guidelines, is not recommended by the BTBC. Length of Treatment Length of Treatment • Eighteen months after culture conversion For both patients who are HIV negative and • Patients with extensive cavitary disease or HIV positive: with prolonged time to culture conversion, patients who are HIV positive, other immuno- • Option A. Eighteen months total treatment with suppressed patients and patients with isoniazid, pyrazinamide, ethambutol and an behavioral risk factors for HIV infection who aminoglycoside or capreomycin. If an amino- decline HIV testing may need to have treatment glycoside or capreomycin has been used, it extended to 24 months after culture conversion. may be discontinued 2 to 3 months after culture conversion. However, in patients with extensive • The aminoglycoside or capreomycin can disease or slow conversion of sputum cultures, usually be discontinued 6 months after use the injectable for 4 to 6 months after culture culture conversion. conversion; after this point, dosing for the

V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT injectable can be 2 to 3 times per week. • However, in some patients, especially those with extensive disease, slow conversion of • Option B. Use isoniazid, pyrazinamide sputum cultures or extensive second-line drug and streptomycin for a total of 9 months of resistance, the injectable can be used for treatment. After culture conversion, dosing longer than 6 months after culture conversion. for the injectable can be 2 to 3 times a week for the total duration of treatment. • Intermittent dosing for the injectable may be used after culture conversion. • Surgery should be considered if a patient’s cultures fail to convert to negative after 4 months of • Resistance to rifampin is generally associated appropriate treatment (See p. 95.) with cross-resistance to rifabutin and rifapentine. When rifampin resistance is present but in vitro susceptibility to rifabutin is reported and this drug is added to the regimen, treatment should be the same as in the case of rifampin resistance.

