Antifungals%20and%20Anti-Tuberculosis%20Agents

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Antifungals and Anti-Tuberculosis Agents

• Christine Kubin, Pharm.D., BCPS
• Clinical Pharmacist, Infectious Diseases
• New York-Presbyterian Hospital
• Columbia University Medical Center
• November 12,2004

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Antifungal Agents
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Fungi
Yeasts
Moulds
Mucormycosis (rarely septate) Rhizopus Rhizomucor
Mucor Absidia Zygomycetes
Aspergillus sp. (septate)
Pneumocystis jervici
Candida sp.
Dimorphic Histoplasmosis Blastomycosis
Coccidioidomycosis Paracoccidioidomycosis
Sporotrichosis Chromoblastomycosis
Cryptococcus neoformans
Dermatophytes Trichophyton Microsporum
Epidermophyton
Miscellaneous Pseudoallerscheria boydii
(Scedosporium apiospermum)
Scedosporium prolificans Penicillium
marneffei Fusarium sp.
Phaeohyphomycosis (dark walled fungi)
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An optimal antifungal drug has..

• Wide spectrum of activity
• Favorable pharmacokinetic profile
• Adequate in vivo efficacy
• Low rate of toxicity
• Low cost

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Risk Factors for Fungal Disease

• Candidiasis
• Antibiotics
• Indwelling catheters
• Hyperalimentation
• Multiple abdominal surgeries
• Prosthetic material
• Severe burns
• Neoplastic diseases/chemotherapy
• Immunosuppressive therapy
• Diabetes mellitus
• Extremes of age

• Aspergillosis
• granulocytopenia (? neutrophil numbers or
  function)
• T-cell dysfunction
• hematologic and other malignancies
• organ allograft recipients
• immunosuppressive therapy
• corticosteroids
• chronic granulomatous disease
• AIDS
• Burn patients

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Invasive Aspergillosis Mortality
Review of 1941 Patients from 50 Studies
Lin S-J et al, Clin Infect Dis 2001 32358-66
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Systemic Antifungal AgentsBy Mechanism of Action

• Membrane disrupting agents
• Amphotericin B
• Ergosterol synthesis inhibitors
• Azoles

• Nucleic acid inhibitor
• Flucytosine
• Glucan synthesis inhibitors
• Echinocandins

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Amphotericin B

• A polyene
• Clinical use since 1960
• Insoluble in water
• Solubilized by sodium deoxycholate
• Most broad spectrum antifungal
• gold standard
• Pharmacokinetics
• Extensively tissue bound
• Highest concentrations in liver, spleen, bone
  marrow with less in kidneys and lung
• Half-life
• Tissue 15 days, Plasma 5 days

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Amphotericin B Binds to Ergosterol and Generates
Pores

• Mechanism of action
• Bind to ergosterol and alter cell membrane
  permeability ? cell death
• Also binds to cholesterol ? adverse effects
• Clin Microbiol Rev
  1999 12 501

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Amphotericin BSpectrum of Activity

• Clinical activity
• Candida sp.
• C. lusitaniae often resistant
• Cryptococcus neoformans
• Blastomycosis
• Histoplasmosis
• Aspergillus sp.
• Zygomycetes
• Rhizopus sp., Mucor sp., etc.
• Little to no activity
• Aspergillus terreus, Fusarium sp.,
  Pseudoallescheria boydii, Scedosporium
  prolificans, Trichosporon beigelii

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Ampho-Terrible

• Nephrotoxicity
• Risk factors
• Cumulative dose
• Concomitant nephrotoxic agents
• Hypotension
• Intravascular volume depletion
• Pre-existing renal disease
• BMT patients
• Hydration and sodium loading may lessen effects
• Infusion Related Reactions (IRRs)
• Very common
• Most severe with first few doses
• Electrolyte Abnormalities
• ? K, Mg2, PO4
• Other
• Thrombophlebitis (try to avoid peripheral lines)
• Anemia

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Amphotericin B Lipid Formulations

