and Agents Anti-Tuberculosis Agents

Christine Kubin, Pharm.D., BCPS Clinical Pharmacist, Infectious Diseases NewYork-Presbyterian Hospital Columbia University Medical Center

Fungi Review of our Fungal “Players”

Yeasts Moulds Opportunistic fungi Newly emerging fungi Mucormycosis – Normal flora Fusarium (rarely septate) Pneumocystis Aspergillus sp. Candida spp. Scedosporidium Candida sp. jiroveci Dimorphic (septate) Rhizopus Rhizomucor – Ubiquitous in our environment Trichosporin Histoplasmosis Mucor Aspergillus spp. Cryptococcus Blastomycosis Absidia neoformans Coccidioidomycosis Cryptococcus spp. Paracoccidioidomycosis [Zygomycetes] Mucor spp. Sporotrichosis Chromoblastomycosis Dermatophytes Trichophyton Endemic geographically restricted Microsporum Miscellaneous Epidermophyton Blastomyces sp. Pseudoallerscheria boydii Coccidioides sp. (Scedosporium apiospermum) Scedosporium prolificans Histoplasma sp. Penicillium marneffei Fusarium sp. Phaeohyphomycosis (dark walled fungi)

Risk Factors for Fungal Disease An optimal antifungal drug has...

Candidiasis Aspergillosis – – Granulocytopenia (↓ neutrophil numbers or – Indwelling catheters neutrophil numbers or Wide spectrum of activity function) – Hyperalimentation function) – T-cell dysfunction Favorable pharmacokinetic profile – Multiple abdominal – T-cell dysfunction Adequate in vivo efficacy HOST FUNGUS surgeries hematologic and other malignancies Low rate of toxicity – Prosthetic material Low rate of toxicity organ allograft recipients Low cost – Severe burns immunosuppressive – Neoplastic therapy diseases/ – – Immunosuppressive – Chronic granulomatous therapy disease DRUG – Diabetes mellitus – AIDS – Extremes of age – Burn patients

1 Invasive Aspergillosis Mortality Systemic Antifungal Agents By Mechanism of Action Review of 1941 Patients from 50 Studies 100 Membrane disrupting Nucleic acid inhibitor agents – 80 – Amphotericin B Glucan synthesis 60 Ergosterol synthesis inhibitors inhibitors – Echinocandins 40 – Azoles

Case Fatality Rate (%) 20

0 Overall (1941) BMT (285) Leuk/Lymph (288) Pulm (1153) CNS/Dissem (175)

Lin S-J et al, Clin Infect Dis 2001; 32:358-66

The Promise of a Dynamic Era… Systemic Antifungal Agents

Fluconazole The Azoles – Fluconazole (Diflucan®) Ketoconazole Caspofungin – Itraconazole (Sporanox®) Amphotericin B Itraconazole – Voriconazole (Vfend®) Flucytosine Voriconazole – Posaconazole (Noxafil®) Posaconazole Amphotericin B – Amphotericin B deoxycholate (Fungizone®) – ABCD (Amphotec®) – ABLC (Abelcet®) 1950 1960 19701980 1990 2000 – Liposomal Amphotericin B (Ambisome®) Echinocandins Micafungin – Caspofungin (Cancidas®) Lipid – Micafungin (Mycamine®) amphotericin – Anidulafungin (Eraxis®) products Flucytosine (Ancobon®)

Targets of Antifungal Agents Amphotericin B

mannoproteins A polyene Clinical use since 1960

Yeast Insoluble in water β1,3 – Solubilized by sodium deoxycholate β1,6 Most broad spectrum antifungal glucans Most broad spectrum antifungal – “gold standard” PPL bilayer beta-1,3 glucan synthase chitin Pharmacokinetics Echinocandins – Extensively tissue bound - Caspofungin Ergosterol Highest concentrations in liver, spleen, - Micafungin • Polyene antibiotics marrow with less in kidneys and - Anidulafungin lung - Amphotericin B lung - Lipid-AMB – Half-life • Azole antifungals Tissue ~15 days, Plasma ~5 days - Ketoconazole DNA Synthesis - Itraconazole - Fluctyosine - Fluconazole - Voriconazole - Posaconazole