88 Tuberculosis Clinical Policies and Protocols, 4th Edition e okCt eateto elhadMna Hygiene Mental and Health of Department City York New • • • Treatment of Length • • • Regimens Resistance) Streptomycin without or (with Resistance Ethambutol and Rifampin Isoniazid, • utr conversion. culture after months 6 discontinued be usually can capreomycin or aminoglycoside The culture have conversion. after months to 24 need to extended may treatment testing HIV decline infection HIV and for factors risk behavioral have or positive, conversion; HIV immunosuppressed are patients who culture to time prolonged or with disease cavitary extensive with Patients conversion culture after months Eighteen drugs. first-line with treated patient being the was while acquired been have this may as resistance pyrazinamide for of available, acquisition if specimen, new a Assess or susceptible. known be is to strain likely the which to 2 agents to other 1 and capreomycin, appropriate or an aminoglycoside with along regimen the to fluoroquinolone a add and Continue pyrazinamide ethambutol. and isoniazid, rifampin discontinue ethambutol, and pyrazinamide rifampin, isoniazid, taking been has patient the after discovered is streptomycin resistance) without and or (with rifampin ethambutol isoniazid, to resistance If documented. been has it rifabutin to Use susceptibility treatment. if of start the at known is streptomycin-resistance if streptomycin than other aminoglycoside an or capreomycin Use acid. para-aminosalicylic ethionomide, or (e.g., cycloserine susceptible be to likely or known is strain the which to second-line agents capreomycin; with or aminoglycoside appropriate an with pyrazinamideUse fluoroquinolone, a and along 95.) p. (See treatment. 4 appropriate after of negative months to convert to patient’s fail a cultures if considered be should Surgery s o2other 2 to 1 use addition, in • • • • ihu tetmcnResistance) Streptomycin without or (with Resistance Pyrazinamide and Rifampin Isoniazid, • • • Regimens rghsbe documented. been has drug the to susceptibility if rifabutin Use of treatment. start the at known is resistance streptomycin if streptomycin than other aminoglycoside or an capreomycin Use susceptible. be to likely knownor is strain the which to agents second-line other 2 to 1 use addition, capreomycin. In appropriate with aminoglycoside an or with fluoroquinolone ethambutolUse a and along ethionamide susceptible para-aminosalicylic acid). be and likely (e.g., to which or known to is agents strain other the 2 to 1 and capreomycin, or aminoglycoside appropriate along an regimen, with the to fluoroquinolone a mg/kg). Add (25 dosage its increasing consider and ethambutol, Continue pyrazinamide. and rifampin isoniazid, discontinue ethambutol, and pyrazinamide rifampin, isoniazid, taking has been patient the after discovered is resistance) streptomycin without or (with pyrazinamide and rifampin isoniazid, to resistance If en rae ihfrtln drugs. first-line with was treated patient being the while acquired may been it have as resistance ethambutol for of available, acquisition if specimen, new a Assess otso prpit ramn sep 95). p. (see treatment 4 appropriate after of negative months to convert to patient’s fail a cultures if considered be should Surgery resistance. rifampin as of same case the the the to be in added should is treatment drug regimen, this and reported is is but resistance present rifampin When and rifapentine. rifabutin to cross-resistance with associated generally is rifampin to Resistance conversion. culture after used be may injectable the for dosing Intermittent conversion. culture after for months used 6 be than longer can injectable the second-line resistance) drug extensive or of cultures conversion sputum slow disease, those extensive (especially with patients some in However, nvitro in ucpiiiyt rifabutin to susceptibility 89 V. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS Length of Treatment and ethambutol, discontinue all 4 drugs. Start • Eighteen months after culture conversion a regimen of a fluoroquinolone, along with an appropriate aminoglycoside or capreomycin, • Patients with extensive cavitary disease or and at least 2, and preferably 3, other agents with prolonged time to culture conversion, to which the strain is known or likely to be patients who are HIV positive, other immuno- susceptible (e.g., ethionamide, cycloserine suppressed patients and patients with behav- and para-aminosalicylic acid). ioral risk factors for HIV infection who decline HIV testing may need to have treatment Length of Treatment extended to 24 months after culture conversion. • Eighteen months after culture conversion • The aminoglycoside or capreomycin can • Patients with extensive cavitary disease or usually be discontinued 6 months after with prolonged time to culture conversion, culture conversion. patients who are HIV positive, other immuno- • However, in some patients (especially those suppressed patients and patients with with extensive disease, slow conversion of behavioral risk factors for HIV infection who sputum cultures or extensive second-line decline HIV testing may need to have treatment drug resistance) the injectable can be used for extended to 24 months after culture conversion. longer than 6 months after culture conversion. • In both of the above situations, the • Intermittent dosing for the injectable may be aminoglycoside or capreomycin may used after culture conversion. be discontinued 6 months after culture conversion. However, in some patients • Resistance to rifampin is generally associated (especially those with extensive disease or with cross-resistance to rifabutin and slow conversion of sputum cultures), the rifapentine. When rifampin resistance is injectable should be used for longer than 6 present but in vitro susceptibility to rifabutin months after culture conversion. Intermittent is reported and this drug is added to the dosing of the injectable may be used after regimen, treatment should be the same as culture conversion. in the case of rifampin resistance. • Resistance to rifampin is generally associated • Surgery should be considered if a patient’s with cross-resistance to rifabutin and cultures fail to convert to negative after 4 rifapentine. When rifampin resistance is months of appropriate treatment. (See p. 95). present but in vitro susceptibility to rifabutin is reported and this drug is added to the Isoniazid, Rifampin, Pyrazinamide regimen, treatment should be the same as and Ethambutol Resistance (with or in the case of rifampin resistance. V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT without Streptomycin Resistance) • Surgery should be considered if a patient’s Regimens cultures fail to convert to negative after 4 months of appropriate treatment (See p. 95). • Use a fluoroquinolone, along with an appropriate aminoglycoside or with capreomycin. In addition, use at least 2, and preferably 3, Isoniazid, Rifampin, Ethambutol, other second-line agents to which the strain is Streptomycin, Kanamycin, known or likely to be susceptible. Use capre- Ethionamide and Rifabutin Resistance omycin or an aminoglycoside other than (“Strain W”) streptomycin if streptomycin resistance is known at the start of treatment. Use rifabutin if Regimens susceptibility to the drug has been documented. • In patients suspected of having this strain, start with a regimen of isoniazid, rifampin • If resistance to isoniazid, rifampin, pyrazinamide and pyrazinamide (in the event the strain is and ethambutol (with or without streptomycin found to be susceptible to these medications), resistance) is discovered after the patient has plus 3 other anti-TB medications to which the been taking isoniazid, rifampin, pyrazinamide strain is likely to be susceptible. The 3 addi-

