ANTI-TUBERCULOSIS DRUGS

First Line greatest level of efficacy with acceptable degree of tox Isoniazid H MOA / Activation / Use Prodrug + mycobacterial catalase peroxidase (Kat G) active H covalent complex w/ an acyl carrier protein (AcpM) + -ketoacyl carrier protein synthetase (KasA) Blocks mycolic acid synthesis 1:106 tubercle baciili due to mutations in Kat G and Inh A (14.9% has 1 resistance) Cidal Intra & extra rapid growers (MIC 0.01-0.02mcg/mL) Static slow growers / intermittent orally complete in fasting, less with food / antacids Take 1h before or 2h after meals; (Tmax 1-2 hr fasting; Cmax 3-5mcg/mL after a dose of 5mg/kg) rapidly in all tissues + CSF, no PB, penetrates well into caseous material Liver via N-acetyltransferase (NAT2; genetically determined if slow/rapid; 90% Filipinos rapid so take 2x/week); t1/2 slow 3h, rapid < 1h; metabolite monoacetatehydrazine thru N-hydroxylation is hepatotoxic via formatin of acetyl free radicals; hydrazine inactivates pyridoxine phosphokinase and another metabolite dec. activity of pyridoxal phosphate But no significant correlation & ADRs metabolites and unchanged drug via Urine Rifampicin R Inhibits DNA-dependent RNA polymerase transcription Pyrazinamde Z Metabolized by bacterial pyrazinamidase to bactericidal pyrazinoic acid inh. Mycolic acid synthesis resistant mutant occur due to impaired uptake of Z or mutations in pncA impairs conversion to active form Cidal Intra @ acidic ph 5.5; inactive at neutral ph Streptomycin S Inhibits CHON synthesis by binding to 30s ribosomal subunit (aminoglycoside) For suspected or proven 1 H resistance, life-threatening forms 1:106 tubercle baciili; due to mutations leading to altered ribosomal unit or in gene ecoding 16s ribosomal rRNA w/c alters ribosomal binding site Cidal active extra in alk, caseous lining of the walls of pulmonary cavitations (MIC 1-10mcg/mL) Ethambutol E Inhibition of mycobacterial arabinosyl transferase (polymerizes arabinoglycan = essential component of mycobac cell wall) resistance to E develops slowly; due to mutations resulting in over expressin by emb gene products or w/in emb B structural genes Static 15mg/Kg/day antiresistance Cidal >25mg/Kg/day intermittent therapy, drug-resistant MTB good orally, not affected by food, delayed by AlOH and ethanol (alcohol), Tmax w/in 2h; Cmax 4mcg/mL after 15mg/kg/dose most tissues, inflamed BBB, gathers in lung, age no impact on distribution

Resistance

1:107 1:108 tubercle baciili due to mutation in rpo gene-reducing its affinity for drug Cidal Intra & extra both rapidly dividing and slow growing bacilli (MIC 0.005-0.2mcg/mL)

Activity

Absorption

Distn.

complete orally in fasting, 1st pass metab. less with food; Bioavailability dependent on formulation; Tmax w/in 2h fasting; Cmax 710mcg/mL (600mg dose); all tissues, phagocytic cells and fluid w/ CSF also in tears, saliva, sweat and stools red orange discoloration; BBB inflamed; PB; penetrates caseous and cavities Liver: deacylated (active) conjugated with glucuronide (inactive) R and its desacylated metabolites undergo enterohepatic recirc. T1/2 2-5h 30% urine, 60-65% feces 150, 300, 450mg tabs; 600mg capsule 100, 200mg/5mL susp not in US 600mg vial injection not available

GIT good, readily absorbed orally; Tmax 1-2h, Cmax 3050mcg/mL at 25mg/kg dose all tissues, CSF (inflammed)

not absorbed in GIT; Tmax 1h after IM injection; Cmax 40mcg/mL after IM of 15mg/kg dose Polar, most tissues, BBB inflamed, poor penetration into cells

Metab

Liver: Z + hepatic deaminase pyrizinoic acid + xanthine oxidase hydroxylated to 5hydroxypyrazinoic acid (major excretory product) T1/2 9-10h in healthy

T1/2 3h

T1/2 10-15h at normal renal function; prolonged in renal failure

Excretion

unchanged renally (glomerular filtration)

unchanged in urine

Formuln.& Dosage

100, 300, 400mg tablet 100, 200mg/5mL syrup (sucrose syrup unstable in heat and light, sorbitol syrup less unstable, kept cool) Dose: <12y/o = 10-20 max 300mg daily, 2040 max 900mg 3x/week; >12y/o = 5 max 300mg daily, 15 max 900mg 3x/week Orally singe dose on empty stomach