2 Amphotericin B Binds to Ergosterol Amphotericin B and Generates Pores Most broad spectrum antifungal – long considered the “gold standard” Clinical activity Pharmacokinetics – Candida sp. – Intravenous formulation only Mechanism of action C. lusitaniae often resistant – Distribution – Binds to ergosterol and alter cell – Cryptococcus neoformans Extensively tissue bound membrane permeability → cell – Blastomycosis – Half-life death – Histoplasmosis Tissue ~15 days – Also binds to cholesterol → – Aspergillus sp. Plasma ~5 days adverse effects – Zygomycetes Toxicities Rhizopus sp., Mucor sp., etc. – Nephrotoxicity Little to no activity – Infusion Related Reactions – Aspergillus terreus, (IRRs) Aspergillus nidulans, – Electrolyte Abnormalities Aspergillus flavus, Fusarium – Thrombophlebitis sp., Pseudoallescheria boydii, – Anemia Scedosporium prolificans, Trichosporon beigelii

Clin Microbiol Rev 1999; 12: 501.

Available Lipid-Based Lipid Amphotericin B Product Amphotericin B Agents Comparison Amphotericin B Amphotericin B lipid Amphotericin B colloidal Liposomal amphotericin B Factor complex deoxycholate dispersion (ABCD, (Ambisome) Product Chemical Structure (ABLC, Abelcet®) Amphotec®) Liposomes, small Particle Micelle Lipid disks Ribbons, sheets unilamellar vesicles Flattened, ribbon-like complex. Lipid Complex Molecular ratio (drug:lipid) = 3:7 Size (nm) <25 100 500-5000 90 ABLC; Abelcet®

Particle size = 1,600 – 11,000 nm. Infusion related toxicity High High Moderate Mild

Nephrotoxicity ++++ ± ± ± Colloidal Dispersion Elongated disk structure. ABCD; Molecular ratio (drug:lipid) = 1:1 Serum concentrations Amphocil® or compared to conventional ↓ ↓ ↑ Particle size = 120 - 140 nm. amphotericin Amphotec®

Tissue concentrations Liver: ↑ Liver: ↑ Liver: ↑ compared to conventional Lungs: ↔ Lungs: ↑ Lungs: ↔ Closed, fluid-filled liposome. amphotericin Kidney: ↔ Kidney: ↔ Kidney: ↔ Liposomal Molecular ratio (drug:lipid) = 1:9 L-AmB; Molecular ratio (drug:lipid) = 1:9 0.5-1.5 Dosage 3-4 mg/kg/day 5 mg/kg/day 3-5 mg/kg/day Ambisome® Particle size = 45 - 80 nm. mg/kg/day

Aggregate Efficacy Estimates of AMB Azole Antifungals Formulations in Open-Label Studies – Ketoconazole

Invasive Aspergillosis Invasive Candidiasis Triazoles

AMB-deoxy AMB-deoxy – Itraconazole – Fluconazole L-AmB L-AmB – Voriconazole – Posaconazole ABLC ABLC Mechanism of action ABCD ABCD Mechanism of action – Inhibit ergosterol synthesis through inhibition of 5 15 25 35 45 55 65 75 85 95 5 15 25 35 45 55 65 75 85 95 CYP450-dependent lanosterol 14-α-demethylase % Complete and Partial Response % Complete and Partial Response Depletion of ergosterol on fungal cell membrane

The EFFICACY of the lipid-based amphotericin B products appears Resistance to be COMPARABLE to AMB or better with LESS TOXICITY. – ERG 11 mutations (gene encoding 14-α sterol demethylase) leading to overexpression – ↑ azole efflux – ↑ production or alteration 14-α-demethylase Ostrosky-Zeichner et al. Clin Infect Dis 2003;37:415-25.