90 Tuberculosis Clinical Policies and Protocols, 4th Edition e okCt eateto elhadMna Hygiene Mental and Health of Department City York New • • • • • Treatment of Length • oee,d o eyo h effectiveness the isoniazid. on of isoniazid. rely of not levels do low strain However, to this only because resistant is week), a dosage twice high mg a (900 at intermittently isoniazid use necessary, there If as kanamycin. strain, to cross-resistance this is with amikacin 95). use p. not (see questionable Do is latter the of antituberculous activity the are strain although and this acid clofazimine, of treatment para-aminosalicylic the ethionamide, in may role that a medications have anti-TB other capreomycin. Three and cycloserine susceptible), (if levofloxacin, pyrazinamide with treat rifampin discontinue and confirmed, is strain this If otso prpit ramn sep 95). p. (see treatment 4 appropriate after of negative months to convert to patient’s fail a cultures if considered be should Surgery rifabutin. to resistant is strain This after used conversion. be culture may injectable the for than dosing longer Intermittent conversion. culture for after months used 6 be can injectable resistance), the drug or second-line cultures extensive sputum of disease, conversion slow extensive with those patients (especially some in However, conversion. culture after months 6 can discontinued be usually capreomycin or aminoglycoside The conversion. after culture months 24 to to extended need treatment may have therapy testing HIV infection decline HIV who for factors risk behavioral with patients and other patients positive, immunosuppressed HIV are conversion, who culture patients to or time disease prolonged with cavitary extensive with Patients conversion. culture after months Eighteen B vitamin with (in conjunction cycloserine fluoroquinolones, with are used success been have that medications tional fchoice. fluoroquinolone of the as levofloxacin uses BTBC Currently, the capreomycin. intravenous or lar 6 n intramuscu- and ) • Treatment of Length • • • Regimen agents) injectable several or Pyrazinamide either without or (with Resistance Fluoroquinolone Streptomycin, Ethambutol, Rifampin, Isoniazid, hw t oetatvt against activity potent its shown Many in adults. infections tract respiratory the of for treatment 1999 in approved was Moxifloxacin gatifloxacin. recently, are until TB and, latent moxifloxacin and levofloxacin, active with commonly patients most in ones used The TB. potential treating have in years use few last the in approved been have that fluoroquinolones Several Tuberculosis Treating for Fluoroquinolones Newer of Use ailxcnfo h olwd market. worldwide the of from withdrawal gatifloxacin voluntary a has made recently manufacturer the Furthermore, agent. preferred generation the newer is a moxifloxacin use fluoroquinolone, to necessary is it when Therefore, agents. hypoglycemic oral diabetic on patients and elderly the in hypoglycemia cause can and moxifloxacin than cardiotoxicity tb; M. shows also Gatifloxacin efficacy clinical and use. safety prolonged on for data of lack TB a treating is in moxifloxacin major using The with underway. issue are and trials II clinical Phase — III agent Phase anti-TB an as study for further Development Global Drug the Tuberculosis and for CDC Alliance the by chosen been has tlat2 otsatrclueconversion culture after months 24 least At 95). p. (see treatment of course the in considered early be should intervention Surgical occur. must Director BTBC the culture- with and Consultation smear- positive. AFB still are dis- who pulmonary ease with patients select consid- for be ered may interferon gamma Inhaled organism the which to susceptible. drugs is 4 to 3 any Use oee,i a rae oeta for potential greater has it however, nvitro in n nmlsuishave studies animal and nvitro in ciiyagainst activity .tb. M. h drug The 91 V. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS Levofloxacin, at present, remains the features of the fluoroquinolones . Most adverse fluoroquinolone of choice; its safety profile for effects, including gastrointestinal problems long-term use is documented over several years and chondrotoxicity/arthropathy, have not in patients with DRTB who are intolerant to been attributed to specific structural features isoniazid or a rifamycin. of the fluoroquinolones.

