NOTICE AND DISCLAIMER

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1 NOTICE AND DISCLAIMER This publication is intended to be a resource for physicians and other healthcare professionals who provide care and treatment to patients in resource poor settings. Reasonable efforts have been made to ensure that the material presented here is accurate, reliable, and in accord with current standards as of the date of publication. However, as new research and experience expand our knowledge, recommendations for care and treatment change. Your use of this publication is provided on an as is basis without warranty of any kind, and none of the individuals or entities listed below represent or warrant that the information contained herein is complete or accurate or free from error. It is therefore the responsibility of the individual physician or healthcare professional to use his/her best medical judgment in determining appropriate patient care or treatment. To the maximum extent permitted under applicable laws, no responsibility is assumed by any party involved in the production or publication of this publication, including without limitation, each of the contributors and authors; Partners In Health; the Program in Infectious Disease and Social Change, Harvard Medical School; Harvard Medical School Division of AIDS; the Division of Social Medicine and Health Inequalities, Brigham and Womenʹs Hospital; and each of their affiliates, divisions, directors, officers, trustees, agents and employees (referred to collectively as the Publishers and Contributors ). The Publishers and Contributors hereby disclaim all liability for errors, omissions, or any injury and/or damage (actual or perceived) to persons or property as a result of any actual or alleged product liability, libelous statement, or infringement of intellectual property or privacy rights, whether resulting from negligence or otherwise, including without limitation, from any reliance upon, use or operation of, any ideas, instructions, procedures, products or methods contained in the material included in this publication. References to specific drugs or products within this publication do not constitute endorsement by the Publishers and Contributors. Individual patient needs may vary on a case by case basis, and physicians and other healthcare professionals should consult their standard resources before prescribing specific drugs or products to their patients. This disclaimer and your use of this publication are and shall be governed and construed in accordance with the internal laws of the Commonwealth of Massachusetts, without regard to its rules concerning conflicts of laws. In the event of any conflict between foreign laws, rules and regulations and those of the United States, the laws, rules and regulations of the United States shall govern. By choosing to use this publication, you acknowledge and agree to the terms of this disclaimer. Published in the United States by Partners In Health. Subject to the rights of Partners In Health, this publication may be freely reviewed, abstracted, reproduced or translated, provided that all copyright, trademark and other proprietary notices are included in each such use. The foregoing notwithstanding, no portion of this publication may be sold or otherwise used or distributed in conjunction with any commercial purpose. PIH and Partners In Health are trademarks of Partners In Health, and the PIH logo is a United States registered service mark of Partners In Health. All other trademarks, service marks, trade names and logos appearing in this publication, including drug brands and names, are the property of their respective owners. Copyright Partners In Health All rights reserved under International and Pan American Copyright Convention BUSDOCS/

2 Chapter Five Therapy for MDR TB Directly observed therapy (DOT) Review of antituberculous agents Individualized versus standardized approaches to MDR TB treatment Initial approach to MDR TB treatment Principles of foundation design Parenteral agents First-line agents Fluoroquinolones Remaining second-line agents Principles of regimen reinforcement Design of the definitive regimen Discrepant susceptibility results MDR TB in pediatrics and obstetrics Treatment of children with MDR TB MDR TB and pregnancy Adjuvant therapies for MDR TB Addressing other barriers to treatment success Corticosteroids Surgery Conclusion 86

3 Table of Figures Figure 5.1 Comparison of approaches to MDR TB treatment 70 Figure 5.2 Suspecting MDR TB 71 Figure 5.3 Design of an empiric individualized treatment regimen 72 Figure 5.4 Foundation design of definitive ITR 74 Figure 5.5 Reinforcing the regimen 76 Figure 5.6 Case example 8: Predicting amplification in designing empiric therapy 77 Figure 5.7 Case example 9: Treatment failure 77 Figure 5.8 Case example 10: Primary MDR TB 78 Figure 5.9 Case example 11: Primary MDR TB and treatment failure 78 Figure 5.10 Case example 12: High-grade resistance 79 Figure 5.11 Discrepant results 80 Figure 5.12 Case example 13: Discrepant drug susceptibility results 80 Figure 5.13 Case example 14: Pediatric MDR TB 81 Figure 5.14 MDR TB in pediatrics 82 Figure 5.15 Safety class and safety in breastfeeding of antituberculous medications 82 Figure 5.16 MDR TB in obstetrics 83 Figure 5.17 Case example 15: Pregnancy and MDR TB 83 Figure 5.18 Adjuvant therapies for MDR TB 85 Figure 5.19 Case example 16: Adjunctive surgery 85 Figure 5.20 Summary 86

