Drugs in tuberculosis and leprosy

C H A P T E R

28 Drugs in tuberculosis and leprosy Meenakshi R. Ramanathan, PhamD, BCPS, BCIDP*,†,1, Crystal K. Howell, PharmD, BCPS, BCIDP*,‡, James M. Sanders, PhD, PharmD, BCIDP, AAHIVP*,§ *University of North Texas System College of Pharmacy, Fort Worth, TX, United States † Medical City Arlington, Arlington, TX, United States ‡ Medical City Dallas, Dallas, TX, United States § UT Southwestern Medical Center, Dallas, TX, United States 1 Corresponding author: [email protected]

Abbreviations AE AKI ALT AMG AST ATT AUC BDQ CDC CFZ Cmax/MIC CS CYP 3A4 DM DRESS EMB ESRD FDA FQ HAART HIV IM INH IPT IV LFTs LNZ LTBI MDR-TB PAS PLT PRCA PZA QTc RBT

adverse effect acute kidney injury alanine transaminase aminoglycoside aspartate transaminase anti-tuberculosis treatment area under the curve bedaquiline center for disease control and prevention clofazimine maximum concentration to minimum inhibitory concentration cycloserine cytochrome P450 3A4 diabetes mellitus drug reaction with eosinophilia and systemic symptoms ethambutol end-stage renal disease U.S. food and drug administration fluoroquinolone highly active antiretroviral therapy human immunodeficiency virus intramuscular isoniazid isoniazid preventive therapy intravenous liver function tests linezolid latent tuberculosis infection multidrug-resistant tuberculosis para-aminosalicylic acid platelet pure red cell aplasia pyrazinamide corrected Q-T interval rifabutin

Side Effects of Drugs Annual, Volume 41 ISSN: 0378-6080 https://doi.org/10.1016/bs.seda.2019.08.010

RIF RIPE RMP RPT TB TDF ULN US XDR-TB

rifampin rifampin, isoniazid, pyrazinamide, ethambutol combination therapy rifampicin rifapentine tuberculosis tenofovir disoproxil fumarate upper limit of normal United States extensively drug-resistant

AMINOGLYCOSIDES Aminoglycosides (AMGs) may cause severe treatment limiting toxicities, most notably ototoxicity (vestibular and auditory) and nephrotoxicity, relegating them to second-line therapy for the treatment of TB [1S,2R].

Ototoxicity A review of 108 patients treated from 2014 to 2015 at a TB referral center in India found 13% of the patients experienced ototoxicity—often associated with AMGs. In this study, five patients discontinued kanamycin due to hearing loss and one discontinued kanamycin due to vertigo [3C]. Heysell and colleagues reviewed a prospective cohort of adults treated at a multidrug-resistant tuberculosis (MDR-TB) referral center in Bangladesh. Of the 40 patients with baseline auditory testing available, 45% had underlying hearing loss; upon subsequent treatment with kanamycin, 77.8% of tested patients developed additional hearing loss. Diabetes mellitus (DM) and high dose kanamycin (median dose 18.9 mg/kg)

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© 2019 Elsevier B.V. All rights reserved.

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were purported as underlying factors contributing to higher rates of ototoxicity [4c]. A retrospective cohort of children demonstrated that one-third of children receiving amikacin developed hearing loss, while only 14.3% of kanamycin treated patients developed hearing impairment—primarily sensorineural and high frequency loss [5C].

Nephrotoxicity Shah and colleagues determined that approximately 15% of children treated with AMGs developed nephrotoxicity with only 40% of the patients developing the toxicity while on AMGs [5C]. Concomitant nephrotoxic medications may exacerbate AMG nephrotoxicity. Perumal and colleagues reviewed 215 patients with drug-resistant TB that received treatment with kanamycin/capreomycin based regimens with or without concomitant tenofovir disoproxil fumarate (TDF), a common antiretroviral associated with nephrotoxicity [6R,7C]. Nephrotoxicity occurred in 32.5% (53/163) of patients on kanamycin and TDF and 16.7% (7/42) on kanamycin without TDF [7C]. Management of patients on AMGs and concomitant TDF may require more intensive monitoring and/or consideration of alternative antiretroviral therapy.

Administration AMGs require parenteral administration limiting ease of delivery, especially in the ambulatory setting. The utilization of intramuscular (IM) injections offers an alternative administration strategy. A randomized single-blinded crossover study compared IM kanamycin injections with and without lidocaine. Lidocaine reduced pain at the time of injection and 15 min after the dose [8c]. A qualitative review, utilizing patient and guardian interviews, focusing on community-based guardian delivery of IM streptomycin showed acceptance and preference over hospital-based treatment [9c]. Guardian delivery may offer a better accepted and safe means for treating TB that may lead to enhanced compliance.

Monitoring Therapeutic drug monitoring provides a potential means for preventing AMG-associated toxicity and optimizing treatment [10R]. A systematic review of amikacin dosing for the treatment of MDR-TB found a maximum concentration to minimum inhibitory concentration (Cmax/MIC) of 10 to be the optimal parameter for efficacy while area under the curve (AUC) over time correlated to toxicity [11M]. Audiometric monitoring remains a mainstay of long-term AMGs administration for the treatment of MDR-TB [2R]. A longitudinal prospective cohort of 10 patients receiving amikacin for 6 months found

pure-tone and high-frequency audiometry as the best modalities for monitoring for AMG-associated hearing loss [12c]. Salivary monitoring of antitubercular agents represents a less invasive technique to that of blood sampling. A systematic review of salivary therapeutic drug monitoring found insufficient data for AMGs [13M]. Van den Elsen and colleagues tested amikacin saliva concentrations for six patients and found no detectable levels despite detectable serum concentrations [14c].

BEDAQUILINE Bedaquiline (BDQ), a diarylquinoline with enhanced activity against MDR-TB and limited to no crossresistance, provides an attractive alternative, yet concerns remain regarding safety and efficacy [15R,16R]. Possible rationales for providing BDQ to a more expansive population include poor outcomes associated with MDR-TB, potential to shorten therapy duration, relatively benign safety profile relative to other second-line agents, and an associated mortality benefit. On the other hand, the associated cardiotoxicity, pharmacokinetic interactions, potential for development of resistance, and paucity of efficacy trials limit the widespread use of this agent [17R]. Ndejeka and colleagues reviewed 200 patients with extensively drug-resistant TB (XDR-TB) and preXDRTB that received 24 weeks of BDQ in tandem with an optimized background regimen. The median increase in QT interval with Fridericia formula correction (QTcF) was 11 ms and 15 AEs related to a QTcF increase were reported [18C]. A prospective review of 272 patients (68 on BDQ-containing regimen) on XDR-TB treatment in South Africa revealed that 58.8% vs 38.2% of patients had one drug withdrawn due to AE in the BDQ and non-BDQ groups, respectively. Approximately 10 patients had documented QT prolongation, yet no patients had BDQ therapy withdrawn [19C]. Hewison and colleagues conducted a retrospective analysis of BDQ containing MDR-TB treatment regimens. Of the 82 patients, over 75% experienced an AE and 8.5% had a QTcF greater than 500 ms. Two serious AEs were possibly related to BDQ: myocardial infarction and cardiopulmonary failure [20c]. In a retrospective observational study of 57 cases of MDR-TB receiving concomitant BDQ and adjunctive surgery, only 1 patient had QT-interval prolongation [21c]. BDQ does not require renal adjustment for mild to moderate renal failure [15R]. Limited data exist regarding BDQ therapy in end stage renal disease (ESRD). Two patients with ESRD (one on hemodialysis thrice weekly and one with a serum creatinine of 5.1 mg/dL post AMG-induced toxicity) were successfully treated with BDQ-containing regimen. Both patients experienced increases in QTcF from baseline. Nonetheless, no cardiac events were reported [22A].