To provide comparable levofloxacin exposures Of the newer fluoroquinolones in use, levofloxacin associated with clinical effectiveness and safety is cleared by the kidney and is the preferred agent in adults, children 5 years or older need a daily for patients with hepatic insufficiency; however, dose of 10 mg/kg whereas children 6 months to it should be used with caution. In patients with younger than 5 years should receive 10 mg/kg renal failure, the interval between doses of every 12 hours. levofloxacin should be increased. Moxifloxacin is mostly cleared by the liver and therefore may The following patients are potential candidates be the preferred fluoroquinolone in a patient for moxifloxacin during TB treatment: with renal insufficiency.

• Adults and children with MDRTB who are Flouroquinolones can cause hypersensitivity not tolerating levofloxacin but may still be reaction either after a single dose or multiple a candidate for a fluoroquinolone (e.g., an doses. Treatment should be discontinued at the adverse reaction is unlikely to occur with a first appearance of a skin rash, jaundice or any different one) other sign of hypersensitivity. • Adults and children with MDRTB that is Photosensitivity and Cardiotoxicity resistant to most first- and second-line drugs and for whom a regimen of 3 to 4 drugs can- Although fluoroquinolones are generally not be identified. considered to have favorable adverse event profiles, 2 potentially serious adverse events— To date, there is no evidence for the use of photosensitivity and QT interval prolongation— fluoroquinolones as a single agent for treatment have been associated with certain drugs in of latent tuberculosis infection (LTBI) due to a the class. multidrug-resistant organism. It is recommended that if a fluoroquinolone is used for LTBI, it • Photosensitivity is defined as a non-immuno- be used in combination with another agent. logical, light-activated irritation that occurs However, in select situations, moxifloxacin may after exposure to a photoactive chemical. This be used as a single agent after consultation is an infrequent adverse event of most fluoro- with the BTBC Director. quinolones; however, the incidence varies according to the individual drug. Toxicities of Fluoroquinolones Phototoxicity has been described with all V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT fluoroquinolones except moxifloxacin, but Adverse events can vary markedly among appears to occur most frequently in the different fluoroquinolones, which most derivatives that have a halogen atom at C-8. commonly cause nausea, vomiting, diarrhea (often due to C. difficile) and abdominal pain. • Some second-generation fluoroquinolones Current data suggest that the newer ones, have been associated with prolonged QT especially in high-dose regimens, cause a intervals and the potential for ventricular higher incidence of these adverse effects tachyarrhythmia. Cardiac events, such as QT than do older agents such as ciprofloxacin prolongation and the potential for ventricular and ofloxacin. Cholestasis, hepatitis and hepatic tachyarrhythmia, are most notably associated failure have been infrequently reported. with the use of levofloxacin and moxifloxacin. Reversible transaminase elevation may occur in up to 2% to 3% of patients. Tendinopathy/Tendinitis Some common adverse effects (phototoxicity, Fluoroquinolone-induced tendinopathy is central nervous system effects and inhibition of diagnosed by a sudden onset of swelling drug metabolism) are associated with structural and tenderness concurrent with or shortly after fluoroquinolone therapy. There is tendon