3 Azole Antifungals Spectrum of Activity Understanding the Candida species

Organism Ketoconazole Fluconazole Itraconazole Voriconazole Posaconazole

Yeast Fluconazole Itraconazole Voriconazole Posaconazole Flucytosine Ampho B Echinocandins

C. albicans ++ ++++ +++ ++++ ++++ C. albicans S S S S S S S Resistant yeasts + ++ ++ +++ +++ C. tropicalis S S S S S S S Cryptococcus ++ ++++ +++ ++++ ++++

C. Moulds S S S S S S S to R (?) parapsilosis Aspergillus 0 0 +++ ++++ ++++ C. glabrata S-DD to R S-DD to R S to I S to I S S to I S Other moulds 0 0 + +++ +++

C. krusei R S-DD to R S to I S to I I to R S to I S Zygomycetes 0 0 0 0 +++

C. lusitaniae S S S S S S to R S Endemic fungi ++ +++ ++++ +++ +++

Pappas et al. CID 2004; 38: 161-89.

Fluconazole Itraconazole

Favorable pharmacokinetic and toxicity profile LIMITATIONS Pharmacokinetics Drug Interactions – Low mw and high water solubility → rapid absorption and ↑ bioavailability – Only ionized at low pH → wide interpatient – Propensity and extent greater than >90% bioavailability (IV and PO interchangeable) variability in plasma concentrations fluconazole – Nonlinear serum PK – Substrate of CYP3A4 and inhibitor of CYP3A4 – No dependence on low gastric pH – Extensively liver metabolized Rifampin, phenytoin, phenobarbital – Effectively penetrates CSF (50-90% plasma levels) Adverse effects CYA Brain and eye too! – Transient GI upset, dizziness, headache IV itraconazole – >90% renal excretion – Hepatotoxicity (~5%) – Formulated in hydroxypropyl-β- – Negative inotrope Adverse effects cyclodextrin Adverse effects – Increases solubility of itraconazole – Very well tolerated – Renal dysfunction Even up to 1600 mg/day A 6-fold ↓ cyclodextrin clearance in pts with CrCL<20 ml/min (therefore – GI, reversible transaminase elevations not recommended in pts with Dose CrCL<30 ml/min) – 100-800 mg/d (max 1600 mg/d) Spectrum – Paraccoccidiodomycosis, blastomycosis, histoplasmosis and sporotrichosis, cutaneous and 6 mg/kg/d for susceptible strains (400 mg/d) mucosal candidiasis, Aspergillosis 12 mg/kg/d for S-DD strains (800 mg/d) Dosing – IV and oral interchangeable (>90% bioavailability) – 200 mg IV q12h x 4 doses, then 200 mg IV q24h followed by 200 mg PO q12h oral solution Target troughs >0.5 mcg/mL

Voriconazole Voriconazole Precautions (AND LIMITATIONS?) Second generation synthetic derivative of fluconazole Adverse effects – addition of methyl group to the propyl backbone – Transient, dose related visual disturbances (30%) – substitution of triazole moiety with a fluropyrimidine group Mechanism unknown – ↓ electrical currents in retina – Elevated liver function tests (~13%) May be dose-related – Skin reactions (6%) Drug interactions Dosing – Intravenous 6 mg/kg IV q12h x 2 doses, then 4 mg/kg IV q12h Active against yeast and moulds – Oral (>95% bioavailability on empty stomach) – Fungicidal in vitro against Aspergillus spp., Scedosporium spp., Fusarium spp. <40 kg – 100 mg PO q12h – Fungistatic in vitro against Candida spp. >40 kg – 200 mg PO q12h Organ dysfunction Indications – Renal disease Oral dosing recommended in patients with CrCL<50 ml/min – Invasive aspergillosis IV vehicle, sulfobutyl ether beta-cyclodextrin, accumulates – Esophageal candidiasis – Hepatic disease – Fungal caused by Scedosporium apiospermum and Fusarium spp. in Maintenance dose should be halved in patients with mild/moderate liver disease patients intolerant of or refractory to other therapy Maintenance dose should be halved in patients with mild/moderate liver disease