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CYCLOSERINE

Drug–drug interactions BDQ metabolism occurs via the cytochrome P450 3A4 (CYP 3A4) pathway, which is a common pathway for other antitubercular medications [17R]. A randomized, open-label, prospective study in 33 healthy volunteers compared BDQ levels with daily administration of rifabutin (RBT) or rifampin (RIF). RBT selectively elevated BDQ metabolites suggesting the potential for enhanced toxicity [23c]. Combination therapy with novel agents has been employed due to increasing difficulties in managing MDR-TB and XDR-TB. In particular, the combination of BDQ and delamanid, both sequentially and concomitantly, has been explored to improve efficacy, yet caution exists due to potential for additive cardiotoxicity limiting widespread options of these agents [24MC,25R]. A review of the 11 patients treated with both BDQ and delamanid (one patient on concomitant therapy) found 81.8% had significant QTcF prolongation with 18.2% of patients discontinuing one of the agents due to the effect [26c]. A retrospective cohort of 28 patients in South Africa that received 6–12 months of BDQ and delamanid showed a median increase in QTcF of 16 ms at the 6-month time point. No patients permanently discontinued dual therapy [27c]. A systematic review of available studies with combined BDQ and delamanid found less than 3% of patients had treatment interruptions resulting from life-threatening cardiac events [28M].

CARBAPENEMS Carbapenems demonstrate in vitro activity against Mycobacterium tuberculosis and limited literature support this class as adjunctive therapy for MDR-TB [1S,29R]. Van Rijn and colleagues performed a systematic review and meta-analysis of carbapenem treatment for MDR-and XDR-TB utilizing 50 studies and over 12 000 patients. The authors found better outcomes in patients receiving carbapenems relative to traditional treatment [30M]. A study of 18 patients on meropenem–clavulanate treatment for XDR-TB showed no AEs linked specifically to the medication [31c]. A pharmacokinetic evaluation of ertapenem in TB patients suggests that a 2000 mg dose would achieve target of attainment in over 90% of those tested [32c].

CLOFAZIMINE Clofazimine (CFZ) constitutes an adjunctive therapy for several mycobacterial infections including leprosy and TB with a toxicity profile of skin discoloration and cardiotoxicity (QTc prolongation) [15R,33R]. A 19-year review of 901 leprosy cases treated with multidrug

therapy found no cases of CFZ AEs [34C]. Patients with nonresponsive leprosy treated with multidrug therapy— minocycline, CFZ, and ofloxacin—all had hyperpigmentation,
33% had a gastrointestinal event, and
15% showed transaminitis [35C]. Duan and colleagues conducted a randomized, controlled trial assessing the efficacy of adjunctive CFZ to standard treatment of TB. Of the 66 patients receiving CFZ, 30 reported an AE during the 24-month treatment period. Skin discoloration and hepatic damage were significantly more common in the CFZ group [36C]. CFZ adjunctive therapy for XDR-TB resulted in over half of the patients experiencing a treatment-related AE with skin discoloration being significantly more common in the CFZ group relative to controls, 23% vs 0% (P ¼ 0.014), respectively [37c]. Aznar and colleagues retrospectively reviewed 47 patients with non-tuberculous mycobacterial infections treated with CFZ. Seventy-six percent of the patients reported at least one AE with skin abnormalities occurring in half the patients. QT-prolongation occurred in 10 of the 17 patients tested [38c]. A 55 year old female presented to the emergency department after accidental ingestion of an unknown medication—suspected to be the CFZ—she was taking for leprosy treatment. The patient had a SpO2 of 87% on presentation with further decline and escalation of care to the intensive care unit. Her methemoglobin (MetHb) level was elevated at 26.7 mg% and continued to rise. The patient was treated with ascorbic acid and N-acetylcysteine due to the unavailability of methylene blue. The patient responded over the next few days and left in stable condition [39A]. An observational study of 18 patients showed that CFZ did not significantly prolong QTc with a mean change of 39 ms [40c]. Maartens and colleagues compared concomitant CFZ on bioavailability and metabolites of BDQ and found no significant drug–drug interactions [41c].

CYCLOSERINE Cycloserine-induced neuropsychiatric effects occur in upwards of 50% of patients limiting its use to second-line therapy [1S,42c]. A review of 27 patients on cycloserine (CS) for MDR-TB in China demonstrated an efficacy of
40% and only 2 patients had documented anxiety and depression [43c]. In addition, a 55 year old male following initiation of TB regimen with CS presented to the clinic with suicidal ideation along with insomnia, depression, and restlessness. His regimen also included ethambutol (EMB), pyrazinamide (PZA), ethionamide, kanamycin, levofloxacin, and pyridoxine. His past medical history included no psychiatric history for self or family. CS was stopped and suicidal thoughts resided, but relapsed after patient self-resumed CS with further exacerbation of suicidal thoughts [44A].

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Drug monitoring Highly variable CS levels were seen with therapeutic drug monitoring utilizing doses of 500–750 mg daily. The lower dose resulted in levels less than 20 μg/mL in a third of the patients [43c]. A pharmacokinetic/ pharmacodynamic dosing assessment found that optimizing dosing to achieve cidality may come at the expense of neurotoxicity [45M]. An analysis of CS levels in 25 children found only 44% fell within a therapeutic range of 20–35 μg/mL [46c]. Zhu and colleagues collected 390 samples and over half had CS levels lower than 20 μg/mL. Eleven patients experienced CS-associated AE with levels ranging from 11.7 to 36.9 μg/mL [47C]. Taken together, these studies support the utilization of therapeutic monitoring to ensure an effective balance between efficacy and toxicity.

DAPSONE The treatment of leprosy, similar to TB, relies on multidrug therapy with dapsone being a key component. Established toxicities from dapsone include hematologic abnormalities, gastrointestinal intolerance, hypersensitivity reactions, and hepatitis [33R].

Hypersensitivity A 52 year old female presented to several centers of care with longstanding fever and pruritus while on dapsone. Dapsone hypersensitivity was missed until the patient subsequently presented in organ failure at a tertiary center [48A]. A separate case of dapsone-induced drug reaction was found to be associated with HLAB*13:01 [49A]. A review of dapsone drug reaction with eosinophilia and systemic symptoms (DRESS) in Taiwanese patients found that 85.7% of cases had the HLAB*13:01 allele detected [50c]. These cases illustrate the need for more established screening processes or biomarkers, such as HLA-B*13:01, to aid in predicting and/or identifying dapsone hypersensitivity.

ascorbic acid due to short-term effect in dapsone-induced methemoglobinemia [52E]. A 51 year old male presented to a diabetes clinic upon referral for a low hemoglobin A1c (HbA1c). He reported chest palpitations and dizziness. Cardiac workup was unremarkable, and the patient was found to be on dapsone. His pertinent labs were as follows: hemoglobin ¼ 12.1 g/dL, thyroid stimulating hormone (TSH) ¼ 2.52 mU/L, and HbA1c ¼ 13 mmol/mol. HbA1c returned to 42 mmol/mol upon cessation of dapsone and the patient became asymptomatic [53A].

DELAMANID Delamanid is a nitroimidazole antibiotic used in the treatment of MDR-TB and XDR-TB. It is a well-tolerated medication, but there have been reports of QTc interval prolongation. Previous literature has shown an increased cardiotoxicity risk when taken with BDQ due to increased QT prolonging effects. No adverse effect (AE) data were found in 2018 for delamanid use in TB or leprosy [54A].

ETHAMBUTOL Considered first-line treatment in the intensive phase of active TB, EMB is used in conjunction with RIF, isoniazid (INH), PZA to prevent resistance. However, once the isolate is known to be RIF and INH susceptible, it is generally the first to be removed from the patient’s regimen due to its well-known AE of causing dose-related optic neuropathy. EMB inhibits mycobacterial species by inhibiting the enzyme arabinosyl transferase III, which in turn inhibits the production of arabinogalactan, a cell component of the mycobacteria. The most common optic neuritis AEs patients complain of include decreased visual acuity and red-green color blindness. This AE is reversible once EMB is stopped and generally occurs in a dosedependent, duration-dependent manner. Providers are encouraged to check visual acuity tests at the beginning of treatment and periodically throughout to prevent optic neuritis from occurring [1S,55S,56S,57S,58R].