92 Tuberculosis Clinical Policies and Protocols, 4th Edition e okCt eateto elhadMna Hygiene Mental and Health of Department City York New studies several use, long-term for safe be to appear generally fluoroquinolones Although Fluoroquinolones of Use Long-Term regularly. monitored glucose blood their having including monitored, closely be should fluoroquinolones on Patients of TB. use for gatifloxacin the recommend not do we treatment, TB in periods prolonged for used generally are fluoroquinolones Since function. renal in decline age-related an experience may the who elderly, in accumulate may kidneys) the by excreted is (which gatifloxacin that is phenomenon this for mechanism possible elderly, A in patients. non-diabetic particularly alone, with gatifloxacin severe hyperglycemia of and reports hypoglycemia recent more are There elderly. oral the taking especially agents, are hypoglycemic who diabetes 2 type with patients in hypoglycemia symptomatic severe cause can gatifloxacin, generation specifically newer fluoroquinolones, the that indicated have reports recent Several level. P450 cytochrome the at interaction glyburide to and due ciprofloxacin be between to believed are in sugar Changes blood agents. the these despite of rare use be widespread to believed are sugar on blood effects such however, hyperglycemia: and hypoglycemia cause can fluoroquinolones All Hyperglycemia and Hypoglycemia prolonged. be may and treatment in early needed be may therapy Physical tendons. the resting and Treatment years). fluoroquinolone 65 the discontinuationinvolves of than (older in elderly especially the fluoroquinolones, tendinopathy developing taking for while factor risk a be considered to is corticosteroids of use weeks. Concomitant 3 than longer lasts frequently therapy more when rupture tendon days and 5 therapy than of less after occurs generally tendinitis is Uncomplicated duration. treatment proportional severity to been symptom has however, tendinopathy observed; of treatment incidence of the and duration between correlation No after discontinuation. months drug even noted been have ruptures tendon Achilles hand aponeuroeses. knee, plantar shoulder, and the in reported it been however, site has tendon: main Achilles The the cases. is all affected of 33% about in rupture eefudi eerheaiigteueof leprosy. use for the fluoroquinolones examining research in results found Similar were patients. 3 in discontinued therapy was Drug ofloxacin. for and similar ciprofloxacin were both and reactions reversible, Most and time. mild of were period drugs prolonged other a to for addition given in were fluoroquinolones who disease mycobacterial patients 100 with over in fluoro- reviewed generation was first quinolones of use the 1991, In month months). 1 3 (usually or use by long-term limited of are definition to studies the 7 These therapy. first of the days in 10 highest is ciprofloxacin adverse for of effects incidence the that documented have lnclysgiiatbayadaadacute ischemia. and myocardial bradycardia as significant such with clinically patients conditions in pro-arrhythmic caution ongoing with used be moxifloxacin should experience, of clinical Because limited to prolongation. susceptible QT more that drug-induced be expected may is individuals it these however, has studied; interval QT been the not with of patients prolongation on congenital moxifloxacin of effect The drugs. given these when with caution concurrently with used be therefore, should excluded; it be cannot drugs these and moxifloxacin of tricyclic effect additive antidepressants. An and cisapride, antipsychotics as such erythromycin, interval QT the prolong drugs that other with combination of in studies moxifloxacin phamacokinetic no are There populations. these should in drug avoided the be agents, amiodarone, antiarrythmic (e.g., sotalol) III class quinidine, or (e.g., procainamide) IA class and/or receiving patients hypokalemia uncorrected the of interval, prolongation QT known the with with patients experience in clinical drug of lack the to patients. Due some in QT electrocardiogram the on prolong interval to shown been has Moxifloxacin patients. of 3.8% in drug-related be to to thought due reactions adverse discontinued was no drug required the and treatment; severity in moderate as to described mild are trials moxifloxacin in events reported adverse Most periods. moxifloxacin prolonged of for use the on available is data Little Moxifloxacin 93 V. TREATMENT OF DRUG-RESISTANT TUBERCULOSIS Moxifloxacin is non-formulary at present in the Linezolid is available for oral use as well as for BTBC chest centers and requires approval of intravenous administration. A dose of 600 mg the Bureau Director prior to use. The BTBC does twice a day has been used with good response. not recommend routine EKG testing of patients Food delays absorption, but does not lower on moxifloxacin unless clinically indicated. peak plasma concentrations. The drug is partly metabolized in the liver and does not affect the Adverse reactions occurring in greater than or cytochrome P450 enzyme system; it is excreted equal to 1% of moxifloxacin treated patients that in the urine. The linezolid oral suspension may be at least possibly drug-related are: contains phenylalanine and should not be given to patients with phenylketonuria. • Nausea (8%) Side effects of linezolid include: • Diarrhea (6%) • Myelosuppression (including anemia, leukopenia, • Dizziness (3%) pancytopenia and thrombocytopenia) • Headache (2%) • Hemolytic anemia • Abdominal pain (2%) • Diarrhea • Vomiting (2%) • Nausea, vomiting (patients who have recurrent • Taste alteration (1%) nausea and vomiting, unexplained acidosis or a low bicarbonate level should receive immediate • Abnormal liver function test results (1%) medical attention to rule out lactic acidosis)