4 Posaconazole (Noxafil®) Azole Inhibition of CYP P450 Indications – Prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised hosts, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia (≥ 13 yrs old) Dose (40 mg/5 mL oral suspension ONLY) – Prophylaxis: 200 mg (5 mL) PO TID with a high fat meal or nutritional Posaconazole supplement – Treatment: 200 mg PO 4x/day or 400 mg PO BID Drug interactions – Substrate of P-gp and inhibitor of CYP3A4 – Cimetidine decreases POSA bioavailability Adverse effects – N/V, hepatic Clinical uses – Prophylaxis – Salvage therapy – Zygomycetes

Flucytosine (5-FC) Flucytosine Pharmacokinetics – Oral only – Distribution Mechanism of action CSF levels ~75% of serum levels – Flucytosine is deaminated to 5-fluorocytosine (5-FC) – Elimination – Incorporated into RNA and disrupts protein synthesis 90% excreted via glomerular filtration Half-life ~3-6 hours Resistance – Renal/hepatic disease – Develops during therapy, especially monotherapy Dose adjust in renal dysfunction Single point mutation Adverse effects – Loss of permease necessary for cytosine transport – Dose-dependent bone marrow suppression (↓ WBC, ↓ ) – ↓ activity of UMP pyrophosphorylase or cytosine deaminase – GI (nausea/vomiting/diarrhea) Clinical uses Spectrum – Cryptococcal meningitis, hepatosplenic candidiasis, Candida – Cryptococcus neoformans endophthalmitis – Candida sp. (except C. krusei) – Used in combination ONLY (usually with amphotericin) – Little to no activity against Aspergillus sp. and other molds Minimizes development of resistance Amphotericin potentiates uptake

Fungal cell wall components β 1-6 Branched Targets of Antifungal Agents Fibrous (β −(1,3) Glucan Glucan β 1-6 Tail Surface-Layer Mannoprotein

mannoproteins

Yeast β1,3 Chitin β1,6 Entrapped glucans Glycosyl Phosphatidylinositol “(GPI) Mannoprotein Anchor” PPL (to mannoproteins) bilayer beta-1,3 glucan synthase chitin Echinocandins Plasma Membrane - Caspofungin (phospholipid Ergosterol Regulatory Subunit bilayer) - Micafungin Plasma Membrane • Polyene antibiotics (GTPase) - Anidulafungin Catalytic subunit - Amphotericin B GTP - Lipid-AMB β (1,3) Glucan Synthase Enzyme Complex Continuous fibrils of • Azole antifungals UDP Non-competitive Inhibition by glucose Glucan - Ketoconazole DNA Synthesis Enchinocandins Ergosterol - Itraconazole - Fluctyosine - Fluconazole - Voriconazole 1. Adapted from: Kurtz, MB, ASM News, Jan 98, Vol 64, No 1, pp. 31-9. Chitin Synthase 2. Walsh, TJ, et al, The Oncologist, 2000, 5;120-135 - Posaconazole* 3. Module 1, Introduction to Medical Mycology, Merck & Co. Inc, , 2000, pp 8-11.

5 Echinocandins - spectrum Echinocandin Indications Highly Active Very Active Some Activity Caspofungin Micafungin C. albicans C. parapsilosis C. immitis – Candidemia and the following – Esophageal candidiasis Candida infections: intra-abdominal C. glabrata C. gulliermondii B. dermatididis – Prophylaxis of Candida infections abscesses, peritonitis and pleural in patients undergoing HSCT C. tropicalis A. fumigatus Scedosporium species space infections C. krusei A. flavus P. variotii Not studied in endocarditis, osteomyelitis or meningitis due to Anidulafungin A. terreus H. capsulatum Anidulafungin C. kefyr Candida sp. – Esophageal candidiasis C. lusitaniae P. carinii* – Esophageal candidiasis – Candidemia and other forms of – Invasive Aspergillosis in patients Candida infections (intra-abd who are refractory to or intolerant of abscess, and peritonitis) Very low MIC, with Detectable activity, which other therapies fungicidal activity and Low MIC, but without might have therapeutic Not studied as initial therapy for IA good in-vivo activity. fungicidal activity in most potential for man (in some – Empirical therapy for presumed instances. cases in combination with fungal infections in febrile *only active against cyst other drugs). neutropenic patients forms, and probably only useful for prophylaxis