Hematologic disorders A 53 year old female receiving dapsone for immune thrombocytopenia presented to an emergency department with excess fatigue and was found to be cyanotic. SpO2 was found to be 85% on 2 L of oxygen and pO2 of 81 mmHg. The MetHb resulted as 35.2 g%. She was successfully treated with a combination of methylene blue, N-acetylcysteine, and ascorbic acid [51A]. Ascorbic acid is often used as adjunctive therapy for dapsone-induced methemoglobinemia. Kang and colleagues demonstrate similar effectiveness to methylene-blue in rats and their data supports the practice of repeat administration of

Neurotoxicity and visual disturbances Si and colleagues describe a case report of a 36-year-old Chinese male who was hospitalized for weakness in the lower extremities. The patient had a past medical history of ESRD requiring continuous ambulatory peritoneal dialysis (CAPD) and was diagnosed with pulmonary TB for which he was taking INH, EMB, and rifapentine (RPT) for the past 4 months. The patient developed progressive paralysis of his lower limbs, vision loss, and hoarseness. Final diagnosis was deemed as peripheral neuropathy, retrobulbar neuritis, and laryngeal paralysis.

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HEPATOTOXICITY

For treatment, all anti-tuberculosis treatment (ATT) were discontinued and the patient received pyridoxine 1 mg/kg body weight/day intravenous (IV), mecobalamin 2 mg/day, memantine 10 mg/day, and ganglioside 20 mg/day. The patient was started on a new ATT of levofloxacin 500 mg by mouth every other day and RPT 600 mg/week, which was started 2 weeks after the discontinuation of INH/EMB. The authors concluded that caution is advised in patients with ESRD, as renal clearance is reduced for these medications, predisposing the patients to AEs and that close supervision and increased monitoring is recommended [59A].

FLUOROQUINOLONES The fluoroquinolones (FQs), specifically moxifloxacin, levofloxacin, and ofloxacin, have been used as secondline agents in the treatment of active TB. They work to inhibit DNA supercoiling by blocking DNA topoisomerase II and topoisomerase IV (also known as DNA gyrase). Over the years, more and more data are coming out on the increased risk vs benefit of using FQs in infections that are less severe in nature, such as acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections, including a black box warning to avoid FQ use when alternate agents are available [60S,61S]. AEs such as photosensitivity, neurotoxicity, tendon rupture, and QTc interval prolongation have been well-known. In July 2018, the United States (US) Food and Drug Administration (FDA) released a press release on the increasing risks of FQs on mental health and serious blood sugar disturbances [62S]. In December 2018, the FDA released a safety communication on FQs having increased risk of causing aortic dissection and aortic aneurysm rupture [63S]. Because of their teratogenic nature, FQs should not be used in pregnant TB patients. Caution is advised in the pediatric population due to the risk of cartilage damage. When deciding to use FQs as an alternate agent for active TB, the risks vs the benefits should be weighed due to the increasing amount of evidence of serious AEs associated with the FQs [1S,55S,56S,57S,58R]. No AE data were found for FQ use in TB or leprosy in 2018.

ISONIAZID Considered one of the most active agents against TB, INH is a backbone, preferred medication for active TB (if susceptible) and latent tuberculosis infection (LTBI). It inhibits the synthesis of mycolic acids in the cell walls of mycobacterial species. However, it is not without its AEs, specifically hepatotoxicity, neuropathy, and gastrointestinal disturbances. To reduce the risk of peripheral neuropathy, INH is administered with pyridoxine (vitamin B6) [55S,56S,57S,58R,64S,65S].

HEMATOLOGIC DISORDERS Holla and colleagues describe a patient case of a 28 year old male with pulmonary TB presenting with INHinduced pure red cell aplasia (PRCA). By definition, PRCA is a normocytic, normochromic anemia with severe decreases in reticulocyte count and reduction or absence of erythroid precursor release from the bone marrow. Upon presentation, the patient complained of generalized weakness, being easily fatigued, breathlessness on exertion, and swelling of lower extremities for the past 2 months. The patient had been diagnosed with pulmonary TB 4 months prior and had received an intensive phase with INH 300 mg, rifampicin (RMP) 600 mg, EMB 1100 mg, and PZA 1600 mg for 2 months, followed by 2 months of continuation phase with INH 300 mg, RMP 600 mg, and EMB 1100 mg. The patient’s physical examination was positive for pallor, positive pitting edema in both lower extremities, and increased jugular venous pulse. The patient’s hemoglobin was at 2.8 g/dL with a normochromic normocytic film and a reticulocyte count of 1.1  109/L. INH was thought to be the culprit of the PRCA, and subsequently discontinued. The patient continued with a modified ATT regimen of RMP 600 mg, EMB 1100 mg, and levofloxacin 750 mg. Patient received four blood transfusions with an improvement in hemoglobin to 7 mg/dL along with diuresis. The exact mechanism of INH causing PRCA has not been elucidated, but likely mechanisms include toxic interference by INH metabolites, antibody production against red cell precursors, or DNA synthesis inhibition [66A].

HEPATOTOXICITY Mounika and colleagues studied the rate of hepatotoxicity and other AEs of RIF, INH, and PZA in pulmonary TB Koch patients. This was a prospective, observational study that included 49 patients, which occurred over a 6-month period at the Krishna Institute Medical Sciences (KIMS) hospital in the outpatient pulmonology department in Secunderabad, Telangana, India. The study included TB outpatient’s ages ranged from 18 to 80 years with and without comorbidities. Pregnant/lactating females and patients not willing to provide consent were excluded. Twenty-one males (42.86%) and 28 females (57.14%) were part of this study. Gender differences were noted amongst the patients in terms of prevalence and proportion of AEs. Common AEs reported in female patients included: vomiting (22.81%), diarrhea (22.81%), joint pain (17.54%), skin rash (10.53%), hepatotoxicity (3.51%), and headache (22.81%). Common AEs reported in male patients included: vomiting (25%), diarrhea (25%), joint pain (15%), skin rash (15%), hepatotoxicity (5%), and headache (15%). More headache and joint pain were noted in the female patients, while more vomiting,

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diarrhea, skin rash, and hepatotoxicity were more prominently noted in the male patients. The study concluded that hepatotoxicity was more prevalent in the male population and suggested that further studies should be conducted to determine why male patients are more prone to hepatotoxicity than females [67c]. Past literature has shown the use of INH preventive therapy (IPT) in special populations, including human immunodeficiency virus (HIV) patients. Russom and colleagues present a case series looking at the causal relationship of IPT and hepatotoxicity in HIV patients on highly active antiretroviral therapy (HAART), along with possible risk factors. Thirty-one cases of hepatotoxicity were reported, with a majority of cases considered serious hepatotoxicity (aspartate transaminase (AST)/ alanine transaminase (ALT) elevation of 5.1–10  upper limit of normal (ULN); n ¼ 7) or very serious (potentially life threatening with AST/ALT elevation of >10  ULN; n ¼ 12). Of the cases, 15 patients had life-threatening issues, 6 patients were hospitalized, and 4 patients died. INH was subsequently stopped in 26 patients (83.9%), 12 patients had their HAART switched, and 3 patients had their HAART temporarily stopped. Nineteen of the 31 cases had normal liver function tests (LFTs) at baseline/IPT initiation and had been stable on HAART for several years; thus, discounting that the hepatotoxicity risk was due to HAART. After withdrawal of INH, the hepatotoxicity subsided within a few weeks in 22 cases, while 1 patient had recurrent hepatotoxicity with the reintroduction of IPT. The authors identified that one possible reason for INH-induced hepatotoxicity amongst the patients was inappropriate laboratory monitoring as the World Health Organization (WHO) does not recommend routine laboratory monitoring since INH-induced hepatotoxicity is rare. Overdose is also a possibility as a majority of the patients weighed 50 kg and were receiving INH 300 mg by mouth daily. Patients 35 years or older were also at a greater risk of hepatotoxicity. The authors concluded that close routine laboratory monitoring and effectiveness/risk assessments were necessary to minimize INH-induced hepatotoxicity [68c].

Skin lesions resolved 3 months after INH discontinuation [69A]. The exact mechanism of INH-induced subacute cutaneous lupus erythematosus is unknown, but a genetic predisposition has been linked with slow acetylators with genetic deficiency of N-acetyltransferase. Reactive metabolites may increase the production of lupus-like antibody either directly or indirectly through decreased T-cell methylation with increased lymphocyte function-associated antigen 1 (LFA-1) expression [70r].