ADR

Nervous system: peripheral neuropathy if >5mg/kg/day coz dose dependent (relative pyridoxine by excretion; pyridoxal phosphate needed for conversion of Glu GABA; free pyridoxine react w/ metabolites of H and excreted w/o conversion to active form), psychosis, altered

Oral susp = R capsule powder + sweetened water or fruit juice R should no be formulated as FDC susp w/ H and Z coz R becomes unstable FDC of H&R or H,R&Z tablet offers improved compliance, avoid inapp monotherapy and easy monitoring Dose: <12y/o = 10-20 max 600mg daily or 3x/week; >12y/o 10 max 600mg daily or 3x/week Hepatotox in alcoholics

500mg tablet 250mg/5mL suspension shaken vigorously, crystallizes when fridged Dose: <12y/o and >12y/o = 15-30 max 2g daily, 50-70 max 3g 3x/week;

1g vial IM Dose: <12y/o and >12y/o = 1525 max 1g daily, 25-30 max 1.5g 3x/week

Dose: <12y/o = 15-25 1st 2 mos. Then 15 max 2.5g daily, 25-30 3x/week; >12y/o = 15-25 max 2.5g daily, 25-30 3x/week Not for children less than 6 y/o

Hepatotox

Hypersens flushing, fever, pruritus, eosinophilia, hemolytic anemia, interstitial nephritis, flu-like syndrome, arthritis, arthralgia GIT: nausea, vomiting

Hyperuricemia (+/symptoms) arthralgia, gout GIT: nausea Flushing: cutaneous

PRC: D Ototox: vestibular (8%), tinnitus, high freq hearing loss Nephrotox rare Paresthesia, dizziness, nausea Peripheral neuropathy

Retrobulbar neuritis; impairment of visual acuity and reg/green color vision (dose & duration related) rare in kids with N kidneys GIT symptoms Hyperuricemia due to dec. urate

sensorium, seizures

DI

Liver: asymptomatic serum ALT (10-20%), hepatitis (most frequent toxicity, age related); higher in alcoholics and patients w/ liver disease Allergic rash ANA + on long term use (20%) SLE G6PD deficiency hemolysis DME inhibitor - phenytoin and theophylline tox, hepatotox with R + alcohol (additive) With VitC inactivate isoniazid suspension

Red-orange discoloration of body fluids, permanent for soft contact lens Acute tubular necrosis DME inducer - requirements for oral anticoags, corticosteroids for Addisons effectiveness of drugs PI Treat TB, alternative to INH in latent TB, prophylaxis of meningococcal and H. influenzae meningitis, eliminate nasopharyngeal carriage of N. meningitides, treat serious staph inf.: osteomyelitis and prosthetic valve endocarditis, eradicate staph nasal carrier Pregnancy Risk factor C Semisynthetic derivative of Rifamycin B Most potent sterilizing drug available

hypersens

Allergy, fever, skin rashes, anaphylaxis, exfoliative dermatitis

excretion Hypersens dermatitis, fever, arthralgia

Indication

Treatment of TB, latent infection (dormant take H for 6 mos.), prophylaxis of close contact of infectious cases, TST negative a hydrazide of isonicotinic acid, pregnancy categ C

Short term (6mos.) multiple drug therapy for TB

Serious form of TB as disseminated TB meningitis and treatment of infection resistant to other drugs

To prevent emergence of microbial resistance to other anti-Tb drugs (15mg/kg/d) Intermittent therapy and for drug resistant TB (>25mg/kg/d) Treatment of some NTMB

Notes

rapid acetylators have conc. Of active H 1/31/2 of slow acetylators if allergic to H, give R for 4 mos. Daily of intermittently (2x/3x a week)

Pregnancy Risk Factor C Similar to H; synthetic pyrazine analog of nicotinamide

Surveill.