• Amphotericin B Colloidal Dispersion (ABCD)
  (Amphotec)
• Amphotericin B Lipid Complex (ABLC) (Abelcet)
• Liposomal amphotericin B (AmB) (Ambisome)
• Advantages
• Less nephrotoxicity (still cause nephrotoxicity)
• Lower levels in kidney compared to conventional
  ampho
• Ambisome ? less IRRs
• Disadvantages
• Cost
• No difference in efficacy compared to
  conventional ampho and between lipid products
• Allow delivery of higher doses of amphotericin,
  but higher doses required for equivalent
  antifungal efficacy
• Tolerance differences define the upper dose that
  can be administered

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Lipid Amphotericin B Product Comparison
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Clinical Case

• 57 y.o. woman with HIV (CD4 27, VL gt100K OIs
  thrush, MAC) admitted 3 weeks ago with
  increasing SOB. Treated for PCP with T/S,
  steroids. Last night, she was transferred to the
  MICU febrile to 38.2C, hypotensive (BP 80/60
  despite fluids), hypoxic (O2 sat 75), and with
  altered MS. Blood, urine, and sputum cultures
  were sent. Broad spectrum antibacterials
  (vancomycin P/T) started.
• The next morning, the lab calls you that the
  blood cultures drawn last evening are positive
  for yeast.
• WHAT ANTIFUNGAL DO YOU START???

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Candidiasis

• What are your choices?
• Amphotericin B
• Fluconazole
• Itraconazole
• Voriconazole
• Caspofungin

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How to Choose?

• Spectrum
• Likely pathogens
• Documented pathogens
• Site of infection
• Concomitant diseases
• Hepatic/renal function
• Toxicities
• Drug Interactions
• IV/PO
• Cost

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Antifungal Timeline
Fluconazole
Caspofungin
Ketoconazole
Amphotericin B
Itraconazole
Flucytosine
Voriconazole
1950
1960
1970
1990
1980
2000
Lipid amphotericin products
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Azole Antifungals

• Imidazoles
• Ketoconazole
• Triazoles
• Itraconazole
• Fluconazole
• Voriconazole
• Mechanism of action
• Inhibit ergosterol synthesis through inhibition
  of CYP450-dependent lanosterol 14-?-demethylase
• Depletion of ergosterol on fungal cell membrane
• Resistance
• ERG 11 mutations (gene encoding 14-? sterol
  demethylase) leading to overexpression
• ? azole efflux
• ? production or alteration 14-?-demethylase

Voriconazole
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Comparative PharmacokineticsAzole Antifungals
Ketoconazole Fluconazole Itraconazole Voriconazole
Dosage forms PO IV/PO IV/PO IV/PO
Half-life (h) 8 30 21-64 6
Oral bioavailability () 75 gt90 55 gt95
Effect of gastric pH Decrease None Decrease None
Protein binding High (99) Very Low (12) High (99) Low (58)
CSF penetration Poor (lt10) Excellent (80) Poor (lt10) Good (40-60)
Elimination route Hepatic Renal Hepatic Hepatic
Hepatic/Renal Adjustment Hepatic Renal Hepatic Hepatic
Dose PO 200-400 mg q24h IV/PO 100-400 mg q24h IV 200 mg IV q12h x 2, then 200 mg q24h PO 200 mg q12h IV 6 mg/kg q12h x 2, then 4 mg/kg q12h PO 200 mg q12h (gt40 kg)
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Azole Comparison
Ketoconazole Fluconazole Itraconazole Voriconazole
Adverse effects N/V Anti-androgen effects hepatotoxicity Hepatoxicity (high doses, prolonged tx) GI Hepatoxicity Negative inotropic effects Visual disturbances Hepatotoxicity Rash Hallucinations (4)
Drug Interactions
Induction/ Inhibition Substrate of CYP3A4 Inhibitor CYP1A2, CYP2C9, CYP2C19, CYP3A4 Inhibits CYP3A4 and other CYP isoforms Interacts with enzymes involved with glucuronidation Substrate of CYP3A4 Inhibitor CYP3A4 Substrate and Inhibitor CYP2C19 gt CYP2C9 gt CYP3A4
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Fluconazole