Cancidas Product Information, Merck & Co. Inc. May 2004 Denning DW, Lancet 2003 (Oct 4);1142-51. Mycamine Product Information, Astellas Pharma US, Inc. April 2005 Eraxis Product Information, Pfizer, Inc., March 2006

Caspofungin Micafungin Anidulafungin

Dosage forms IV IV IV Understanding the Candida species Dosing (MTD) 35 – 70 mg (100 mg) 50 – 150 mg (896 mg) 50 – 200 mg (400 mg) Cmax 14.03 mcg/mL (100 mg) 16.4 mcg/mL (150 mg) 8.6 mcg/mL (100 mg) Half-life ~9-11 hrs ~15 hrs ~40-50 hrs Fluconazole Itraconazole Voriconazole Posaconazole Flucytosine Ampho B Echinocandins Vd 9.67 L 0.39 L/kg 30-50 L Protein binding ~97% (albumin) >99% (albumin) 84% (albumin)

Rat study: levels in brain C. albicans S S S S S S S CNS penetration Probably poor unknown approximately 2% plasma

C. tropicalis S S S S S S S N-acetylation and hydrolysis Catechol-O-methyltransferase Slow chemical degradation

Renal adjustment None None None C. S S S S S S S to R (?) Child Pugh 7 to 9 None parapsilosis Hepatic Adjustment None (no data in severe) (no data in severe)

Hepatotoxicity (0.3-2.3%) C. glabrata S-DD to R S-DD to R S to I S to I S S to I S Hepatotoxicity (1.9 – 10.3%) Hepatotoxicity (2 – 4%) Common ADR Histamine release Anemia (0.9 – 10%) Anemia (2 – 4%) (rare if infused < 1.1 mg/min) C. krusei R S-DD to R S to I S to I I to R S to I S Reduces AUC of tacrolimus Sirolimus and nifedipine (20%) levels are increased by micafungin (<20%). C. lusitaniae S S S S S S to R S Drug-Drug Cyclosporine increases Cyclosporine increases interactions caspofungin levels (35%) No interaction seen with anidulafungin levels (22%) Caspofungin levels may be fluconazole, CsA, FK506, decreased by inducers MMF, rifampin, and ritonavir Pappas et al. CID 2004; 38: 161-89.

How to Choose? Treatment Options for Candida sp. Spectrum – Likely pathogens Amphotericin B – Documented pathogens Fluconazole Site of Itraconazole Concomitant diseases Voriconazole Hepatic/renal function Posaconazole (?) Toxicities Caspofungin / Micafungin / Anidulafungin Drug Interactions IV/PO Cost

6 Echinocandins vs. Fluconazole Aspergillosis Treatment

Risk factors Echinocandins Fluconazole Drug therapy options – granulocytopenia (↓ – Pros – Pros – Amphotericin B product – Pros – Pros neutrophil numbers or – Itraconazole Cidal against Candida sp. Clinical experience and function) – Itraconazole comparable outcomes Expanded spectrum to – T-cell dysfunction – Echinocandins include Aspergillus sp. Activity against the hematologic and other – Voriconazole Activity against azole- majority of Candida malignancies resistant Candida species species – Posaconazole (?) organ allograft recipients Lack of clinically Well tolerated significant drug IV/PO immunosuppressive therapy interactions Less costly – corticosteroids Well tolerated – Cons – corticosteroids – Cons Potential resistance – chronic granulomatous Lack of superiority disease IV only – AIDS $$$ – Burn patients Methenamine silver (GMS) stained tissue section of lung showing dichotomously branched, septate hyphae of Aspergillus fumigatus.