<5y/o, neonates = H 3 mos. repeat tuberculin if (+), do x-ray; if (-) stop drug Adults Pretreatment liver function ALT&AST (>35yo) repeat if fatigue, anorexia, nausea vomiting, weakness (>3d) and at 2, 4, 6 mo (>50yo) Infants & kids monthly clinical observation

In AIDS, problem w/ protease inhibitor 7 NNRTI dec. levels so instead, give Rifabutin coz less inducer

Pregnancy risk Factor D Only injectable drug An aminoglycoside

Pregnancy Risk category B

Adults - Pretreatment liver function (repeat if fatigue, anorexia, nausea vomiting, weakness)

Adults Pretreatment liver function, monthly SGPT, uric acid

Monthly audiogram Serum crea, BUN at onset (in older pxs)

Monthly evaluation of red/green color vision and visual acuity @ >15mg/Kg dose

Second Line Drugs less effective, more toxic; used when: resistance to 1st line suspected/confirmed, severe adverse effects to 1st line, in case of failure of clinical response to 1st line; used when expert guidance is available to deal w/ toxicity Drug Activity Daily dose (mg/Kg) Notes Via ADR Amikacin Cidal AMG, for NMTB 15-30 max 1g Capreomycin Static AMG-like, for Streptomycin resistant strains IM Ototox, nephrotox Kanamycin Cidal AMG, very toxic versus amikacin 10-20mg/g/d usually 500-750mg/d in GI irritant, hepatotox, peripheral neuritis (reversible by giving Ethionamide isngle daily dose or 2 divided does PO pyridoxine), hypersens Para-aminosalicylic 8-12g/d in 2-3 doses Competes with PABA, taken after meals GI irritant, hypersens, reversible lupus-like Static acid (PAS) Thiacetazone 2.5 max 150mg Cheapest, static only, anti-resistance, not for HIV GI irritant, bone marrow suppress, cutaneous rxn w/ HIV Cycloserine 10-15mg/kg/d max 1g in 2 div. doses Early cell wall inhibition Psychosis, convulsions, peripheral neuropathy, rash PO Weaky A-400-800mg/day max 800mg Ofloxacin cidal Headache, dizziness, insomnia, tremors, confusion, seizures, Ciprofloxacin A-500-1500mg/day mac. 1.5g Fluoroquinolone (GABA inhibition) nausea vomiting, abd pain; (most active cidal so preferred) Cidal Levofloxacin 500-1000 daily Linezolid Static 1200mg in 2 doses drug of last resort Rifapantine Cidal 10mg/kg (600mg) Cross resistance w/ Rifampicin, long duration of action Hepatotox, myositis, thrombocytopenia, neutropenia, hypersens, orange color of body fluids, pseudojaundice (yellowish tan skin) Rifabutin cidal 5mg/kg (300mg) 50% less induction vs R, used instead of R when with Protease inhibitors

Tuberculosis

5% of all TB cases have MDR-TB resistant to H and R Isoniazid H Rifampicin R Pyrazinimide Z Streptomycin S Ethambutol E

XDR-TB MDR + resistant to fluoroquinolone + 1 of 3 injectable agents (amikacin/capreomycin/kanamycin (virtually untreatable) Characteristics of MTB lipid rich mycolic acid cell wall impermeable to some drugs slow growers harder to target with bacteriocidal drugs develops resistance slow response to therapy Subpopulations of TB bacilli that could exist in an infected patient w/ TB disease rapidly growing w/ high bacillary load as in wall of a cavitary lesion where O2 is high and pH neutral = H,R,S,(E) spurters w/in caseous material where O2 is low but pH neutral = R, (H), (S) slow growing located intracellularly (macrophages) and at inflamed sites where pH is low = Z, R, H dormant. Some bacilli remain totally inactive for prolonged periods = no drug is effective Tuberculosis Clinical Forms

Rapidly growing extracellular (neutral pH) ++ ++ 0 ++ +/

Slowly growing extracellular (neutral pH) + ++ 0 +/ 0

Slowly growing Intracellular (acid pH) + ++ ++ 0 +/

Infection + Mantoux, asymptomatic, latent phase Disease + Mantoux & CXR symptomatic

Exposure may be occult lymphohematologic spread all organs seeded but asymptomatic Main Properties of AntiTB Drugs Bactericidal activity vs active multipliers (H, R, S) 2 weeks noninfectious Sterilizing activity vs slow growers (R, Z)

Prevents or delays emergence of resistance thiacetazone, ethambutol Aims of Treatment cure the px prevent death from TB or later effects prevent relapse anti-persisters decrease transmission anti-active growers prevent acquired drug resistance cavities

Basic Principles

multiple drug therapy

sufficient duration to fully eradicate never add a single drug to a failing regimen DOTS Direct Observation Therapy Short Course

Bactericidal 1st 2 mos. Larger burden of TB More replication Cidal drugs needed At least 4 drugs needed

Sterilizing 3-6 mos. Fewer organism Slower growth phase Sterilizing drugs 2 drugs needed