4 Therapy for MDR TB In this section, the principles of MDR TB regimen design will be outlined. The clinician is ultimately the judge of whether additional medications or adjunctive measures should be used to treat each patient with MDR. However, we feel that the following principles summarize the fundamental approach to drug therapy for patients with MDR TB. 5.1 Directly observed therapy (DOT) Although directly observed therapy (DOT) for TB has been official policy at the global level for a mere six years, the idea is over 40 years old. 1,2 In the United States, the CDC established DOT as a cornerstone of federal TB policy in WHO adopted universal DOT a year later as part of a set of recommendations for effective TB control programs (DOTS), which would require: 1. Political commitment, 2. Case finding using smear microscopy among symptomatic patients, 3. Standardized, supervised short-course therapy for all sputum smear-positive cases, 4. A regular supply of essential anti-tb drugs, and; 5. A standardized program monitoring and evaluation system. 4 DOTS-Plus works best when it is an extension of national TB programs already committed to DOTS. With the exception of relying on fixed-dose, short-course chemotherapy, the remaining components of DOTS are essential to DOTS-Plus programs as well. Indeed, DOT is even more crucial in treating MDR TB because of the extended duration of therapy and the potential for greater adverse effects. Adverse effects associated with antituberculous medications have been reviewed extensively by others. 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33 Although some clinicians regard these adverse effects as reasons to avoid or interrupt the treatment of patients with MDR TB, emerging data suggest that in cohorts of younger patients with few comorbidities, the occurrence of serious adverse effects is rare and does not compromise treatment outcomes. 34 Nonetheless, mild side effects to MDR TB regimens occur frequently, and close surveillance for rare but serious side effects is recommended. These adverse effects will be reviewed in Chapter 7. Through daily contact between patients and supervising health workers, DOT not only ensures adherence, but also permits the prompt identification and management of adverse effects. Through effective side-effect management and regular therapy, aggressive treatment is tolerated and amplification of resistance is avoided, thus minimizing chances of treatment default or failure. 35 The DOTS-Plus program should be firm yet supple: without compromising directly observed therapy and regular clinical attendance, flexibility of hours and site should be allowed when needed. Given practical implications of MDR TB treatment which may involve three doses a day for two or more years administration of DOT must often occur outside of health centers to accommodate patients work constraints and family obligations. In fact, administration of medications exclusively in health centers may promote nosocomial transmission of MDR TB; we recommend that DOT occur at home rather than in the clinic until MDR TB patients smear-convert. 36 While therapy is best supervised by individuals trained in the use of second-line drugs, as noted in prior chapters, a broad variety of health workers can be trained to administer these agents in an effective manner, including people involved in community projects, local shop owners, neighbors, Chapter Five Therapy for MDR TB 67

5 relatives and community health workers. A number of studies have demonstrated the effectiveness of community health workers in responding to serious challenges to health. 37,38,39,40,41,42,43,44,45,46,47,48 In Peru and Haiti, local community residents have been trained to serve as DOTS-Plus outreach workers. Their role includes supervision of DOT, identification of adverse effects, communication with other health providers, and provision of social and emotional support. 5.2 Review of antituberculous agents Effective therapy for TB has existed since the 1940s. 49 When compared to the body of knowledge concerning drugs developed in the last three decades to treat other bacterial infections, scant information is available concerning antimycobacterial drugs. 50 No new antituberculous drugs have been developed for years. The lack of information about antituberculous drugs reflects the paucity of research on TB therapeutics over the last 20 to 30 years. Now, MDR TB has sparked renewed interest in both historical drugs for TB as well as newer drugs with potential antituberculous activity.while we mention key aspects of the agents used to treat MDR TB below, please refer to Apppendix 2 for more detailed information on these agents. First-line drugs are defined as those used in combination in the standard WHO recommended DOTS program. Isoniazid (INH): 51,52 One of the two most potent antituberculous agents (along with RIF), INH is one of the most bactericidal. INH is a nictotinic acid derivative that inhibits mycolic acid synthesis. Drug susceptibility testing at serial concentrations to INH is often performed because INH may still be effective at high doses in multi-drug resistant strains. 53,54 By definition, MDR TB is resistant to at least INH and RIF. Rifampin (RIF): 55,56 As noted, is one of the two most potent antituberculous agents. RIF blocks mrna transcription and synthesis. It is highly bactericidal. Of note, rifabutin and rifapentine are derivatives of RIF that possess partial cross-resistance to RIF. 57,58 Pyrazinamide (PZA): 59 Pyrazinamide is an important bactericidal drug. It is a nicotinamide derivative whose precise mechanism of action is unknown. The addition of two months of PZA to INH and RIF was the first short-course (6-month) regimen known to cure TB. In treating MDR TB, we recommend doses of mg/kg. Ethambutol (EMB): 60,61 Ethambutol was introduced in the 1960s to replace PAS (Para-aminosalicylic acid) because it is better tolerated than PAS. It is bacteriostatic at conventional doses (15mg/kg). Its mechanism of action is the inhibition of lipid and cell wall metabolism. As with pyrazinamide, higher doses (up to 25 mg/kg) are used when treating drug-resistant strains. Streptomycin (SM): 62,63 Streptomycin, the first antituberculous drug, was discovered in the 1940s by Dr. Waksman who went on to win the Nobel Prize. Streptomycin is bactericidal. Its mechanism of action is the inhibition of protein synthesis through disruption of ribosomal function. It must be given as an intramuscular injection since it forms an insoluable precipitate in intravenous solution. Second-line drugs include other agents used to treat resistant strains of TB. Kanamycin (KM), Amikacin (AMK) and Capreomycin (CM): 64,65,66,67 Aside from SM, other aminoglycosides such as kanamycin and amikacin are effective against TB. Capreomycin, while not an aminoglycoside, is equally bactericidal and has a similar side-effect profile as the aminoglycosides. These agents also work by interfering with protein synthesis at the level of the ribosome. 68 Chapter Five Therapy for MDR TB