• Dyspepsia (1%) • Liver function test elevations Linezolid • Tongue discoloration • Severe hypertension (if taken concomitantly Linezolid belongs to a new class of antibiotics, with large amounts of tyramine) the oxazolidinones, and was approved by the FDA in 2000 for treatment of infections with • Peripheral neuropathy, including optic neuritis resistant gram-positive organisms. In vitro (in patients who have taken linezolid longer studies have shown that linezolid is active than the maximum recommended 28 days; against M. tb, including strains resistant to optic neuropathy may be reversible upon many first-line anti-TB drugs. Linezolid may discontinuation, but peripheral neuropathy be used as part of a regimen for treating may be irreversible) patients with MDRTB and persistent positive Administration of vitamin B6 (daily dose,

V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT sputum cultures (whose treatment options are 25 mg/day) may ameliorate some of these severely limited) and who also: adverse reactions, though this remains • Are already prescribed a regimen to which controversial. A complete blood count should be the organism is susceptible obtained every 1 to 2 weeks, especially in those with pre-existing myelosuppression, and those • Have extensive second-line drug resistance or receiving concomitant drugs that induce bone are intolerant to many second-line drugs marrow suppression. CBC and SMA-18 profile should be monitored every 2 to 4 weeks, vision • Are on DOT should be monitored every month and patients • May not be surgical candidates should overall be monitored post-treatment per BTBC protocol. • Have no other treatment options

94 Tuberculosis Clinical Policies and Protocols, 4th Edition Yearly updates must be sent to the FDA for Note: Linezolid is a reversible, non-selective continued use, and the physician caring for the inhibitor of monoamine oxidase and therefore patient must document the continued use of the may interact with adrenergic and serotonergic drug, its risks and benefits, and the patient’s agents. Co-administration of drugs containing: agreement to continue with the medication. • Pseudoephedrine The patient should be informed of this process • Phenylpropanolamine (and sign a brief consent form), and monitored • Selective serotonin reuptake inhibitors monthly or more frequently for sputum • Possibly other antidepressants conversion, continued need for the drug should be undertaken with caution, as serotonin and side effects, which frequently include: syndrome may occur, manifesting as cognitive dysfunction, hyperpyrexia, hyperreflexia and • Pink to brownish-black discoloration of the incoordination; such patients may need referral skin; the degree of discoloration is dose-related to a psychiatrist. The benefit of taking linezolid and is most pronounced on exposed parts of with these drugs must be weighed against the body these risks. • Ichthyosis and dry skin; pruritis and In summary, the current cost and high rate non-specific rash of adverse effects of linezolid preclude its widespread use. Linezolid use must be • Reversible, dose-related red-brown approved by the BTBC Director. discoloration of the conjunctiva, cornea and lacrimal fluid Clofazimine • GI side effects such as abdominal and epigastric pain, diarrhea, nausea, vomiting Clofazimine (an FDA-approved drug previously and GI intolerance on the BTBC formulary) has been used, when absolutely necessary, in BTBC chest centers • Nervous system effects (reported in less than for many years to treat MDRTB. Since it has 1% of patients) such as dizziness, drowsiness, in vitro activity against M. tb and some non- fatigue, headache, giddiness, neuralgia and mycobacterium TB (mycobacterium avium taste disorders complex [MAC]), this drug has been used in the treatment of drug-resistant M. tb and non- Monitoring and tuberculous mycobacteria patients.