• Favorable pharmacokinetic and toxicity profile
• Low mw and high water solubility ? rapid
  absorption and ? bioavailability
• gt90 bioavailability (IV and PO interchangeable)
• No dependence on low gastric pH
• Effectively penetrates CSF (50-90 plasma levels)
• Brain and eye too!
• gt90 renal excretion
• Adverse effects
• Very well tolerated
• Even up to 1600 mg/day
• GI, reversible transaminase elevations
• Dose
• 100-800 mg/d (max 1600 mg/d)
• 6 mg/kg/d for susceptible strains (400 mg/d)
• 12 mg/kg/d for S-DD strains (800 mg/d)
• IV and oral interchangeable (gt90
  bioavailability)

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Itraconazole

• LIMITATIONS
• Pharmacokinetics
• Only ionized at low pH ? wide interpatient
  variability in plasma concentrations
• Nonlinear serum PK
• Extensively liver metabolized
• Adverse effects
• Transient GI upset, dizziness, headache
• Hepatotoxicity (5)
• Negative inotrope
• Drug Interactions
• Propensity and extent greater than fluconazole
• Substrate of CYP3A4 and inhibitor of CYP3A4
• Rifampin, phenytoin, phenobarbital
• CYA
• Spectrum
• Paraccoccidiodomycosis, blastomycosis,
  histoplasmosis and sporotrichosis, cutaneous and
  mucosal candidiasis, Aspergillosis
• Dose
• 200-400 mg/d (following a load)

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IV Itraconazole

• Formulated in hydroxypropyl-?-cyclodextrin
• Increases solubility of itraconazole
• Some cyclodextrins are nephrotoxic (? lacking
  with this compound)
• Dosing
• 200 mg IV q12h x 4 doses, then 200 mg IV q24h
  followed by 200 mg PO q12h oral solution
• Renal dysfunction
• T1/2 of itraconazole does not differ
• A 6-fold ? cyclodextrin clearance in pts with
  CrCLlt20 ml/min (therefore not recommended in pts
  with CrCLlt30 ml/min)
• Indications
• Pulmonary and extrapulmonary blastomycosis
• Histoplasmosis, including chronic cavitary
  pulmonary disease and disseminated, nonmeningeal
  histoplasmosis
• Pulmonary and extrapulmonary aspergillosis in
  patients who are intolerant of or who are
  refractory to ampho B
• Empiric antifungal therapy in neutropenic
  patients

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Voriconazole

• Second generation synthetic derivative of
  fluconazole
• addition of methyl group to the propyl backbone
• substitution of triazole moiety with a
  fluropyrimidine group
• Active against yeast and moulds
• Fungicidal in vitro against Aspergillus spp.,
  Scedosporium spp., Fusarium spp.
• Fungistatic in vitro against Candida spp.
• Indications
• Invasive aspergillosis
• Esophageal candidiasis
• Fungal infections caused by Scedosporium
  apiospermum and Fusarium spp. in patients
  intolerant of or refractory to other therapy

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Azole Antifungals Spectrum of Activity
Organism Ketoconazole Fluconazole Itraconazole Voriconazole
Yeast
C. albicans
Resistant yeasts
Other yeasts
Cryptococcus
Moulds
Aspergillus 0 0
Other moulds 0 0
Zygomycetes 0 0 0 0
Endemic fungi

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VoriconazolePrecautions (AND LIMITATIONS?)

• Adverse effects
• Transient, dose related visual disturbances (30)
• Mechanism unknown ? electrical currents in
  retina
• Elevated liver function tests (13)
• Greater frequency for voriconazole than for
  fluconazole
• May be dose-related
• Skin reactions (6)
• Dosing
• Intravenous
• 6 mg/kg IV q12h x 2 doses, then 4 mg/kg IV q12h
• Oral (gt95 bioavailability on empty stomach)
• lt40 kg 100 mg PO q12h
• gt40 kg 200 mg PO q12h
• Organ dysfunction
• Renal disease
• Oral dosing recommended in patients with CrCLlt50
  ml/min
• IV vehicle, sulfobutyl ether beta-cyclodextrin,
  accumulates

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VoriconazoleDrug Interactions

• Metabolized through CYP2C19 gt CYP2C9 gt CYP3A4
• Also inhibitor of these enzyme systems