6 Quinolones: 68,69,70,71 The fluoroquinolones are a relatively new class of drugs that were not developed to treat mycobacterial infection. However, the quinolones are bactericidal against M. tuberculosis and importantly, they are also active in macrophages where bacilli are concentrated. Their mechanism of action is through inhibition of DNA gyrase. Quinolones are considered by many experts to have the best activity and least toxicity of the second-line antituberculous drugs. 72 Levofloxacin is the active moiety of ofloxacin and therefore may be more potent than ofloxacin. Newer broad-spectrum quinolones such as sparfloxacin and moxifloxacin may be more active against TB than ofloxacin and ciprofloxacin. 73 Although cross-resistance among quinolones is felt to be near-complete, there is some data to suggest that the broader-spectrum quinolones may still be active against strains which are resistant in vitro to a narrow-spectrum quinolone. 74 Ethionamide (THA), Prothionamide (PTH): 75,76 These are isonicotinic acid derivatives that are bacteriostatic against tuberculosis. Dose is often limited by GI side effects and prothionomide may be better tolerated. They have a high degree of cross resistance with one another and with INH and thiacetazone as well. Para-aminosalicylic acid (PAS): 77,78 Para-aminosalicylic acid is bacteriostatic. Less GI toxicity may be observed in the delayed-release microcapsule formulation of PAS.The microcapsules must be taken with something acidic (e.g. juice or yogurt) in order to be completely absorbed. Cycloserine (CS): 79,80 Cycloserine is an alanine analogue that interferes with cell-wall proteoglycan synthesis. Cycloserine is also bacteriostatic. Because it penetrates the blood-brain barrier, CS is the drug of choice for TB involving the central nervous system. However, the high CNS penetration and interaction with the NMDA receptor results in neuro-psychiatric side effects. 81 Thiacetazone (THZ): 82 A weakly bactericidal inhibitor of mycolic acid synthesis, thiacetazone has been widely used despite its high side-effect profile because of its low cost. Cross-resistance is frequently observed between THZ and both INH and THA. Other drugs for TB possess in vitro activity against TB with little in vivo data. Although not considered true antituberculous agents, they may provide therapeutic reinforcement in cases with highly resistant strains. Clofazimine (CFZ): 83,84 Clofazimine is a bacteriostatic drug and generally considered a weak antituberculous agent because of early animal studies. It is active within macrophages and is used against Mycobacteria leprae. Clofazimine is active against tuberculosis in vitro and results in reduced mortality in mouse models. Because clofazimine is highly concentrated in tissues, the concentration of drug in the lung, spleen, and liver is significantly higher than the mean inhibitory concentration (MIC). Amoxicillin-clavulanic acid (AMX-CLV): 85 Mycobacteria produce β lactamase enzymes which make β lactam antibiotics ineffective against them. However, the addition of a β lactamase inhibitor, such as clavulanic acid, inhibits the mycobacteria s ability to hydrolyze β lactam antibiotics. Thus, AMX-CLV has bacteriostatic activity against TB in vitro, though this activity is weak and may be improved by other drugs. 86 Clarithromycin (CLR): 87,88 Although this macrolide has demonstrated efficacy against M. avium complex, data on its role against M. tuberculosis are conflicting. Although in vitro antimycobacterial properties have been reported, the clinical utility of clarithromycin remains to be determined. 89,90,91,92 Chapter Five Therapy for MDR TB 69

7 Other drugs have been suggested for use against MDR TB, but given the scant literature available on their effectiveness, we have chosen not to use these drugs in our program. Some of these medications include metronidazole, imepenem, inhaled interferon, linezolid, and immunotherapy with M. vaccae. 93,94,95,96,97,98 If more data emerges showing that these agents have high levels of efficacy in vitro and their costs are not prohibitive, they may prove to be useful therapeutic tools for future use. 5.3 Individualized versus standardized approaches to MDR TB treatment Under the DOTS-Plus aegis two basic models of MDR TB treatment have been proposed; one using individualized treatment regimens (ITR) based on drug susceptibility testing (DST) to the full range of first- and second-line drugs and another using standardized, empiric, MDR TB treatment regimens (STR). The attributes of each of these are outlined below. Figure 5.1 Comparison of approaches to MDR TB treatment ITR STR Efficacy Maximum Moderate-High Cost High Moderate-High Risk of amplification Very Low Low-Moderate Toxicity Moderate Moderate Technical capacity required 99,100,101 High Moderate ITRs allow clinicians to design regimens based on data for each particular patient, thus minimizing the likelihood of inadvertent amplification of drug resistance since patients will not receive drugs to which their infecting strains have documented resistance. This approach requires initial DST, adjustment of treatment regimens based on laboratory results and often, non-standardized dosing of antituberculous agents, all of which render this approach initially expensive. However, the long-term costs of ITRs may well prove lower as they can achieve high cure rates and avoid the recruitment of additional resistance. In the standardized approach, all patients enrolled are administered a single treatment regimen regardless of the susceptibility pattern of each patient s infecting strain. It does not rely on DST for each patient and thus can be initially less costly, but it requires knowledge of local epidemiology to design an empiric MDR TB treatment regimen appropriate for the setting in question. Since all patients receive standardized doses of the same drugs, it provides greater ease of administration and management, but the likelihood of treatment success may be lower depending on the proportion of cases with strains resistant to the drugs included in the STR.The long-term costs of the standardized approach may be higher as those cases that fail the STRs recruit additional resistance in the process, require subsequent treatments, and pose an infectious risk for a longer duration of time Chapter Five Therapy for MDR TB