1.
control

sustained political commitment to TB

2.
positive)

access to quality-assured TB sputum microscopy to ID infectious patients (sputum standardized short course chemotherapy under proper care management conditions including uninterrupted supply of quality - assured antiTB drugs provided free from DOH Drugs S, H, R Z, R, H Used against rapidly growing extracellular bacilli slowly growing intracellular bacilli and closed caseous lesions Inadequate Treatment Treatment failure Relapse Adequate Treatment Bactericidal elimination of extracellular bacilli Sterilizing elimination of persisters

3.
DOT

4. 5.

recording or reporting system enabling outcome assessment of each and every patient and assessment of the overall programme performance

Recommended Regimens TB Dx Category based on public health interest I Sources of transmission (6 mos.) II (8 mos.) III IV Infection (non-WHO) Regimens TB Px Initial Phase (daily or 3x weekly) 2 HRZE (S > E, esp in meningeal TB) 2 HRZES / 1 HRZE 2 HRZE (may omit E initially in: noncavitary smear (-) HIV (-) px, px w/ full drug susceptible bacilli & kids w/ 1 TB) Continuation Phase (daily or 3x weekly) 4 HR 6 HE daily ( relapse %) 5 HRE 4 HR 6 HE daily ( relapse %)

New smear + px New smear PTB w/ extensive parenchymal involvement Severe concomitant HIV or severe EPTB Previously treated smear + PTB (those who dev. Resistance) Relapse, Tx interruption, Tx failure (test for drug sensitivity)

New smear neg PTB (other than Category I) Less severe forms of PTB Chronic & MDR-TB cases (sputum + after supervised re-Tx) o Contacts with above px early culture and sensitivity testing

Specially designed standardized or individualized, immediate referral to PMTM 9 H kids, 6 H adults

+ Mantoux, asymptomatic, latent phase

H+E H+R H+R+Z FIXED DOSE COMBINATION (FDC) 2,3, or 4 drugs in a single tablet Adv: simplicity of tx, monotherapy is avoided less drug resistance and improved patient compliance (# tablets to ingest fewer, px cannot be selective n choice of drugs to ingest) Disadv: prescription errors may result in excess dosage or sub-inhibitory concentration of all drugs, doesnt guarantee patients adherence, bioavailability problem of R is some formulations Additional Notes: o TB spread by droplet nuclei w/c is 1-5 um each containing 1-400 bacilli o 3000 droplet nuclei is generated thru coughing and talking for 5 mins., singing generates 3000 droplet nuclei in one minute H+R+Z+E H + Thiazetazone

o Sneezing generates the most droplet nuclei by far which can can spread to individuals up to 10 feet Category of TB cases according to previous treatment received by patient o New = patient who has never had tx for TB or if w/ previous anti-TB medications, this was taken for less than 4 wks o Relapse = px who has been declared cured of any form of TB in the past after one full course of anti-TB meds, and now has become sputum (+) o Return to treatment after default = px who stops taking his meds for 2 mos. Or more and comes back to clinic smear (+)
Failure = px while on tx, remained or become smear (+) again at 5th month of anti-TB tx or later, or px who has smear (-) at start of tx and becomes smear (+) at 2nd month o Transfer-in = px whose management was started from another area and now transferred to a new clinic o Chronic case = px who became or remained smear (+) after completing full course of supervised retreatment regimen Treatment of MDR-TB o Use 1st line agents showing susceptibility o Include injectable agent (strep, kana, ami, capreo) o One FQ (Levofloxacin, Ofloxacin) And 2nd line anti-TB agents (cycloserine, PAS, clofazimine) o Treat for 2 years after culture conversion Risk factors for drug resistance o Prior therapy, non-adherance, under dosing, country of origin has high prevalence of drug resistant TB (Latin America, Asia, Africa)

* Combined drug therapy is more effective than monotherapy coz monotherapy results in selection of drug resistant bacilli, diff. subpopulations of tubercle bacilli showing distinct pattern of susceptibility may co-exist in a px w/ TB
Drugs for Non-TB Mycobacteria (MOTT, ATYPICAL)