MUSCULOSKELETAL DISORDERS Komai and colleagues describe a Japanese 76 YOM patient with a past medical history of rheumatoid arthritis and ESRD presenting with INH-induced rhabdomyolysis [71A]. The patient was taking INH 300 mg by mouth daily for LTBI prior to the start of his biologic agents for rheumatoid arthritis to prevent reactivation of LTBI. On the 8th day of INH therapy, the patient presented with fever, petechiae in the lower limbs, and intermittent myalgia and tenderness in the thighs without weakness. Laboratory tests showed the patient had the following elevated values: serum creatinine 3.8 mg/dL, creatine kinase 11 253 U/L; myoglobin 13900 ng/mL; urine myoglobin 21 850 ng/mL. INH was thought to be the culprit and subsequently discontinued, along with supportive therapy with adequate IV hydration. Within 7 days, the patient’s rhabdomyolysis and AKI had subsided. A month after recovery, the patient was re-challenged with one low dose of INH 200 mg by mouth. The patient again presented with fever and myalgia without elevated serum creatine kinase; thus, diagnosing him with INH-induced rhabdomyolysis. Although rhabdomyolysis has been shown to occur in doses >2.4 g of INH, very few cases reported INH-induced rhabdomyolysis occurring at therapeutic doses [72C,73A, 74A,75A]. Although, the precise mechanism by which this occurs is unclear, one theory is that INH-induced rhabdomyolysis is caused by ATP depletion and mitochondrial dysfunction, similar to statin-induced myopathy and rhabdomyolysis [71A].

IMMUNOLOGIC DISORDERS

LTBI

Luwanda and colleagues present a case report of INHinduced subacute cutaneous lupus erythematosus in a 40-year-old HIV-positive female. Prior to presentation, the erythematous macular eruption, which was located in the malar and periorbital areas, the forehead, and neck, was present for 6 weeks. Eighteen weeks prior, the patient had been started on antiretroviral therapy with coformulated tenofovir/lamivudine/efavirenz once daily and IPT. The patient’s CD4 count was 496 cells/μL and the patient’s INH was subsequently stopped.

In 2018, the literature related to INH AEs in LTBI primarily focused on the use of short-course regimens, which looked into the safety and efficacy of these regimens. According to the Centers for Disease Control and Prevention (CDC), INH 300 mg by mouth daily for 9 months is the preferred regimen for LTBI, but the long duration of therapy may lead to non-adherence [65S]. Thus, researchers have looked into alternate regimens for LTBI, which would show similar efficacy in the prevention of active TB, while also being safe. We present some of the data here:

LTBI

• Safety and Efficacy  A systematic review by Pease and colleagues looking at the AEs associated with RPT and INH vs other regimens for LTBI. Twenty-three randomized and 55 non-randomized studies were included for analysis. The study aimed to see if INH/RPT for 12 weeks once weekly (INH/RPT-3) had similar AEs to standard regimens of INH daily for 9 months (INH-9), INH daily for 6 months (INH-6), 3–4 months of daily INH plus RMP (INH/RMP 3–4), and 3–4 months of RMP daily (RMP 3–4). INH/RPT-3 showed increased frequency of flu-like reactions, but decreased hepatotoxicity with a lower frequency compared to standard therapy. Anaphylaxis, angioedema, and mortality were also reviewed. Higher mortality rates were seen in the INH-6 group. Of the randomized trials, the highest incidence of hepatotoxicity was within the INH/RMP 3–4 group at 6.8% of patients; the lowest incidence was in the INH/RPT-3 group at 1% of 4520 patients. Limitations of the systematic review were the heterogeneity amongst the trials and inconsistent AE reporting [76M]. • Adults  An open-label, parallel-group, multi-center, randomized, controlled, phase 3 study compared the safety and efficacy of oral RIF 10 mg/kg (maximum dose, 600 mg) vs standard treatment with oral INH 5 mg/kg (max dose, 300 mg) with vitamin B6 (pyridoxine) for LTBI. The modified intention-to-treat analysis included 6012 adults (18 years of age or older) from nine countries (Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea). Patients in the RIF group had significantly lower grade 3–5 AEs compared to all of the AEs in the INH group (rate difference, 1.1 percentage points; 95%, 1.9 to 0.4) and also reduced AEs related to the trial drug as decided by an independent panel (1.0 percentage points; 95%, 1.6 to 0.4). The most common grade 3 or 4 events overall were drug-induced hepatitis, which occurred more frequently in the INH group. There was no statistical difference in the rates of conversion to active TB between the groups (P ¼ 0.82). The authors concluded that RIF was non-inferior to INH for the prevention of active TB. The RIF patients were more likely to attain treatment completion with better safety outcomes [77C].  Similarly, two shorter course regimens with RPT and INH (3-month once weekly and a 2-month twice weekly regimen) were examined in older, rural LTBI Chinese patients aged 50–69 in a randomized, controlled study by Gao and

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colleagues. The primary outcome was microbiologically confirmed active pulmonary TB or clinically determined pulmonary TB. The secondary outcomes focused on completion of study therapy, permanent discontinuation of therapy, permanent discontinuation because of AEs, grade 3 and 4 drug-related toxic effects, or death from any cause. A total of 3738 patients were randomized: 1284 patients to the 3-month once weekly regimen (Group A), 1299 patients to a 2-month twice weekly regimen (Group B), and 1155 patients were considered untreated controls (Group C). The study was terminated early due to an unexpectedly high frequency of AEs in both arms. The patients completed a modified regimen for both drugs (8 weeks for Group A and 6 weeks for Group B) and patients were followed for 2 years to check for efficacy of prevention of active TB. Group B showed protective efficacy of >60% at 2 years, despite early termination. There was no difference in the number of deaths amongst the groups (P ¼ 0.245). The rate of hepatotoxicity was similar between the groups (1.02% in Group A vs 1.17% in Group B; P ¼ 0.704). With the modified courses, Group A patients experienced more gastrointestinal reactions (8.60% vs 5.16%, P ¼ 0.006) and influenzalike symptoms (3.60% vs 2.27%, P ¼ 0.046); while more hypersensitivity or allergy was noted in Group B (5.08% vs 3.36%; P ¼ 0.031). The authors concluded that although AEs led to early termination of the study, more studies are needed to assess the efficacy of short LTBI regimens in the elderly given the 2-year protective effect of the 6-week twice weekly RPT plus INH regimen at >60% [78MC].  Kim and colleagues report a case of a 51-year-old female nurse with minimal change disease from her treatment with RIF 600 mg/day and INH 300 mg/ day for LTBI. She presented with nausea, vomiting, general weakness, edema, blood urea nitrogen (BUN) of 18 mg/dL, and a serum creatinine (SCr) of 1.0 mg/dL to clinic. Her RIF and INH were discontinued, but her symptoms continued and a urinalysis had 4+ protein prompted hospital admissions. Renal biopsy confirmed nephrotic syndrome with acute nonoliguric renal failure and minimal change disease. After a week, hemodialysis was discontinued and after 3 months the prednisolone was discontinued. The patient completed 25 days of RIF and INH treatment and was not restarted after her diagnosis of minimal change disease [79c]. • Pediatrics  The safety of LTBI regimens, such as RIF vs INH, was studied in the pediatric population