Contraindications Dose Adjustment of Voriconazole Dose Adjustment and/or Monitoring of other Drugs No Dose Adjustment of Voriconazole or other Drugs Required
Rifampin Rifabutin Sirolimus Barbiturates (long-acting) Carbamazepine Astemizole Cisapride Terfenadine Pimozide Quinidine Ergot alkaloids Phenytoin Cyclosporine Tacrolimus Omeprazole Warfarin Phenytoin Sulfonylureas Statins Benzodiazepines Dihydropyridine CCBs Vinca alkaloids HIV PIs and NNRTIs (other than indinavir) Indinavir Mycophenolate mofetil Cimetidine Ranitidine Macrolide antibiotics Prednisolone Digoxin
Pfizer. Vfend package insert 5/02
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Flucytosine (5-FC)

• Mechanism of action
• Flucytosine is deaminated to 5-fluorocytosine
  (5-FC)
• Incorporated into RNA and disrupts protein
  synthesis
• Resistance
• Develops during therapy, especially monotherapy
• Single point mutation
• Loss of permease necessary for cytosine transport
• ? activity of UMP pyrophosphorylase or cytosine
  deaminase
• Spectrum
• Cryptococcus neoformans
• Candida sp. (except C. krusei)
• Little to no activity against Aspergillus sp. and
  other molds

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Flucytosine

• Pharmacokinetics
• Oral only
• Distribution
• CSF levels 75 of serum levels
• Elimination
• 90 excreted via glomerular filtration
• Half-life 3-6 hours
• Renal/hepatic disease
• Dose adjust in renal dysfunction
• Adverse effects
• Dose-dependent bone marrow suppression (? WBC, ?
  platelets)
• GI (nausea/vomiting/diarrhea)
• Clinical uses
• Cryptococcal meningitis, hepatosplenic
  candidiasis, Candida endophthalmitis
• Used in combination ONLY (usually with
  amphotericin)
• Minimizes development of resistance
• Amphotericin potentiates uptake

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Echinocandins

• Caspofungin (Cancidas)
• Micafungin (FK-463)
• Anidulafungin (VER-002)
• Mechanism of action
• Non-competitively inhibit ß (1,3)-D-glucan
  synthase, blocking synthesis of ß (1,3)-D-glucan,
  thereby compromising the integrity of the fungal
  cell wall
• Glucan maintains osmotic integrity of the fungal
  cell wall and play a key role in cell division
  and cell growth
• Resistance
• Little known
• Spectrum
• Aspergillus sp. (static)
• Rapidly cidal class of drugs against Candida sp.
• Lack of activity against Cryptococcus,
  zygomycetes

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Fungal cell wall components
b 1-6 Branched Glucan
b 1-6 Tail
Fibrous (b -(1,3) Glucan
Surface-Layer Mannoprotein
Chitin
Entrapped Mannoprotein
Glycosyl Phosphatidylinositol (GPI) Anchor
(to mannoproteins)
Plasma Membrane (phospholipid bilayer)
Regulatory Subunit (GTPase)
Plasma Membrane
Catalytic subunit
GTP
Continuous fibrils of Glucan
b (1,3) Glucan Synthase Enzyme Complex Non-competi
tive Inhibition by Lipopeptide Class of
Antifungals (Enchinocandins, Pneumocandins,
Papulacandins)
UDP glucose
Ergosterol
Chitin Synthase
1. Adapted from Kurtz, MB, ASM News, Jan 98,
Vol 64, No 1, pp. 31-9. 2. Walsh, TJ, et al,
The Oncologist, 2000, 5120-135 3. Module 1,
Introduction to Medical Mycology, Merck Co.
Inc, , 2000, pp 8-11.
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Understanding Aspergillus

• Echinocandins are cidal for the growing tips and
  some interior cells
• Static, non-growing interior cells are not killed

Visible Light
Stain only the viable fungal segments
Douglas CM et al. ICAAC 2000, Abstract 1683
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Echinocandins - spectrum
Very Active C. parapsilosisC.
gulliermondiiA. fumigatusA. flavusA.
terreusC. lusitaniae Low MIC, but without
fungicidal activity in most instances.
Some Activity C. immitisB.
dermatididisScedosporium speciesP. variotiiH.
capsulatum Detectable activity, which might
have therapeutic potential for man (in some cases
in combination with other drugs).