Combination Antifungal Therapy Combination Antifungal Therapy

Fungi more difficulty to diagnose, less amenable to Advantages Disadvantages treatment, and associated with highest attributable – Enhanced rate and extent – Decreased rate and extent mortality compared to bacterial pathogens of killing (additivity, of killing (antagonism) synergy) – Often consider combination therapy in refractory mycoses synergy) – Increase in drug-related – Decrease in antifungal drug toxicity resistance – Increased risk of drug-drug Benefits – Increase in the spectrum of interactions – Improved clinical and microbiologic outcome activity – Increased cost compared – Decreased toxicity – Enhancement in the tissue to monotherapy – Decreased likelihood of resistance distribution of the two drugs – Broader spectrum in empiric therapy – Reduction in drug-related toxicity, particularly if the dosage of a toxic drug can Little objective clinical data be reduced Cuenca-Estrella M. JAC 2004; 54: 854-69. Little objective clinical data Mukherjee PK et al. Clin Micro Reviews 2005; 18: 163-94. Marr K. Oncology 2004; 18: S24-29.

Conclusions Related to Combination Antifungal Therapy In vitro studies controversial Clinical efficacy data rely on case reports/series Anti-Tuberculosis Agents Literature probably biased towards reports of success Many questions remain… – What combination? – When? Sequence Initial vs. salvage Multiresistant species

7 Anti-Tuberculosis Agents Anti-Tuberculosis Therapy

First-line Drugs Drug therapy is the cornerstone of TB management – Rifampin – Goals – – Kill TB rapidly – – Prevent emergence of resistance – Streptomycin – Eliminate persistent bacilli from the host to prevent relapse Second-line Drugs – Drug therapy – Quinolones – First line agents – Greatest efficacy with acceptable toxicity – Amikacin, kanamycin – Second-line agents – Para-aminosalicylic acid (PAS) Less efficacy, greater toxicity, or both – – If properly used, can achieve cure rate ~98% – Increasing prevalence of multidrug resistant TB (MDRTB)

Treatment Principles Treatment Principles (cont.)

Disease burden 3 subpopulations of mycobacteria proposed to exist 3 – Asymptomatic patients have an organism load of ~10 – Extracellular, rapidly dividing mycobacteria, often within cavities organisms – Extracellular, rapidly dividing mycobacteria, often within cavities (107 to 109) – Cavitary pulmonary TB has a load of 1011 organisms (10 to 10 ) As the number of organisms increases, likelihood of Killed most readily by INH > RIF > streptomycin > other drugs drug-resistant mutants increases – Organisms residing within caseating granulomas (semi-dormant 5 7 – Mutants found at rates of 1 in 106 to 1 in 108 organisms metabolic state; 10 to 10 ) Drug therapy regimens Activity of PZA > INH and RIF – Latent TB – Intracellular mycobacteria present within macrophages (104 to Monotherapy, usually with isoniazid (INH) 106) Risk of selecting out resistant organisms is low RIF, INH, PZA and quinolones believed to be most active –Active TB Combination therapy of at least 2 drugs, generally three or more Rates for multiple drug mutations occur as an additive function –1 in 1013 (INH rate of 106 + RIF rate of 107)

Treatment Principles (cont.)

Early bactericidal Prevent emergence of Sterilizing activity activity resistance Rifampin √ √√ √√ Isoniazid √√ √ √√ Pyrazinamide X √√ X First-Line Agents Ethambutol √ X √ Streptomycin X X √

Toxicities – Hepatoxicity Risk factors = multiple hepatotoxic agents, alcohol abuse Regimen and Dosing – Duration varies Condition of patient, extent of disease, presence of drug resistance, and tolerance of medications – Adherence is important (DOT) – Daily vs. TIW – PO vs. IV vs. IM