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(< 18 years of age) in a non-inferiority, multicenter, open-label trial conducted by Diallo and colleagues. A total of 844 LTBI children were randomized from 7 countries (Australia, Benin, Brazil, Canada, Ghana, Guinea, and Indonesia). Of those included in the trial, 128 were under the age of 5 years and none had HIV. Children were randomized to receive either RIF 10–20 mg/kg for 4 months or INH 10–15 mg/kg for 9 months. Primary outcomes focused on AEs of grade 1–5 requiring permanent discontinuation of study medication, while the secondary outcomes focused on treatment adherence, AE profile, and efficacy. The authors concluded that there was no difference in rates of AEs as no events of grades 1 through 5 or permanent discontinuation due to AEs occurred in either group. The RIF group had better adherence/ treatment completion rates. Both treatment arms had similar rates of minor symptoms. The authors stated that the lower frequency of AEs may be due to the lower drug exposure overall. Two patients developed TB in the INH group, compared to no cases in the RIF group (rate difference, 0.37 cases per 100 person-years; 95% CI, 0.88 to 0.14). The authors concluded that RIF had similar rates of safety and efficacy with increased adherence due to the shorter duration of therapy [80C].  Tersigni and colleagues compared the tolerability of INH monotherapy for 6–9 months vs INH/RMP combination therapy for 3–4 months in pediatric patients in a retrospective study. The INH monotherapy group consisted of 64/441 children (14.5%), while 377/441 (88.5%) were treated with INH/RMP combination therapy. The study primarily focused on hepatotoxicity, which was defined as an increase in serum ALT 3  ULN if the patient had symptoms of hepatitis and/or jaundice, or an increase in serum ALT 5  ULN without symptoms, and slight increase of transaminase levels (SITL), which was defined as an ALT value between normal and hepatotoxicity. Normal serum ALT was defined as 46 IU/L. Hepatotoxicity was found in five of the INH/RMP combination therapy patients, while none in the INH monotherapy group experienced hepatotoxicity. No difference was found between the groups from a SITL standpoint (18.7% in the INH monotherapy group and 10.3% in the INH/ RMP combination therapy group). The authors concluded that both regimens were safe and that hepatotoxicity was a rare occurrence, which generally happened within the first month; thus, LFTs should be performed after 1 month of therapy to assess for hepatotoxicity [81C].

LINEZOLID Considered a second-line agent in the treatment of active TB, specifically MDR-TB and XDR-TB, linezolid (LNZ) is an oxazolidinone antibiotic, which inhibits protein synthesis within the mycobacteria by binding to the 50S ribosomal subunit. Well-known AEs for LNZ include hematologic and neurological AEs. Lactic acidosis may occur with longer durations of therapy (months). Because it is known as a weak monoamine oxidase (MAOI) inhibitor, caution is advised with patients taking other serotonergic medications that may place the patient at risk for serotonin syndrome, such as the selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs). In the literature, LNZ AEs have been shown to be dose- and duration-dependent [1S,55S,57S,82A].

HEMATOLOGIC DISORDERS Wang and colleagues presented a case report of a 70 year old female with reversible, recurrent profound thrombocytopenia secondary to LNZ being used to treat MDR-TB. The patient originally presented in July 2016 with pulmonary and extra-pulmonary TB for which she was started on 2 months of RMP, INH, PZA, and EMB combination therapy (RIPE), followed by 3 months of INH and RMP. After completing treatment, the patient was admitted to a tertiary hospital in December 2016 for an enlarged mass in her lower right thoracic wall, which was negative for TB. The patient was found to have MDR-TB and started on amikacin, moxifloxacin, prothionamide, and CS in January 2017. After 2 months of treatment, the patient’s mass became smaller, but due to hearing loss, amikacin was discontinued. However, in August 2017, after 7 months of treatment the mass had worsened and a new-found lymphadenopathy appeared. The patient was readmitted and LNZ 600 mg every 12 h was started. Ten days after treatment initiation, in September 2017, the patient’s platelet (PLT) count dropped from 197  109/L to 5  109/L (normal range 100–300 109/L), and the patient presented with petechiae and ecchymosis in her lower limbs. LNZ was stopped immediately and was given a PLT transfusion. Thirteen days after stopping LNZ, the patient’s PLTs recovered to 121  109/L. LNZ was restarted at a lower dose of LNZ 300 mg/day at the end of September 2017. On the third day of re-introduction, the patient’s PLTs dropped to 75 109/L; thus, LNZ was discontinued once again. On the ninth day after LNZ withdrawal, the patient’s PLT count dropped to a nadir of 5  109/L. Two weeks after discontinuation, the patient’s PLT count recovered to 153  109/L. CFZ was selected to replace LNZ in the patient’s current regimen. In the 10 months of follow-up, no recurrence of thrombocytopenia was seen and the

329

RIFAMYCINS

mass had disappeared. The mechanism of action (MOA) behind this AE remains unclear. Proposed hypotheses are that LNZ may inhibit the release of PLTs from mature megakaryocytes, resulting in thrombocytopenia, inhibit of PLT formation, and/or cause PLT destruction via an immune-mediated mechanism. Factors such as low body weight, longer duration of therapy 14 days, and decreased creatinine clearance have been thought to increase the risk of thrombocytopenia [83A].

MACROLIDES Macrolides are intracellular antibacterial agents that inhibit protein synthesis by binding to the 50S ribosomal subunit of susceptible bacteria. Both clarithromycin and azithromycin have been associated with hepatotoxicity, as well as corrected QT interval (QTc) prolongation. Clarithromycin is contraindicated in patients with cholestatic jaundice or hepatic dysfunction from prior clarithromycin use. Drug interactions are of significant concern with clarithromycin. According to the WHO 2010 guidelines for the treatment of TB, these agents have an unclear role in the treatment of MDR-TB [56S]. In the 2016 update, the guidelines no longer recommend macrolides for treatment of MDR-TB [1S]. No AEs for macrolides were found in the 2018 literature for TB and leprosy.

PYRAZINAMIDE Pyrazinamide (PZA), a pyrazine analogue of nicotinamide, is considered a first-line agent in the treatment of TB. Originally approved in 1971 by the FDA for treatment of TB, the exact MOA is unknown. Common AEs attributed to PZA include nausea, vomiting, hyperuricemia, arthralgia, anemia, and hepatotoxicity. There has been some evidence that the hepatotoxic effects could be attributed to drug-induced decreases in mitochondrial function, are dose-related, and could occur throughout therapy [84E,85S]. Thrombocytopenia, sideroblastic anemia, and an increased serum iron concentrations can also occur. While rare, PZA has been associated with fever, porphyria, dysuria, and photosensitivity. PZA is contraindicated in individuals who have shown hypersensitivity reactions to it, individuals with severe liver damage, and individuals with acute gout [1S,55S,64S]. • Cao and colleagues used urine metabolites from patients diagnosed and treated with RIPE and ultra-performance liquid chromatography–mass spectrometry metabolomics to evaluate drug metabolite pathways in patients that had drug-induced liver injury and those that did not. They found that while PZA is associated with the purine metabolic pathway, the drug and its metabolite’s levels did not correlate with ALT levels [86c].

PARA-AMINOSALICYLIC ACID Para-aminosalicylic acid (PAS) is not currently available in the United States, but is still used in some countries. Even though the drug has been in use since the 1940s, the MOA is still unclear. According to product labeling, the MOA of PAS is suspected to be the inhibition of folic acid synthesis by targeting dihydrofolate reductase and/or iron reduction through inhibition of mycobactin [87E]. Both in vitro and in vivo, PAS has demonstrated to be bacteriostatic against TB and is therefore listed in major guidelines only as combination therapy for MDR-TB [56S,57S,88S]. Historically, this drug has been associated with occurrences of drug-induced hepatitis and is contraindicated in renal disease. In addition, the drug is difficult to tolerate with gastrointestinal symptoms being the most common AE [88S]. • Cheung and colleagues conducted a multi-center retrospective review in Australia to determine predictors and the incidence of hypothyroidism from the use prothionamide and/or PAS for MDR-TB. Nine patients out of 29 developed hypothyroidism including one case of subclinical hypothyroidism. Eight of those cases developed hypothyroidism within 1 year after starting therapy. While there was no difference in the incidence of hypothyroidism between treatment arms, there was a noted trend with higher doses. For prothionamide, there was a statistically higher proportion of hypothyroidism with the 750 mg dose compared to the 500 mg dose (P ¼ 0.03). However, given the small sample size caution must be used when interpreting these results [89c].

POLYPEPTIDES (CAPREOMYCIN) Capreomycin is an intravenous (IV) and IM polypeptide antibiotic used as a second-line agent for MDR-TB. Its MOA is not fully elucidated but does involve inhibition of protein synthesis at the ribosomal level. Although structurally different, capreomycin is often linked to AMGs due to similarities in the proposed mechanisms of action and similar AEs including ototoxicity, nephrotoxicity, and electrolyte disturbances. Serial liver function tests (LFTs) are also recommended with capreomycin due to potential hepatotoxicity. In addition, capreomycin has been observed to cause leukocytosis and leukopenia. Neuromuscular blockade has occurred with rapid infusion of the IV product [90E,91S]. No AEs for polypeptides were found in the 2018 literature for TB and leprosy.