• Highly Active
• C. albicans
• C. glabrata
• C. tropicalis
• C. krusei
• C. kefyr
• P. carinii
• Very low MIC, with fungicidal activity and good
  in-vivo activity.
• only active against cyst forms, and probably
  only useful for prophylaxis

Denning DW, Lancet 2003 (Oct 4)1142-51.
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CaspofunginAdverse effects

• Clinical experience to date suggests that these
  drugs are extremely well-tolerated
• Most common AEs are infusion related
• Phlebitis/Thrombophlebitis (11.3-15.5)
• Mild to moderate infusion-related AE including
• fever (3.6-26.2)
• headache(6-11.3)
• erythema(1.2-1.5)
• rash (0-4.6)
• Symptoms consistent with histamine release (2)
• Most AEs were mild and did not require treatment
  discontinuation
• Most common laboratory AE
• Asymptomatic elevation of serum transaminases
  (10.6-13)

Cancidas Product Information, Merck Co. Inc.
May 2004
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How to Choose?

• Spectrum
• Likely pathogens
• Documented pathogens
• Site of infection
• Concomitant diseases
• Hepatic/renal function
• Toxicities
• Drug Interactions
• IV/PO
• Cost

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Clinical Case continued.

• Later that afternoon, the lab updates the blood
  culture results to
• yeast, not C. albicans
• Do you change the patients antifungal
  coverage?

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Is yeast, not C. albicans the same as
fluconazole-resistant yeast???
Sometimes, but not always!

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Susceptibility of Candida sp. to Antifungal
Agents
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In vitro Susceptibility Testing of Candida
(NCCLS) (mcg/mL)
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Nosocomial Bloodstream Pathogens49 US Hospitals
Rank Pathogen No. of isolates Crude mortality ()
1 Coagulase-negative Staphylococci 3908 31.9 21
2 Staphylococcus aureus 1928 15.7 25
3 Enterococci 1354 11.1 32
4 Candida sp 934 7.6 40
5 E. coli 700 5.7 24
6 Klebsiella sp 662 5.4 27
7 Enterobacter sp 557 4.5 28
8 Pseudomonas sp 542 4.4 33
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Epidemiology of Candida Species Over the Years..
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Treament of Candidemia

• Unknown Candida sp.
• Fluconazole
• Normal or high dose
• Caspofungin
• Voriconazole
• Lipid amphotericin B
• Known Candida sp.
• Based on species and susceptibility results
• Comorbid conditions/toxicities

Yeast cells and pseudohyphae in material from the
oral cavity, KOH preparation, phase-contrast
microscopy.
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Aspergillosis

• Risk factors
• granulocytopenia (? neutrophil numbers or
  function)
• T-cell dysfunction
• hematologic and other malignancies
• organ allograft recipients
• immunosuppressive therapy
• corticosteroids
• chronic granulomatous disease
• AIDS
• Burn patients

• Drug therapy options
• Amphotericin B
• Itraconazole
• Caspofungin
• Voriconazole

Methenamine silver (GMS) stained tissue section
of lung showing dichotomously branched, septate
hyphae of Aspergillus fumigatus.
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Mortality Due to Invasive Mycoses
United States, 1980-1997
McNeil MM, et al. Clin Infect Dis 200133641-7
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Combination therapy???
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Current Therapies Mechanism of Action
Agent
Fungal Cell Target
Activity
Amphotericin B1
Fungal cell membrane1
Binds to ergosterol causes cell death1
Inhibits CYP450enzyme responsiblefor ergosterol
synthesis damages cytoplasmic membrane2
Azoles2
Fungal cell membrane2
Fungal cell wall
Inhibits glucan synthesis disrupts cell-wall
structure
Caspofungin acetate (Cancidas)

1. Fungizone package insert.
2. Sporanox package insert.

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Combination Antifungal Therapy