8 5.4 Initial approach to MDR TB treatment The presence of drug resistance is often suspected before culture and DST are performed. When there is high clinical suspicion of MDR TB, short course chemotherapy should be stopped as soon as possible to avoid the amplifier effect of inappropriate therapy wherein further resistance is generated. 103 In regions with access to DST, the patient s isolate should be sent for testing. If the patient is clinically stable, treatment may be deferred until susceptibility data arrive. Alternatively, empiric MDR TB therapy may be initiated while awaiting drug susceptibility data. Once DST data is available, a definitive regimen can be created based on the DST results. In referred patients with documented drug resistance, any failing therapy should be suspended. Given the possibility of resistance amplification, DST should be repeated if the patient has received any antituberculous drugs since the last susceptibility test. Again, empiric MDR therapy can be administered while awaiting repeat drug susceptibility results, with the definitive regimen to be based on DST results. If there has been no further therapy since the latest DST, the patient may initiate therapy with a definitive regimen. The importance of adequate empiric MDR therapy cannot be overemphasized. Empiric therapy should aim to provide the most efficacious treatment possible and prevent amplification of drug resistance. Improved outcome has been demonstrated when patients with MDR TB receive prompt therapy with multiple drugs to which their isolates are later shown to be susceptible (i.e. multiple drugs that the patient has not received before). 104,105 The use of inappropriate therapy while awaiting susceptibility results may lead to the amplification of drug resistance, rendering the resistance data when it does arrive unreliable. Figure 5.2 Suspecting MDR TB Suspicion of MDR TB Stop failing therapy Confirm positive culture for DST prior to starting empiric MDR TB treatment Base empiric regimen on treatment history, contact susceptibility data, and regional resistance patterns Adjust to definitive regimen according to susceptibility data Documented MDR TB Stop failing therapy If TB treatment since last DST, confirm positive culture for repeat DST prior to starting MDR TB treatment Base regimen on prior susceptibility data, subsequent treatment history Chapter Five Therapy for MDR TB 71

9 Whether empiric or not, an individualized regimen for MDR TB should follow basic principles. First, the history must be reviewed to predict the infecting strain s likely resistance pattern. In addition to those drugs to which resistance has been documented, drugs to which resistance is likely but unconfirmed should also be avoided, if possible. Resistance should be considered when the patient has previously received a drug (in cases where no DST has been performed) or when the patient has received a drug subsequent to documented susceptibility. Additionally, if the patient is a close contact of a patient with MDR TB, primary resistance should be suspected with a similar or identical resistance pattern. Finally, regional resistance data should be considered in cases of suspected primary resistance; for instance, in regions where SM resistance is endemic, empiric therapy should use an alternative parenteral agent. Standardized treatment regimens are designed using similar principles, drawing on regional epidemiology to predict resistance patterns. Figure 5.3 Design of an empiric individualized treatment regimen Principles of empiric ITR design Consider treatment history and previous DST (if available) Consider contact treatment history and DST Consider regional epidemiology Avoid drugs to which resistance is suspected Foundation of at least four, ideally five, drugs including parenteral agent Reinforcement with additional drugs if appropriate Adjust to definitive regimen according to susceptibility data Principles of STR design Consider regional epidemiology Avoid drugs to which resistance is suspected Foundation of at least four, ideally five, drugs including parenteral agent 5.5 Principles of foundation design The MDR TB treatment foundation provides a base around which therapy is subsequently tailored with additional reinforcement and adjuvant measures if needed. The foundation consists of four to five drugs to which the infecting strain is likely susceptible. 106 Guiding principles in foundation design include the following: Use a minimum of four (ideally five) drugs Include a parenteral drug, whenever possible Include first-line drugs to which the infecting strain is likely susceptible Include a fluoroquinolone, whenever possible Avoid drugs to which resistance is documented or suspected 72 Chapter Five Therapy for MDR TB

10 Avoid drugs to which the patient has a documented allergy Choose the most efficacious drugs available (e.g., choose bactericidal over bacteriostatic drugs) Use high-end recommended dosing of all agents as tolerated All patients should receive pyridoxine (B6) during the course of MDR TB treatment, at a dose of 150 mg/day Parenteral agents Because of their bactericidal activity, the use of aminoglycosides and capreomycin are considered a cornerstone in the DOTS-Plus regimen. Each regimen should include an aminoglycoside or capreomycin for a minimum of six months. In addition to local epidemiology, history of previous treatment, drug susceptibility data, and other factors such as relative efficacy and cross-resistance between parenteral drugs influence the choice of parenteral therapy. SM is considered first-line in patients who have not previously received this drug and who have no history of renal insufficiency, hearing loss, or a peripheral neuropathy. However, if data from epidemiologic surveys demonstrate significant rates of primary resistance to SM, as is the case in Russia, an alternative parenteral agent should be chosen for empiric therapy even in patients who have never received SM. For patients who have received SM or who have strains resistant to SM, an alternative parenteral should be considered while awaiting DST data. As a second choice of parenteral agent, we favor capreomycin, which we have found to be very well tolerated. Other aminoglycosides notably, kanamycin and amikacin are also effective against M. tuberculosis; cross-resistance with streptomycin is seen in fewer than 40% of strains. 107,108,109 For patients with renal insufficiency, hearing loss or a peripheral neuropathy, CM should be considered; its side-effect profile is similar to the aminoglycosides, but adverse events may be less common. If creatinine clearance is significantly reduced, parenteral therapy should be renally dosed First-line agents First-line agents should be used whenever possible, since they are more powerful and better tolerated than most second-line drugs. High-end dosing is recommended for EMB (25 mg/kg) and PZA (30 mg/kg) unless poorly tolerated. Although cross-resistance between RIF and its derivatives is common (>70%), rifabutin or rifapentine should be used whenever susceptibility is documented, given their potency and lack of associated adverse effects. 110, Fluoroquinolones Highly efficacious and well tolerated, a quinolone should be included as part of the foundation whenever possible. 112 At this writing, the choice among the fluoroquinolones depends largely on economic considerations. As previously mentioned, broad-spectrum quinolones such as sparfloxacin, gatifloxacin and moxifloxacin may possess more potent antimycobacterial activity; although cross-resistance does exist among the quinolones, the MICs for broad-spectrum fluoroquinolones are much lower and in vivo may benefit despite documented resistance to a narrow-spectrum quinolone. 113 These drugs, however, are expensive in most countries. Sparfloxacin is also associated with rash and photosensitivity in up to eight percent of those who receive it and is less readily available in many markets Remaining second-line agents Other second-line drugs, such as ethionamide, cycloserine and PAS, should be added to complete a foundation of four or five drugs.the choice of second-line agents may be guided by their side effect Chapter Five Therapy for MDR TB 73