In November of 2004, Novartis Pharmaceutical Post-Treatment Evaluation Corporation discontinued commercial Patients being treated for DRTB should be distribution of clofazimine in the United States monitored during treatment as outlined on due to the company’s implementation of a p. 101. For information on adverse reactions in V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT compassionate care program for the treatment patients taking second-line anti-TB medications, of leprosy (Hansen’s disease). The FDA has (see p. 210, Appendix I-B). After completing now made clofazimine available under an treatment, patients with MDRTB should be Investigational New Drug (IND) application for evaluated at 4, 8, 12, 18 and 24 months after these uses and in order to use this drug for a completion of therapy, as described on p. 115 patient, an IND application has to be sent to and on p. 116, Table VI-2. the FDA. The Office of Medical Affairs is responsible for Surgery for Pulmonary obtaining clofazamine for BTBC patients. Once a patient is approved by the FDA to receive it, Tuberculosis a unique IND number is assigned to the patient and a 60-day supply of the drug is sent to the Surgery is not a first-line option in the treatment BTBC. The bottle with that IND number is specifi- of TB because, in most cases, pulmonary TB is cally for use by that patient only and a new supply curable using modern drug regimens. Surgery has to be requested every 60 days. The Office of is, however, one of the last alternatives available Medical Affairs should be contacted 30 days prior for individuals with MDRTB strains in whom to the prescription expiring so that arrangements chemotherapy has failed or is not possible can be made to have clofazamine available. because of a lack of sufficient and effective medications. New York City Department of Health and Mental Hygiene 95 Indications for Surgery Protocol for Surgery Referral In consultation with medical and surgical • Referrals for surgery should be made on an experts, surgery can and should be considered individual basis, and should be reviewed and as an adjunct to chemotherapy when all of the coordinated by the BTBC Director or the following criteria are met: Director of Medical Affairs.

• Adequate first- and second-line regimens of • Chest center physicians may refer a patient anti-TB medications have failed to cure, or to for a CT scan when necessary, after consulting cause M. tb cultures to convert to negative with the physician-in-charge. within 4 to 6 months. • As part of the medical/surgical evaluation, all • Sufficient medications are available to treat of the following should be documented: the patient post-operatively. o Failure to cure TB, as evidenced by persistent • The disease is sufficiently localized to allow positive M. tb sputum cultures or reversion lobectomy or pneumonectomy. from negative to positive cultures, despite the best treatment regimen possible and • The remaining lung tissue is relatively free every effort to achieve adherence to of disease. treatment, including the use of DOT

• The patient has an acceptable surgical risk, o Diagnostic evaluation that shows the majority with sufficient pulmonary reserve to tolerate of disease is anatomically localized, allowing the resection. surgical resection

Some clinical circumstances, such as major o Appropriate evaluation proving that the bronchial obstruction, severe hemoptysis or patient has an acceptable surgical risk bronchopleural fistula are additional possible indications for surgery. • Even after lung resection, the patient must complete a full course of treatment (18 to 24 months after culture conversion) with medications to which the M. tb strain is susceptible. If the patient is culture negative after surgery, then the date of surgery is considered to be the conversion date. V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT

96 Tuberculosis Clinical Policies and Protocols, 4th Edition Key Sources

Caminero JA. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis. 2006 10:829-837. Chan ED, Laurel V, Strand MJ, et.al. Treatment and outcome analysis of 205 patients with multidrug- resistant tuberculosis. Am J Respir Crit Care Med. 2004 15;169:1103-1109. Chien S, Wells TG, Blumer JL, Kearns GL, Bradley JS, Bocchini JA Jr, Natarajan J, Maldonado S, Noel GJ. Levofloxacin pharmacokinetics in children. J Clin Pharmacol. 2005 45(2):153-160. Francis J. Curry National Tuberculosis Center and California Department of Health Services. Drug- Resistant Tuberculosis: A Survival Guide for Clinicians. San Francisco, CA: Francis J. Curry National Tuberculosis Center and California Department of Health Services, 2004. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med. 1993;329:784-791. Ntziora F, Falagas ME. Linezolid for the treatment of patients with mycobacterial infections: a systematic review. Int J Tuberc Lung Dis. 2007 Jun;11(6):606-11. Review. Erratum in: Int J Tuberc Lung Dis. 2007;11(8):936. Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs. 2002;62:2169-2183. von der Lippe B, Sandven P, Brubakk O. Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)-a report of ten cases. J Infect, 2006 52(2):92-96. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2006.361. Geneva, Switzerland: World Health Organization; 2006. Available at: http://whqlibdoc.who.int/publications/2006/9241546956_eng.pdf V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT

New York City Department of Health and Mental Hygiene 97 V. TREATMENT OF TUBERCULOSIS DRUG-RESISTANT

98 Tuberculosis Clinical Policies and Protocols, 4th Edition