A. Anti-Leprosy Drugs outpatient tx, others include ofloxacin, levofloxacin, clarithromycin Aims of Tx: cure disease, render patient noncontagious in order to cut down transmission MDT is the regimen of choice for all cases of Leprosy (problem of resistance) Adv: effective in cases w/ primary dapsone resistance, prevents emergence of drug resistance (dapsone), quick symptom relief & renders MBL noncontagious, reduces total duration of therapy (24 12 mos.) Dapsone (diaminodiphenylsulfone) Competes w/ PABA for dihydropteroate synthetase inhibit folate synthesis; static vs M. leprae all forms of leprosy, dermatitis heptiformis (assoc. w/ Celiac disease), prophylaxis and tx of Pneumocystis carinii pneumonia dapsone hypersensitivity, beware in severe anemia, G6PD hemolysis, hypersensitivity to sulfonamides, PRC C slow complete oral all tissues and fluids, tends to be retained in muscle, liver, kidneys, and skin esp. when M. leprae 1-2days Liver bile, recycled in intestines, finally in urine dose related hemolysis, methemoglobinemia + cyanosis, peripheral neuropathy, insomnia, headache, exfoliative dermatitis, leucopenia, agranulocytosis, cholestatic jaundice, blurred vision, sulfone syndrome, ENL (due to release of dead Ags in circ) after initial therapy in those w/ multibacillary disease 25, 100mg Tablet Effective in lepromatous leprosy (cidal) PRC C Infectivity is reversed rapidly Given with dapsone or another anti-leprosy drug to avoid R-resistant M. leprae single monthly 600mg dose OK in combo therapy (cost limits use) Rifampicin R Clofazimine (Phenazine dye) Weakly bactericidal vs M leprae: binds to myco DNA inhibit growth, anti-inflammatory effect combo regimen with dapsone or R for multibacillary leprosy, erythema nodosum leprosum, M. avium intracellular infection clofazimine hypersensitivity; beware in daily max 100mg, crosses placenta and excreted in breast milk, caution in 1st trimester, PRC C Orally, repository drug, can discontinue & still be effective accumulates in tissues for prolonged periods (therapy every 4 wks OK), lipophilic, cant cross BBB, stored in RES and skin 2mos. liver feces gastric irritation, diarrhea, pink to brownish black skin discoloration (disappears if discontinue drug), conjunctivae and urine, blue black discoloration of lesions, rash pruritus, elevated blood sugar, phototoxicity, hepatitis 50mg capsule Minocycline Long acting tetracycline bacteriostatic for single lesion PRC D

MOA Indications CI

Absorption Distribution T1/2 Metabolism Excretion ADR Preparation

almost complete * 100mg/d dose produces peak blood leels that exceed MIC against M. lepra by 10-20x 16-18h slow = daily dosing OK similar to tetracyclines: vestibular (30-90%), vertigo (33%), ataxia (43%), nausea (50%), vomiting (3%), women more frequent, reversible; hypersensitivity, pneumonitis

Leprosy Tx Regimen Paucibacillary indeterminate, tuberculoid, borderline tuberculoid For single lesion Pacuibacillary disease single dose Multibacillary borderline lepromatous, lepromatous

Dapsone 100mg daily unsupervised + R 600mg/mo for 6mo supervised R 600mg + Ofloxacin 400mg + Minocycline 100mg Unsupervised: Dapsone 100mg daily / Clofazimine 50mg daily + Supervised R 600mg/mo + Clofazimine 300mg/mo minimum 12 mo

Dapsone + R R + Ofloxacin + Minocycline Dapsone / Clofazimine + R

B. Treatment of Erythema Nodosum Leprosum (ENL) commonly occurs in patients w/ multibacillary disease after drug therapy is initiated

Thalidomide DOC, inhibits TNF, PRC X, CI women of child-bearing age, phocomelia Corticosteroids (prednisone) when thalidomide is unacceptable, anti-inflammatory Clofazimine anti-inflammatory effects thru surgical excision, resides in lungs, skin, GIT, soft tissues Tx Ciprofloxacin, clarithromycin, E, H, R, sulfa-trimethoprim Amikacin, clarithromycin, E, doxycycline, minocycline, R, sulfa-trimethoprim Amikacin, erythromycin (macrolides), R, S, surgical excision (TOC) Amikacin, azithromycin, clarithromycin, ciprofloxacin, E, ethioamide, rifabutin Amikacin, doxycycline, imipenem, macrolides, tobramycin Amikacin, cefoxitin, ciprofloxacin, doxycylcine, ofloxacin, sulfa-trimethoprim

C Aytpical Mycobacteria non-TB, environmental mycobacteria, found in air, water, soil, can be removed Species Clinical features kansasii Resembles TB Granulomatous cutaneous disease, most common, marinum swimming pool granuloma, foot spa scrofulaceum Cervical adenitis in kids avium complex Pulmo disease in px w/ chronic lung disease, disseminated infections w/ AIDS, most common cause of systemic disease, intracellular chelonae Abscess, sinus tract, ulcer, bone joint, tendon infection fortuitum

ulcerans

Skin ulcers

H, S, R, minocycline, surgical excision