RIFAMYCINS The rifamycins have continued to be a mainstay for multiple indications including active TB (where it is most

330

28. DRUGS IN TUBERCULOSIS AND LEPROSY

commonly used as a backbone agent), LTBI, and leprosy. There have been numerous attempts in the literature to compare fixed dose combination regimens as well as shorter durations of treatment with rifamycins. Of the rifamycins, rifampicin (RMP) also known as RIF is the most common agent used in practice. Other agents in the rifamycin class used for TB include rifabutin (RBT) and rifapentine (RPT). As the rifamycins, especially RIF, are potent CYP 3A4 inducers, one must take into account the multiple drug–drug interactions at play, especially in HIV co-infected patients. Many of the available antiretroviral therapies including protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are dependent on this cytochrome P450 system for metabolism. Historically, rifamycins have been associated with hepatotoxicity including drug-induced hepatitis, flu-like symptoms, thrombocytopenia, leukopenia, anemia, and hyper-sensitivity reactions such DRESS. The most notable AE for patients is typically the staining of body fluids red [92S]. • Bessaleli and Scheinfeld published a case of a 63 year old female receiving clindamycin, RIF, topical gentamicin, and dapsone gel for hidradenitis suppurativa for 15 weeks before presenting to the emergency room with weakness, nausea, vomiting, headaches, and diarrhea. She was discovered to have a C. difficile infection and was treated with multiple regimens before being diagnosed with post infectious irritable bowel disease. The article postulates that the combination of RIF and clindamycin could have been related to the cause of the C. difficile infection. As this is a case report, it is not possible to differentiate the potential risk factors and confounders [93c]. • A double-blind, randomized, placebo-controlled phase II trial was conducted to determine the appropriate dose (450 mg or 10 mg/kg, 900 mg or 20 mg/kg or 1350 mg or 30 mg/kg) for TB meningitis in patients greater than 14 years of age. There were 60 patients with TB meningitis that received treatment with one of the three doses for RIF plus other ATT, and dexamethasone. HIV was present in only six of the patients. While there was no statistical difference in 6 month mortality between the treatment arms, the overall 6 month mortality was 32% (95% CI 19.5–48.1%). There was no statistical difference in other AEs evaluated including purpura, thrombocytopenia, leukopenia, anemia, hepatotoxicity, nausea, vomitus, abdominal discomfort, diarrhea, pruritus, and rash [94c]. • Te Brake and colleagues evaluated RIF’s effect on metformin concentrations and subsequent blood glucose levels through a pharmacokinetic study of 24 patients (12 men and 12 women) who were taking metformin for DM. RIF did increase metformin AUCs and Cmax but did not significantly impact blood

glucose levels. Notably, the baseline blood glucose with RIF was 127 mg/dL and without RIF was 148 mg/dL (P ¼ 0.081) despite no patients being on 2–2.5 g daily of metformin [95c].

LTBI • A multi-center, open-label, non-inferiority, randomized, controlled trial evaluated AEs in 844 children assigned to either 4 months of RIF or 9 months of INH for LTBI. For further details regarding AE information, please refer to the LTBI section under INH [80C]. • Kim and colleagues report a case of a 51-year-old female nurse with minimal change disease from her treatment with RIF 600 mg/day and INH 300 mg/day for LTBI. For further details regarding AE information, please refer to the LTBI section under INH [79c]. • Menzies and colleagues conducted an open-label, randomized, multi-center, non-inferiority trial comparing 9 months of INH with 4 months of RIF for LTBI. Refer to the INH section on LTBI for more details on the AEs noted in this study [77C]. • Pease and colleagues performed a systematic review of AEs for LTBI comparing INH for 6 months, INH for 9 months, INH and RFP for 3 months, RIF for 3–4 months, and INH and RIF for 3–4 months. Refer to the INH section on LTBI for more details on AEs noted in this systematic review [76M].

TERIZIDONE Terizidone is a bacteriostatic second-line agent for MDR-TB used internationally, but is not currently approved in the United States. It is a combination of two molecules of CS. The MOA includes competitively inhibiting L-alanine racemase and D-alanine ligase to inhibit cell wall synthesis. Known AEs are considered to be fewer than with CS, but still include seizures, dizziness, slurred speech, tremors, insomnia, confusion, depression, and suicidal tendencies. For doses >1 g per day there have been reports of hepatotoxicity, congestive heart failure, convulsions, and coma [96r]. Since terizidone is considered to be as efficacious as CS with fewer AEs, it can be used instead of CS when needed [56S,96r]. No AEs for terizidone were found in the 2018 literature for TB and leprosy.

THIOAMIDES Thioamides including ethionamide and prothionamide are considered interchangeable second-line bacteriostatic agents for MDR-TB [57S]. The MOA is not fully understood but involves inhibiting peptide synthesis.

331

THIOACETAZONE

Ethionamide is contraindicated in patients with severe hepatic impairment. Gastrointestinal AEs compose the majority of reported adverse reactions with 50% of patients unable to tolerate even 1 g of the drug. Psychotic disturbances have also been reported and rare AEs such as optic neuritis, diplopia, blurred vision, a pellagra-like syndrome, and peripheral neuritis have been reported historically. Ethionamide is also known to transiently increase LFTs and cause hepatitis. Product labeling also recommends avoiding taking with alcohol due to a possible psychotic reaction [97S]. Prothionamide has been historically associated with menstrual disturbances and it is recommended that blood sugar levels should be measured in patients with DM [98r]. Due to gastrointestinal symptoms, ethionamide and prothionamide are usually avoided in combination with PAS [56S]. • For information on a retrospective review by Cheung and colleagues evaluating prothionamide’s association with hypothyroidism, please see the section on PAS [89c].

THIOACETAZONE Thioacetazone is bacteriostatic against TB with a relatively unknown MOA. There have been some reports that suggest one of the targets of thioacetazone is cyclopropane mycolic acid synthases [99E]. However, thioacetazone has fallen out of favor due to severe AEs including nausea, vomiting, diarrhea, anemia, thrombocytopenia, abdominal pain, agranulocytosis, ataxia, blurred vision, vertigo, seizures, deafness, and cerebral edema. Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis have also been historically reported to a significant enough degree that the drug has been discontinued and is contraindicated in HIV patients [100r]. According to international guidelines, this agent has an unclear role in the treatment of MDR-TB [56S]. No AEs for thioacetazone were found in the 2018 literature for TB and leprosy. TABLE 1

Outcomes data The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment—2017 reviewed the literature to estimate the treatment success, treatment failure, and death associated with individual TB medications in MDR-TB patients. The collaborative also reviewed the optimal number and duration of treatment with these medications. This individual patient data meta-analysis consisted of 12 030 patients from 25 countries in 50 studies. Of the second-line and thirdline agents, LNZ (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), BDQ (0.10, 0.05 to 0.14), and CFZ (0.06, 0.01 to 0.10) were positively associated with treatment success. LNZ (0.20, 0.23 to 0.16), levofloxacin (0.06, 0.09 to 0.04), moxifloxacin (0.07, 0.10 to 0.04), and BDQ (0.014, 0.19 to 0.10) showed reduced mortality overall. Of the injectable medications, kanamycin and capreomycin showed worsened outcomes, while amikacin proved modest benefits. Patients with XDR-TB had the highest rate of failure or relapse at 14%, while HIVpositive patients, especially patients not on antiretroviral therapy had the highest mortality. The authors emphasized that only susceptible medications should be used in the treatment regimens to increase treatment success and reduce the risk of mortality. Association of treatment success and death for each individual medication can be found in Table 1 for MDR-TB and Table 2 for XDR-TB. The authors concluded that increased rapid expansion of laboratory testing and resistance was necessary to many countries to allow individualization of treatment of patients while avoiding the use of ineffective drugs that may have subsequent toxicities and increased costs. Although further prospective studies are needed, the meta-analysis showed that agents traditionally used for MDR-TB may be less effective in terms of treatment success and increased mortality as compared to later

Association of each drug with treatment success and death during treatment. Propensity score matched multivariate regression

Drug given (events/total)