11 profiles and by any co-morbidities the patient may have. Regional patterns of drug resistance may also influence this decision. While higher-end dosing of these drugs is preferred, lower doses may be necessary depending on weight and tolerance.a gradual increase toward maximum recommended dose is tolerated by most patients with normal weight for height. Figure 5.4 Foundation design of definitive ITR Parenterals SM if never received, no toxicity-related co-morbidities, and low rates of primary resistance CM if suspected or confirmed resistance to SM KM/AMK if suspected or confirmed resistance to SM, although some cross-resistance with SM CM if toxicity-related co-morbidites (renal insufficiency, hearing loss, peripheral neuropathy) First-line drugs First-line agents if susceptibility confirmed or likely Maximum doses for PZA and EMB RIF derivatives if documented susceptibility although cross-resistance with RIF common Quinolones Choice often guided by economic factors Near-complete cross-resistance Broad-spectrum quinolones more active against TB; possible in vivo benefit even when resistance to narrow-spectrum quinolones Remaining second-line agents Complete foundation with THA, CS, PAS Choice guided by side-effect profiles, patient co-morbidities, regional resistance data Maximum doses as tolerated 5.6 Principles of regimen reinforcement In addition to the minimum four- to five-drug foundation, reinforcement of the empiric DOTS-Plus foundation may be considered. If there is a sufficient number of standard antituberculous drugs to constitute a four- or five-drug regimen, the use of additional drugs in an empiric regimen is not always warranted. In clinically advanced cases or in cases with suspected or confirmed high-grade drug resistance, reinforcement is recommended. Radiographic assessment of the degree of parenchymal damage provides a useful indicator of potential treatment response when designing empiric therapy. Patients with extensive bilateral involvement are often those needing more aggressive therapy. 74 Chapter Five Therapy for MDR TB

12 Any first-line drug to which susceptibility is deemed likely but not confirmed can be utilized to provide reinforcement until DST is available. In fact, empiric therapy for any patient lacking drug susceptibility data should often include INH, RIF, and/or PZA in addition to a foundation of second-line drugs to which resistance is less likely. Furthermore, in a patient who receives a first-line drug subsequent to documented susceptibility to this drug, resistance to this agent is possible and, while such agents are not to be counted on, they can be used as reinforcement while awaiting further DST. Additional second-line drugs to which susceptibility is also deemed likely may also reinforce regimens, depending on the clinical picture. Toxicity risks must be weighed against the benefits of regimen reinforcement. However, in some patients with significant disease and worsening course, the use of all available oral second-line drugs available is encouraged. If side effects are promptly identified and aggressively managed, the disadvantages of such aggressive regimens are, in our experience, dwarfed by the advantages. Also used for reinforcement are a number of drugs shown to have antimycobacterial properties in vitro. Because their contribution to the efficacy of multidrug regimens is unclear, these drugs which include amoxicillin-clavulanic acid, clarithromycin, and clofazimine should be considered as reinforcing agents only. Their utility is primarily among patients with longstanding disease ( chronics ) and those sick with strains resistant to six or more drugs. A second parenteral may be incorporated into the DOTS-Plus foundation if the degree of resistance and clinical state of the patient are such that there are an inadequate number of oral agents to comprise an effective regimen. In such instances, CM as a second parenteral minimizes excess aminoglycoside toxicity. Closer surveillance of renal function is appropriate in such circumstances as is regular monitoring of electrolytes. Also to be considered when treating cases due to highly resistant strains are drugs to which intermediate or partial resistance is observed. Certain laboratories report testing at various drug concentrations and/or quantification of colony growth. Susceptibility testing at serial drug concentrations provides data on varying degrees of strain resistance. Strains which demonstrate drug resistance only at low concentrations may respond to higher doses of that drug. For instance, in patients infected with strains demonstrating in vitro susceptibility to high-dose isoniazid, twice weekly isoniazid at 900 mg may be effective in exceeding MICs for strains resistant to this drug at conventional doses. 114 Also relevant are the number of colonies or proportion of growth that may be reported in susceptibility test results. Isolates with fewer colonies or a lower proportion of growth may be partially susceptible or demonstrate intermediate resistance. Although the in vivo benefit of such drugs has not been determined, their use may be considered in clinically advanced cases. Finally, in cases with a high degree of drug resistance and a documented adverse reaction to an antituberculous drug, desensitization may be considered. Chapter Five Therapy for MDR TB 75