• Fungi more difficulty to diagnose, less amenable
  to treatment, and associated with highest
  attributable mortality compared to bacterial
  pathogens
• Often consider combination therapy in refractory
  mycoses
• Benefits
• Improved clinical and microbiologic outcome
• Decreased toxicity
• Decreased likelihood of resistance
• Broader spectrum in empiric therapy
• Little objective clinical data

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Estimated Antifungal Costs
Drug Dose Route Cost per day
Fluconazole 400 mg q24h 400 mg q24h PO IV 22 124
Itraconazole 200 mg q12h 200 mg q24h IV 340 170
Conv amphotericin B 70 mg q24h IV 7
Abelcet 350 mg q24h IV 330
Ambisome 350 mg q24h IV 570
Caspofungin (Cancidas) 70 mg x 1 50 mg q24h IV 400 310
Voriconazole (Vfend) 420 mg q12h 280 mg q12h 200 mg q12h IV IV PO 490 290 60
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How to Choose?

• Spectrum
• Likely pathogens
• Documented pathogens
• Site of infection
• Concomitant diseases
• Hepatic/renal function
• Toxicities
• Drug Interactions
• IV/PO
• Cost

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Conclusions

• Fungal infections in immunocompromised hosts
  associated with high mortality
• Treatment options AND the host are less than
  ideal
• Current and future antifungal agents associated
  with advantages and disadvantages
• Optimize therapy to improve outcome
• Every clinical situation is different

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Anti-Tuberculosis Agents
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Anti-Tuberculosis Agents

• First-line Drugs
• Rifampin
• Isoniazid
• Pyrazinamide
• Ethambutol
• Streptomycin
• Second-line Drugs
• Rifabutin
• Quinolones
• Capreomycin
• Amikacin, kanamycin
• Para-aminosalicylic acid (PAS)
• Cycloserine
• Ethionamide

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Anti-Tuberculosis Therapy

• Goals
• Kill TB rapidly
• Prevent emergence of resistance
• Eliminate persistent bacilli from the host to
  prevent relapse
• Drug therapy
• First line agents
• Greatest efficacy with acceptable toxicity
• Second-line agents
• Less efficacy, greater toxicity, or both
• If properly used, can achieve cure rate 98
• Increasing prevalence of multidrug resistant TB
  (MDRTB)

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General Principles

• Drug therapy regimens
• Latent TB
• Isoniazid (INH)
• Active TB
• Combination therapy!!!
• RIPE
• Toxicities
• Hepatoxicity
• Risk factors multiple hepatotoxic agents,
  alcohol abuse
• Regimen and Dosing
• Adherence is important (DOT)
• Daily vs. TIW

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

• Isoniazid
• Inhibits mycolic acid synthesis
• Long-chain fatty acids of the mycobacterial cell
  wall
• Bactericidal against growing MTB
• Bacteriostatic against nonreplicating MTB
• PO only
• Metabolized in liver by N-acetyltransferase
• Slow vs. fast acetylators
• Half life 2-4 hrs vs. 0.5-1.5 hrs
• gt80 Chinese and Japanese patients are rapid
  acetylators
• Drug interactions more likely in slow acetylators
• Toxicities
• ? serum transaminases (AST, ALT)
• Peripheral neuropathy ? administer pyridoxine
  (vitamin B6) daily
• ? risk alcoholics, children, diabetics,
  malnourished, dialysis patients, HIV

56
First Line Agents

• Rifampin
• Inhibits DNA-dependent RNA polymerase
• Bactericidal (very effective)
• IV/PO
• Toxicities
• ? hepatic enzymes (AST, ALT, bilirubin, alkaline
  phosphatase)
• GI
• Red-orange discoloration of body fluids
• Urine, tears, sweat, contact lenses, etc.
• Rash
• DRUG INTERACTIONS, DRUG INTERACTIONS, DRUG
  INTERACTIONS
• Potent inducer of CYP450 metabolism (?
  concentrations of other drugs)

57
First Line Agents

• Pyrazinamide
• Mechanism unknown
• Fatty acid synthetase-1
• Bactericidal
• PO only
• Metabolized in the liver, but metabolites are
  renally excreted
• Toxicities
• ? liver enzymes
• Hyperuricemia
• Nausea/vomiting