Drug not given (events/total)

Crude OR (95% CI)

Pairs (n)

Adjusted OR (95% CI)

I2

Adjusted RD (95% CI)

• Success

2374/2605

588/667

1.4 (1.1–1.8)

2598

0.9 (0.7–1.1)

5.2%

0.01 (0.03 to 0.01)

• Death

397/3002

95/762

1.1 (0.8–1.4)

3001

1.0 (0.9–1.2)

NC

0.00 (0.02 to 0.02)

• Success

874/1040

3064/3489

0.7 (0.6–0.9)

1040

0.8 (0.6–1.1)

NC

0.02 (0.05 to 0.01)

• Death

307/1347

599/4088

1.7 (1.5–2.0)

1344

1.7 (1.4–2.1)

NC

0.07 (0.04 to 0.10)

Ethambutol Susceptible strains

Resistant strains

Continued

332

28. DRUGS IN TUBERCULOSIS AND LEPROSY

TABLE 1

Association of each drug with treatment success and death during treatment.—cont’d Propensity score matched multivariate regression

Drug given (events/total)

Drug not given (events/total)

Crude OR (95% CI)

Pairs (n)

Adjusted OR (95% CI)

I2

Adjusted RD (95% CI)

• Success

1683/1818

249/268

1.0 (0.6–1.6)

1818

0.7 (0.5–0.9)

NC

0.03 (0.04 to 0.01)

• Death

168/1986

39/307

0.6 (0.4–0.9)

1986

0.7 (0.6–0.8)

NC

0.03 (0.05 to 0.01)

• Success

925/1065

1043/1143

0.6 (0.5–0.8)

1064

0.5 (0.4–0.7)

18.0%

0.05 (0.08 to 0.03)

• Death

197/1262

133/1276

1.6 (1.3–2.0)

1262

1.5 (1.2–1.9)

31.2%

0.05 (0.02 to 0.07)

Pyrazinamide Susceptible strains

Resistant strains

Ethionamide or prothionamide Susceptible strains • Success

3027/3435

306/339

0.8 (0.6–1.2)

3434

0.8 (0.7–0.9)

NC

0.02 (0.04 to 0.01)

• Death

628/4063

55/394

1.1 (0.8–1.15)

4062

0.9 (0.8–1.0)

NC

0.00 (0.02 to 0.01)

• Success

893/1082

426/486

0.7 (0.5–0.9)

1082

0.6 (0.5–0.8)

32.6%

0.06 (0.09 to 0.03)

• Death

209/1291

72/558

1.3 (1.0–1.7)

1291

1.8 (1.4–2.2)

NC

0.06 (0.04 to 0.09)

Resistant strains

Cycloserine or terizidone Susceptible strains • Success

5017/5684

984/1160

1.3 (1.1–1.6)

5682

1.5 (1.4–1.7)

34.1%

0.05 (0.03 to 0.06)

• Death

1065/6749

415/1575

0.5 (0.5–0.6)

6744

0.6 (0.5–0.6)

34.4%

0.09 (0.10 to 0.07)

• Success

217/273

129/144

0.5 (0.2–0.8)

257

0.7 (0.4–1.1)

NC

0.04 (0.10 to 0.01)

• Death

76/349

20/164

2.0 (1.2–3.4)

331

0.9 (0.6–1.3)

NC

0.02 (0.04 to 0.09)

Resistant strains

Para-aminosalicyclic acid Susceptible strains • Success

2230/2605

2865/3272

0.8 (0.7–1.0)

2605

0.8 (0.7–1.0)

0.2%

0.01 (0.03 to 0.01)

• Death

702/3307

678/3950

1.3 (1.2–1.5)

3307

1.2 (1.1–1.4)

68.1%

0.02 (0.00 to 0.04)

244/298

295/334

0.6 (0.4–0.9)

297

0.8 (0.5–1.2)

NC

0.04 (0.10 to 0.02)

50/348

32/366

1.8 (1.1–2.8)

346

2.3 (1.4–3.9)

NC

0.08 (0.4 to 0.12)

• Success

959/1017

406/455

2.0 (1.3–3.0)

1017

1.5 (1.1–2.1)

NC

0.02 (0.00 to 0.04)

• Death

104/1121

78/533

0.6 (0.4–0.8)

1121

0.8 (0.6–1.1)

NC

0.02 (0.04 to 0.01)

• Success

81/93

406/455

0.8 (0.4–1.6)

87

0.3 (0.1–1.1)

NC

0.09 (0.17 to 0.01)

• Death

19/112

78/533

1.2 (0.7–2.1)

109

0.8 (0.4–1.6)

NC

0.03 (0.14 to 0.07)

Resistant strains • Success • Death a

Streptomycin

Susceptible strains

Resistant strains

333

THIOACETAZONE

TABLE 1

Association of each drug with treatment success and death during treatment.—cont’d Propensity score matched multivariate regression

Drug given (events/total)

Drug not given (events/total)

Crude OR (95% CI)

Pairs (n)

Adjusted OR (95% CI)

I2

Adjusted RD (95% CI)

• Success

1302/1394

406/455

1.7 (1.2–2.5)

1393

2.0 (1.5–2.6)

9.4%

0.06 (0.04 to 0.08)

• Death

250/1644

78/533

1.0 (0.8–1.4)

1644

1.0 (0.8–1.2)

NC

0.00 (0.03 to 0.02)

• Success

100/110

406/455

1.2 (0.6–2.5)

110

0.5 (0.2–1.5)

NC

0.06 (0.13 to 0.02)

• Death

25/135

78/533

1.3 (0.8–2.2)

134

1.1 (0.6–2.0)

NC

0.01 (0.11 to 0.08)

• Success

2192/2523

406/455

0.8 (0.6–1.1)

2523

0.5 (0.4–0.6)

52.9%

0.07 (0.08 to 0.05)

• Death

435/2958

78/533

1.0 (0.8–1.3)

2958

1.1 (0.9–1.2)

22.9%

0.01 (0.01 to 0.02)

• Success

118/156

406/455

0.4 (0.2–0.6)

155

0.3 (0.1–0.6)

32.7%

0.15 (0.24 to 0.07)

• Death

41/197

78/533

1.5 (1.0–2.3)

194

2.1 (1.2–3.8)

3.2%

0.10 (0.03 to 0.17)

• Success

821/938

406/455

0.8 (0.6–1.2)

938

0.8 (0.6–1.1)

NC

0.03 (0.06 to 0.00)

• Death

176/1114

78/533

1.1 (0.8–1.5)

1114

1.4 (1.1–1.7)

NC

0.04 (0.01 to 0.7)

186/222

406/455

0.6 (0.4–1.0)

216

0.8 (0.5–1.4)

NC

0.03 (0.09 to 0.04)

42/264

78/533

1.1 (0.7–1.7)

261

2.1 (1.2–3.6)

NC

0.08 (0.02 to 0.13)

• Success

226/230

258/355

21.2 (7.7–58.7)

210

7.9 (2.7–23.2)

NC

0.09 (0.04 to 0.14)

• Death

51/281

292/647

0.3 (0.2–0.4)

263

1.4 (0.9–2.2)

NC

0.09 (0.03 to 0.15)

• Success

1563/1865

258/355

1.9 (1.5–2.5)

1865

1.0 (0.8–1.2)

54.1%

0.01 (0.04 to 0.01)

• Death

420/2285

292/647

0.3 (0.2–0.3)

2285

0.6 (0.5–0.7)

19.1%

0.08 (0.11 to 0.06)

• Success

1361/1450

258/355

5.7 (4.2–7.9)

1450

4.2 (3.3–5.4)

25.8%

0.15 (0.13 to 0.18)

• Death

182/1632

292/647

0.2 (0.1–0.2)

1632

0.6 (0.5–0.7)

NC

0.06 (0.09 to 0.04)

• Success

974/1031

258/355

6.4 (4.5–9.2)

1031

3.8 (2.8–5.2)

21.3%

0.11 (0.08 to 0.14)

• Death

114/1145

292/647

0.1 (0.1–0.2)

1145

0.5 (0.4–0.6)

33.4%

0.07 (0.10 to 0.04)