13 Figure 5.5 Reinforcing the regimen First-line drugs to which susceptibility is thought likely while awaiting DST Additional second-line drugs Drug with in vitro efficacy Second parenteral (CM preferred) Drugs to which partial resistance is observed, e.g. high-dose INH Drugs to which allergy documented, through densensitization 5.7 Design of the definitive regimen While drug susceptibility data may be challenging to interpret, it provides a valuable correlate to the patient s clinical picture. The use of drug susceptibility data in designing a DOTS-Plus regimen ensures appropriate and efficacious treatment. 115 Even in a program where STRs are used, accurate regional drug susceptibility data is essential for designing an appropriate empiric regimen. Although there is considerable variation among laboratories (see Appendix 8), there is evidence to support the use of in vitro drug susceptibility data in guiding clinical decisions. 116 As previously mentioned, if a patient has no DST data or has received antituberculous drugs subsequent to the latest drug susceptibility data, an isolate should be sent for DST just prior to initiating empiric therapy. Upon receipt of susceptibility data, the empiric regimen should be adjusted to yield a definitive DOTS-Plus regimen.the specific changes to be made in each regimen vary from patient to patient and depend on a number of clinical and bacteriological parameters: Always retain, whenever possible, a four- or five-drug foundation Add any efficacious drug to which susceptibility is documented Discontinue any drug to which resistance is documented Choose the most efficacious injectable to which susceptibility is documented Consider discontinuing less efficacious drugs while maintaining an ample foundation, although these agents may be retained as reinforcement Consider additional reinforcement in cases of high-grade resistance Consider further susceptibility testing to additional drugs (e.g. clarithromycin, thiacetazone) in cases of high-grade resistance 76 Chapter Five Therapy for MDR TB

14 Figure 5.6 Case example 8: Predicting amplification in designing empiric therapy MB is a 22 year-old student first diagnosed with TB when he presented with hemoptysis, night sweats, and fever. Despite six months of DOTS, he failed to smear-convert.thereafter, he sought treatment with a private doctor, receiving three months of INH, RIF, EMB, and KM on a regular basis, without improvement. At that time, he was documented to be sick with a strain resistant to INH and RIF, but nonetheless received an eight-month directly observed regimen of INH, RIF, EMB, PZA, and SM. At the time of evaluation, persistent hemoptysis and cavitary disease suggested active TB. Empiric therapy was initiated immediately after a positive culture was confirmed and sent for DST. In addition to his documented resistance to INH and RIF, further resistance to EMB, PZA and SM may have been recruited during subsequent therapy. Thus, his empiric regimen consisted of CM (1 g), CS (1000 mg), CPX (1500 mg),tha (1000 mg), PAS (12 g) as a foundation, using PZA (30 mg/kg) and EMB (25 mg/kg) as reinforcement given possible susceptibility. Figure 5.7 Case example 9:Treatment failure LR is a 46 year-old male first diagnosed with TB when he presented with cough, weight loss, and fever. He failed DOTS (INH, RIF, PZA, EMB) and subsequent therapy with INH, RIF, PZA, EMB, and SM. Once a positive culture was confirmed and sent for DST, empiric therapy was initiated consisting of CM (1 g), THA (1000 mg), CS (1000 mg), CPX (1500 mg), PAS (12 g), with additional reinforcement of INH (300 mg) and RIF (600 mg). Two months later, susceptibility results revealed resistance to INH, RIF, EMB, and SM, while susceptible to PZA and KM. Therefore, the following changes were made: INH and RIF were discontinued. PZA replaced PAS, and KM replaced CM. The definitive regimen was: KM, THA, CS, CPX, and PZA. Chapter Five Therapy for MDR TB 77

15 Figure 5.8 Case example 10: Primary MDR TB AG is a 19 year-old patient with newly diagnosed TB referred for DOTS-Plus evaluation given contact history. He presented two weeks prior with a positive smear and massive hemoptysis. His only TB contact was his mother, whose isolate demonstrated resistance to INH, RIF, EMB, PZA, SM, and THA. Given his dire clinical status, empiric therapy was initiated without delay once a smear-positive sample was sent for conventional and BACTEC DST. AG s empiric regimen was based on his mother s resistance pattern. KM (1 g) was chosen as the injectable, with CPX (1500 mg), CS (1000 mg), and PAS (12 g) completing the foundation. INH (300 mg) and RIF (600 mg) provided reinforcement to the regimen. Four weeks later, BACTEC results confirmed resistance to all first-line drugs; thus INH and RIF were discontinued. Results of conventional testing confirmed a resistance pattern identical to his mother s. At that point, given his life-threatening hemoptysis, additional reinforcements with AMX-CLX (1500 mg) and CFZ (300 mg) were added. Figure 5.9 Case example 11: Primary MDR TB and treatment failure MP is a 16 year-old female first diagnosed with TB when screened as a household contact of an individual with TB. She was found to be smear-positive, and her chest x- ray showed a right upper lobe cavity. She was started on a regimen of INH, RIF, PZA, and EMB but was still smear-positive in her fourth month of directly observed therapy. At that time, her contact was diagnosed with resistance to INH and RIF. MP s sputum was sent for DST as well. Neither MP nor her household contact had received secondor third-line drugs. Based on her own treatment history and the resistance pattern of her contact, MP initiated empiric therapy with SM (1 g), CS (1000 mg), THA (1000 mg), PAS (12 g), OFX (800 mg), as well as EMB (25 mg/kg) and PZA (30 mg/kg). Two months after empiric therapy was initiated, DST revealed resistance to INH at low concentrations, RIF, and EMB. Therefore, high-dose INH (900 mg twice a week) was added, and EMB was discontinued. Given her cavitary disease, no other medications were discontinued, and her definitive regimen consisted of seven drugs to which susceptibility had been demonstrated: SM, PZA, CS,THA, PAS, OFX, and high-dose INH. 78 Chapter Five Therapy for MDR TB