8 Isoniazid (INH) Rifampin Inhibits mycolic acid synthesis – Long-chain fatty acids of the mycobacterial cell wall Inhibits DNA-dependent RNA polymerase – Bactericidal against growing MTB – Bactericidal (very effective) – Bacteriostatic against nonreplicating MTB Allows short course therapy (6-9 mos vs. ≥18 mos) PO only – IV/PO – Well absorbed – Toxicities Metabolized in liver by N-acetyltransferase ↑ hepatic enzymes (AST, ALT, bilirubin, alkaline phosphatase) – Slow vs. fast acetylators GI distress – Half life 2-4 hrs vs. 0.5-1.5 hrs Red-orange discoloration of body fluids – >80% Asian patients are rapid acetylators Rash – Drug interactions more likely in slow acetylators – DRUG INTERACTIONS, DRUG INTERACTIONS, DRUG Toxicities INTERACTIONS – ↑ serum transaminases (AST, ALT) Potent inducer of CYP450 metabolism (↓ concentrations of other Slow acetylators may be at increased risk drugs) – Neurotoxicity Usually manifests as peripheral neuropathy → administer pyridoxine ( B6) daily ↑ risk alcoholics, children, diabetics, malnourished, dialysis patients, HIV+

First Line Agents (cont.) Streptomycin

Pyrazinamide Ethambutol Inhibits protein synthesis (aminoglycoside) – Mechanism unknown – Inhibits cell wall – Bactericidal Fatty acid synthetase-1 components Poor activity in acidic environment of closed foci Converted to pyrazinoic – Generally bacteriostatic Not good sterilizing drug acid (active metabolite) – Bactericidal – PO only – IM/IV – PO only – Renal excretion – Renal excretion – Metabolized in the liver, but – Toxicities – Toxicities metabolites are renally Optic neuritis (dose- Vestibular toxicity excreted related) – Dizziness, problems with balance, tinnitus – Toxicities Hyperuricemia – Can be permanent ↑ liver enzymes Nephrotoxicity Hyperuricemia – Tends to be mild and reversible Nausea/vomiting

Second Line Agents

Rifabutin Quinolones – Often used as an alternative – , , to rifampin Second-Line Agents Less potent inducer CYP450 – Bactericidal against extracellular organisms and Drug interactions still achieve good intracellular important concentrations Cross resistance among – IV/PO – IV/PO – Uses – PO only MDR-TB – Toxicities IV alternative Uveitis (ocular pain, blurred Well tolerated option vision) vision) – Toxicities Nausea, abdominal pain Headache, insomnia, restlessness

9 Second Line Agents Second Line Agents

Capreomycin Para-amino salicylic acid (PAS) Cycloserine Ethionamide – Uses – Synthetic structural analog of – Uses – Uses MDR-TB aminobenzoic acid MDR-TB (bacteriostatic) IM/IV MDR-TB – Bacteriostatic for extracellular – Bacteriostatic for extracellular Cross-resistance with – Bacteriostatic for both – Bacteriostatic for extracellular organisms only organisms only aminoglycosides intracellular and extracellular – Toxicities – Uses – Toxicities organisms – PO only Injection pain MDR-TB (bacteriostatic) – Toxicities Hearing loss, tinnitus PO only – PO only Nausea/vomiting Renal dysfunction – Toxicities (can be severe) – Toxicities Peripheral neuropathy Amikacin, kanamycin GI (N/V/D) Central Psychiatric disturbances – Aminoglycosides Hepatotoxicity effects (confusion, irritability, ↑ liver enzymes Cross-resistance with – Mortality reported ~21% somnolence, headache, ↑ glucose streptomycin Hypothyroidism vertigo, seizures) – Uses Goiter with or without Peripheral neuropathy MDR-TB hypothyroidism IV/IM alternative Gynecomastia, impotence, – Toxicities menstrual irregularities Renal toxicity Hearing loss, tinnitus

Drug-Resistant TB QUESTIONS? Acquired resistance – Suboptimal therapy that encourages selective growth of mutants resistant to one or more drugs

Primary resistance – Infection from a source case who has drug-resistant disease

Factors leading to suboptimal therapy – Intermittent drug supplies – Use of expired drugs – Unavailability of combination preparations – Use of poorly formulated combination preparations – Inappropriate drug regimens – Addition of single drugs to failing regimens in the absence of bacteriologic control – Poor supervision of therapy – Unacceptably high cost to patient (drugs, travel to clinic, time off work)

10