• Ethambutol
• Inhibits cell wall components
• Bacteriostatic
• PO only
• Renal excretion
• Toxicities
• Optic neuritis (dose-related)
• Hyperuricemia

58
First Line Agents

• Streptomycin
• Inhibits protein synthesis (aminoglycoside)
• Bactericidal
• Poor activity in acidic environment of closed
  foci
• Not good sterilizing drug
• IM/IV
• Renal excretion
• Toxicities
• Vestibular toxicity (dizziness, problems with
  balance, tinnitus)
• nephrotoxicity

59
Second Line Agents

• Rifabutin
• Often used as an alternative to rifampin
• Not as potent inducer CYP450
• Drug interactions still important
• PO only
• Toxicities
• Uveitis (ocular pain, blurred vision)

• Quinolones
• Levofloxacin, moxifloxacin, gatifloxacin
• bactericidal
• IV/PO
• Uses
• MDR-TB
• IV alternative
• Well tolerated option
• Toxicities
• Nausea, abdominal pain
• Headache, insomnia, restlessness

60
Second Line Agents

• Capreomycin
• Uses
• MDR-TB
• IM/IV
• Cross-resistance with aminoglycosides
• Toxicities
• Injection pain
• Hearing loss, tinnitus
• Renal dysfunction
• Amikacin, kanamycin
• Aminoglycosides
• Cross-resistance with streptomycin
• Uses
• MDR-TB
• IV/IM alternative
• Toxicities
• Renal toxicity
• Hearing loss, tinnitus

• Para-amino salicylic acid (PAS)
• Uses
• MDR-TB (bacteriostatic)
• PO only
• Toxicities (can be severe)
• GI
• Hepatotoxicity
• hypothyroidism

61
Second Line Agents

• Cycloserine
• Uses
• MDR-TB (bacteriostatic)
• PO only
• Toxicities
• Central nervous system effects (confusion,
  irritability, somnolence, headache, vertigo,
  seizures)
• Peripheral neuropathy

• Ethionamide
• Uses
• MDR-TB (bacteriostatic)
• PO only
• Toxicities
• Nausea/vomiting
• Peripheral neuropathy
• Psychiatric disturbances
• ? liver enzymes
• ? glucose

62
Drug-Resistant TB

• 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)

63
Anti-TB TherapyCase 1

• 37 y.o. homeless man presents with cough, 25-lb
  weight loss over past 3 months, night sweats, and
  fever.
• CXR RUL cavity
• Admitted and placed in respiratory isolation.
• Sputum AFB smear , HIV test -.
• Anti-TB regimen to be started
• How many drugs to start?
• 4 initially
• What drugs to start?
• RIPE
• Additional therapy/counseling?
• Pyridoxine 50 mg daily
• Red-orange discoloration of body fluids
• What to monitor?
• Baseline and follow up LFTs (rifampin, INH, PZA)
• Signs and symptoms of peripheral neuropathy (INH)
• Visual changes (ethambutol)

64
Anti-TB TherapyCase 2

• 28 y.o. M, HIV (last CD4 48, VL 1000) started on
  AZT/3TC and LPV/r 3 weeks ago. Presents now
  with cough, fever, night sweats.
• CXR ?LUL infiltrate
• AFB smear , TB amplification
• Anti-TB treatment to be started
• How many drugs to start?
• 4 initially
• What drugs to start?
• Rifabutin IPE
• Pyridoxine 50 mg daily
• What to monitor?
• LFTs, visual changes, signs and symptoms of
  peripheral neuropathy

65
Anti-TB TherapyCase 2 (cont.)

• 6 days later the patient becomes hypoxic,
  hypotensive, and suffers a cardiac arrest.
  Intubated and transferred to the ICU.
• On pressors, ?LFTs (shock), ?SCr
• Team decides to start antibacterials and wants to
  continue anti-TB drugs, but question the
  patients GI absorptive capacity.
• What do you do?
• Change anti-TB drugs to IV
• Rifampin IV, INH IV, streptomycin IV,
  levofloxacin IV
• Adjust all for renal function
• d/c antiretrovirals
• Rifampin contraindicated due to drug interactions
• No immediate need to continue ART in critical
  setting

66
QUESTIONS?