16 Figure 5.10 Case example 12: High-grade resistance AR is a 22 year-old student with a complicated treatment history and various family contacts. When first diagnosed, she received six months of DOTS, but relapsed a few months later. She was subsequently treated four times between 1994 and 1997 receiving KM, CPX, THA, THZ, and AMX-CLV in addition to first-line drugs. At the time of evaluation for DOTS-Plus, she was receiving no antituberculous medications and had no prior DST data. Her chief symptoms were cough and night sweats. Given her stable clinical status and complicated treatment history, treatment was deferred until receipt of susceptibility data. AR s isolate proved resistant to INH, RIF, EMB, PZA, SM, THA, CPX, while susceptible to CM, CS, AMK, KM, and PAS. Additional DST was requested to RFB and CLR. In designing her definitive regimen, the foundation was comprised of AMK, CS, and PAS, with AMX-CLV and CFZ providing reinforcement. Given the high degree of resistance, her regimen was additionally reinforced with a second injectable, CM. Her definitive regimen was thus CM (1 g), AMK (750 mg), CS (1000 mg), PAS (12 g), AMX-CLV (1500 mg), and CFZ (300 mg). 5.8 Discrepant susceptibility results Drug susceptibility testing is a technically difficult process, defined by parameters of growth in culture in the presence of each drug.117,118 Laboratory techniques and resistance criteria vary among labs. It is not uncommon for conflicting results to be encountered on multiple susceptibility tests. In such instances, drug susceptibility testing interpretation may be guided by the following considerations: Technique variation frequently occurs due to differing susceptibility testing methods and laboratories. Certain testing methods have greater sensitivity and specificity than others. If not reported, inquiry should be made regarding the testing method employed; clinical decisions should be based on data produced by the most reliable methods and laboratories. The WHO/IUATLD have named several laboratories throughout the world as global reference centers, and results from these labs should be considered the most reliable.119 Consider the possibility of resistance amplification, particularly if serial drug susceptibility testing demonstrates a chronological increase in resistance during the course of inappropriate therapy. Evidence of amplification requires careful evaluation for treatment failure. If an explanation for discrepant data is not forthcoming, the laboratory that performed the susceptibility testing should be consulted. In cases where discrepant data is not resolved, therapy should be based on the most resistant antibiogram, if possible. Chapter Five Therapy for MDR TB 79

17 Figure 5.11 Discrepant results Consider technique or laboratory variation (reference laboratories most reliable) Review treatment history to assess for resistance amplification Consult laboratory if no explanation for discrepancy In designing regimen, assume resistance in discrepant instances Figure 5.12 Case example 13: Discrepant drug susceptibility results AV is a 19 year-old patient who is referred for DOTS- Plus evaluation due to multiple treatments. She was first diagnosed with TB seven years prior, receiving first-line treatment with good results. Two years later, she relapsed and was treated with the same regimen, but this time failed to respond. She thereafter persisted smear positive throughout a year-long retreatment regimen. NTP susceptibility testing at that time demonstrated resistance to INH, RIF, EMB, and SM, and susceptibility to PZA. DST was performed at a second laboratory, where her isolate was found to be resistant to INH, RIF, PZA, and SM and susceptible to EMB. In this situation, discrepancies may be due to technique variation among the laboratories. While results from the most reliable laboratory are primarily chosen to guide therapy, caution is made to ensure an adequate regimen in any case. In AV s situation, she is treated with KM (1 g), CS (1000 mg), CPX (1500 mg), THA (1000 mg), PAS (12 g) as the foundation. However, PZA (30 mg/kg) and EMB (25 mg/kg) are added for additional possible efficacy, and DST is repeated at a reference laboratory at the time of treatment initiation, the results ultimately showing resistance to INH, RIF, PZA, and SM. 5.9 MDR TB in pediatrics and obstetrics Treatment of children with MDR TB Although there is a large literature on pediatric tuberculosis, 120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137 literature on the treatment of pediatric MDR TB is scant. 138,139,140,141,142 Nonetheless, given the paucity of drugs available to treat MDR TB, careful consideration of risks and benefits of each drug should be made in designing a regimen. Frank discussion with the patient and family members is critical, especially at the outset of therapy. It should be noted that while fluoroquinolones have been shown to retard cartilage development in beagle puppies, 143 experience in the treatment of children with cystic fibrosis has failed to demonstrate similar effects in humans. 144, Chapter Five Therapy for MDR TB

18 In general, drugs should be dosed according to weight (see Appendix A6). Therefore, monitoring monthly weights is especially important in pediatric cases, with adjustment of doses as the child gains weight. 146 Our experience with pediatric cases has demonstrated good treatment response with remarkably few adverse effects. Figure 5.13 Case example 14: Pediatric MDR TB CC is a boy with disseminated multidrug-resistant tuberculosis, first diagnosed with tuberculosis at the age of 18 months. Although gastric aspirates were smear- and culture-negative, chest radiograph was consistent with milliary TB. His only contact was an uncle with MDR TB. CC was therefore treated for presumed primary MDR TB with a regimen consisting of INH, RIF, PZA, KM, and CPX; however, despite regular therapy, he failed to improve. He was transferred to the Instituto de Salud del Niño, he received INH, RIF, PZA, and SM, in addition to prednisone, with partial response, but returned three months later in respiratory distress. Repeat gastric aspirates were smear-negative but yielded a positive culture which was sent for drug susceptibility testing. In the ensuing months, lack of access to a continuous supply of second-line drugs prevented initiation of appropriate therapy. During this period, CC developed a vertebral mass with progressive lower extremity weakness. At the time of referral for DOTS-Plus therapy, CC was 30 months old. He weighed 10 kg and was oxygen dependent. He was alert, emaciated, and tachypneic. Pulmonary exam was notable for bilateral rhonchi and dense right-sided râles. A vertebral deformity was present at T6-7 with flaccid paralysis of the lower extremities. ELISA for HIV was negative. DST performed at the Instituto Nacional de Salud demonstrated resistance to INH, RIF, PZA, and SM, with susceptibility to EMB. Chest radiograph showed opacification of the left lung as well as right-sided infiltrates. MRI identified two cold abscesses at T5-7 and L2-3 with spinal cord compression. CC initiated treatment with EMB (25 mg/kg/d), THA (15 mg/kg/d), OFX (10 mg/kg/d), CS (15 mg/kg/d), PAS (200 mg/kg/d), CM (15 mg/kg/d), and coadministration of pyridoxine and prednisone. He tolerated the regimen with minimal side effects. His weight increased in the first six months to 12 kg. He was weaned off oxygen and by the second month was able to crawl and stand independently. His chest radiograph showed significant improvement in both lungs. Monthly gastric aspirates were smear- and culture-negative. After 10 months of parenteral therapy, CM was discontinued. He is currently culture-negative in his 18 th month of DOTS-Plus treatment. Chapter Five Therapy for MDR TB 81