Amikacina Susceptible strains

Resistant strains

Kanamycina Susceptible strains

Resistant strains

Capreomycina,b Susceptible strains

Resistant strains • Success • Death c

Ciprofloxacin

Susceptible strains

c

Ofloxacin

Susceptible strains

c

Levofloxacin

Susceptible strains

Moxifloxacin

c

Susceptible strains

c

Levofloxacin or moxifloxacin vs ofloxacin

Continued

334

28. DRUGS IN TUBERCULOSIS AND LEPROSY

TABLE 1

Association of each drug with treatment success and death during treatment.—cont’d Drug given (events/total)

Drug not given (events/total)

Crude OR (95% CI)

Propensity score matched multivariate regression Pairs (n)

Adjusted OR (95% CI)

I2

Adjusted RD (95% CI)

Strains resistant to ofloxacin, and not resistant to levofloxacin or moxifloxacin • Success • Death

581/726d d

59/98e e

2.6 (1.7–4.1)

715

1.7 (1.3–2.2)

31.1%

0.08 (0.04 to 0.13)

202/928

60/158

0.5 (0.3–0.6)

927

0.9 (0.8–1.2)

NC

0.02 (0.01 to 0.06)

• Success

722/799

5066/5864

1.5 (1.2–1.9)

799

3.4 (2.6–4.5)

55.6%

0.15 (0.11 to 0.18)

• Death

84/883

1456/7320

0.4 (0.3–0.5)

883

0.3 (0.2–0.3)

77.0%

0.20 (0.23 to 0.16)

• Success

485/564

5321/6106

0.9 (0.7–1.2)

564

1.5 (1.1–2.1)

28.7%

0.06 (0.01 to 0.10)

• Death

115/679

1292/7398

1.0 (0.8–1.2)

679

0.8 (0.6–1.0)

NC

0.04 (0.08 to 0.00)

f

Linezolid

Susceptible strainsg

Clofazimine Susceptible strainsg

Amoxicillin-clavulanic acid No drug susceptibility testing • Success

768/972

3443/3943

0.5 (0.5–0.7)

972

0.6 (0.5–0.8)

NC

0.07 (0.10 to 0.03)

• Death

234/1206

717/4660

1.3 (1.1–1.6)

1206

1.7 (1.3–2.1)

80.6%

0.06 (0.04 to 0.09)

Macrolides No drug susceptibility testing • Success

560/723

2628/3093

0.6 (0.5–0.7)

722

0.6 (0.5–0.8)

10.9%

0.08 (0.12 to 0.3)

• Death

185/908

562/3655

1.4 (1.2–1.7)

908

1.6 (1.2–2.0)

75.3%

0.06 (0.02 to 0.09)

Bedaquiline No drug susceptibility testing • Success

431/491

6312/7220

1.0 (0.8–1.4)

490

2.0 (1.4–2.9)

NC

0.10 (0.05 to 0.14)

• Death

59/550

1569/8789

0.6 (0.4–0.7)

548

0.4 (0.3–0.5)

33.5%

0.14 (0.19 to 0.10)

Imipenem and meropenem (carbapenems) No drug susceptibility testing • Success

130/139

6871/7861

2.1 (1.1–4.1)

138

4.0 (1.7–9.1)

57.8%

0.14 (0.06 to 0.21)

• Death

30/169

1674/9535

1.0 (0.7–1.5)

168

1.0 (0.5–1.7)

NC

0.00 (0.09 to 0.08)

The analyses were done in patients with isolates with confirmed susceptibility or resistance to each drug. For the analysis of the injectable drugs, 613 individuals did not receive any injectable drug, and we excluded 857 other patients who received two drugs or more. We included 192 patients in this analysis who were switched to a second-line injectable drug from streptomycin because they had isolates that were streptomycin-resistant and susceptible to the second-line injectable, and these patients were analysed as receiving a second-line injectable drug. For the analysis of fluoroquinolones, 828 patients received two or more fluoroquinolones and were excluded from analyses of effect of specific fluoroquinolones on outcomes. The dose of levofloxacin was 750–1000 mg per day in 33 of 36 studies reporting use of this drug, and the dose of moxifloxacin was 400 mg per day in 28 of 32 studies reporting use of this drug. Results were adjusted as described in the Methods. OR, odds ratio; RD, risk difference; NC, not calculated. a Injectable drug: denominator is number of patients who did not receive any injectable drug. b 1838 patients received capreomycin and no other second-line injectable drug (77% of all patients receiving capreomycin) at 18 centres where this was the most commonly used secondline injectable drug. c Fluoroquinolone; denominator is number of patients who did not receive any fluoroquinolone. d Levofloxacin or moxifloxacin used. e Ofloxacin used. f Used in 38 studies. The initial dose of linezolid was 1200 mg for 91 patients in five studies, 600 mg for 784 patients in 28 studies, and 300 mg for 99 patients in five studies. g If drug susceptibility tests were not done, isolates were assumed as being susceptible to these drugs (see Methods).

335

REFERENCES

TABLE 2

Association of selected drugs used in extensively drug-resistant tuberculosis with success and death. Propensity score matched multivariate regression

Drug given (events/total)

Drug not given (events/total)

Pairs (n)

Adjusted OR (95% CI)

I2

Adjusted RD (95% CI)

• Success

62/69

384/551

68

2.5 (0.9–6.6)

NC

0.09 (0.04 to 0.22)

• Death

15/84

395/946

83

0.4 (0.2–0.8)

NC

0.16 (0.30 to 0.03)

• Success

52/74

394/546

73

0.9 (0.5–1.9)

15.1%

0.01 (0.16 to 0.14)

• Death

19/93

391/937

93

0.9 (0.5–1.9)

40.5%

0.01 (0.13 to 0.10)

Injectables Amikacina

b

Kanamycin

Capreomycin (all patients) • Success

217/338

229/282

332

0.5 (0.4–0.7)

3.7%

0.14 (0.20 to 0.07)

• Death

354/692

56/338

675

3.4 (2.7–4.3)

NC

0.25 (0.20 to 0.30)

Capreomycin (sensitive patients only) • Success

72/91

229/282

91

0.8 (0.4–1.7)

6.0%

0.04 (0.16 to 0.08)

• Death

25/116

56/338

115

3.8 (1.6–8.9)

NC

0.16 (0.07 to 0.25)

Other drugs Levofloxacin or moxifloxacinc • Success

279/360

119/182

359

1.2 (0.8–1.6)

7.7%

0.01 (0.05 to 0.06)

• Death

122/482

253/435

482

0.6 (0.4–0.8)

NC

0.07 (0.12 to 0.02)

• Success

255/281

221/392

280

6.6 (4.1–10.6)

7.3%

0.31 (0.24 to 0.38)

• Death

33/314

418/810

314

0.2 (0.1–0.3)

7.5%

0.29 (0.36 to 0.23)

• Success

141/173

335/500

173

1.5 (0.9–2.6)

NC

0.04 (0.04 to 0.13)

• Death

43/216

408/908

216

0.4 (0.2–0.6)

19.7%

0.18 (0.27 to 0.10)

• Success

126/145

350/528

139

2.5 (1.3–4.8)

NC

0.12 (0.03 to 0.21)

• Death

18/163

433/961

155

0.5 (0.2–0.9)

NC

0.09 (0.17 to 0.02)

Linezolid

Clofazimine

Bedaquiline

The analyses were done for all patients with extensively drug-resistant tuberculosis, and all patients who received each drug were compared with all patients who did not receive that drug. Patients who switched injectable drugs were excluded, as were patients who switched fluoroquinolones. OR, adjusted odds ratio; RD, adjusted risk difference; NC, not calculated. a Of the 84 patients that received amikacin, 39 were susceptible. b Of the 93 patients who received kanamycin, 12 were susceptible. c All of these patients were resistant to ofloxacin; only 175 had drug susceptibility testing results to later generation fluoroquinolones, and all of them were resistant.

generation medications like LNZ, levofloxacin, moxifloxacin, BDQ, CFZ, and the carbapenems [101M]. The readers can find additional recent literature in these reviews [102R,103R].

Acknowledgements The authors are grateful to Brook Amen, the research and education librarian at UNTHSC, for her continued support throughout the project, especially in reviewing databases for background literature.

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