19 Figure 5.14 MDR TB in pediatrics Scant literature available Risks and benefits of each drug considered Frank discussion with patient and family Not a contraindication to treatment Weight-based dosing, adjusting as patient gains weight In our experience, good response with few adverse effects MDR TB and pregnancy Treating active tuberculosis during pregnancy has proved challenging. 147,148,149,150,151,152,153,154 While teratogenicity has been demonstrated in few of the drugs used to treat MDR TB, most have not been approved for use in pregnancy in large part because there has been little experience treating pregnant women with MDR TB. 155,156,157 Figure 5.13 below lists the antituberculous drugs commonly used in our program, their safety class, and whether or not they are considered safe in breastfeeding. 158 Our view is that pregnancy is not a contraindication to the treatment of active MDR TB, since active, untreated TB and MDR TB also pose great risks to the life of the mother and fetus. 159,160 Nonetheless, all patients of child-bearing age should be tested for pregnancy upon initial evaluation; birth control is strongly recommended to all women receiving MDR TB therapy. Of note, oral contraceptives may have decreased efficacy given drug interactions with MDR TB drugs and we thus recommend the use of depot-medroxyprogesterone (Depo-provera) as well as with barrier methods (e.g. condoms) for pregnancy prevention. Figure 5.15 Safety class and safety in breastfeeding of antituberculous medications 161 Medication Safety class Safe in breastfeeding? Isoniazid C Yes Rifampin C Yes Ethambutol B Yes Pyrazinamide C Unknown Streptomycin D Yes Kanamycin D Yes Amikacin D Yes Capreomycin C Unknown Fluoroquinolones C No Ethionamide C Unknown Cycloserine C Yes PAS C Unknown Clofazimine C No Amoxicillin-clavulaic acid B Yes Clarithromycin C Unknown Rifabutin B Unknown A= safely established using human studies; B= presumed safety based on animal studies; C= uncertain safety, no human studies and animal studies show an adverse effect; D= unsafe, evidence of risk that may be justifiable under certain clinical circumstances Medication Safety class Safe in breastfeeding? 82 Chapter Five Therapy for MDR TB

20 Gravid patients should be carefully evaluated, taking into consideration gestational age and severity of MDR TB. Risks and benefits of MDR TB treatment should be considered carefully with the primary goal of smear conversion in order to protect the health of the mother and her child, both before and after birth. Since the majority of teratogenic effects occur in the first trimester, therapy may be delayed until the second trimester unless life-threatening symptoms occur. Patients in the third trimester have reduced risk of teratogenicity, although aminoglycosides may still damage the fetal ear. Our strategy is to begin treatment in the second or third trimester with three or four oral drugs with demonstrated efficacy against the infecting strain, and then to reinforce the regimen with an injectable and possibly other drugs immediately post-partum.162 This approach has led to excellent results, since the patient is smear-negative at the time of parturition and mother and infant do not need to be separated. We encourage breast-feeding as long as the patient is smear-negative (and ideally, culture-negative). Figure 5.16 MDR TB in obstetrics Scant literature available Risks and benefits of each drug considered Frank discussion with patient and family Not a contraindication to treatment Family planning for all women of child-bearing age receiving MDR TB therapy Start treatment in second or third trimester, sooner if clinically unstable Aim to minimize fetal toxicity and smear-convert prior to delivery Avoid aminoglycoside during pregnancy; add after delivery Breast feeding encouraged if mother is culture-negative Figure 5.17 Case example 15: Pregnancy and MDR TB EM is a 19 year-old patient who is first diagnosed with tuberculosis while in her first trimester. Given multiple sibling contacts with strains resistant to all first-line drugs, her sputum sample is sent for DST. Empiric treatment is deferred, with the plan to start therapy in her third trimester in order to achieve smear conversion prior to delivery. In the second trimester, the patient begins to experience hoarseness, worsened cough, and weight loss. DST reveals resistance to INH, RIF, EMB, and SM. After discussion with the patient about the risks of disease progression versus potential effects of MDR TB therapy on fetal development, she is started on a regimen of PZA (30mg/kg), OFX (800mg), PAS (12g), THA(750mg), and AMX-CLV(1500mg). She smear and culture converts early in her third trimester and delivers a healthy boy without complications. CM (1g) is added post-partum. Chapter Five Therapy for MDR TB 83