Professional Documents
Culture Documents
14, 2011
Mycobacterium tuberculosis
Kingdom: Bacteria Phylum: Actinobacteria Order: Actinomycetales Suborder:
Corynebacterineae
Mycobacterium tuberculosis
Obligate aerobes growing most successfully in tissues with a high oxygen content, such as the lungs.
Hydrophobic with a high lipid content in the cell wall. Because the cells are hydrophobic and tend to clump together, they are impermeable to the usual stains, e.g. Gram's stain.
Known as "acid-fast bacilli" because of their lipid-rich cell walls, which are relatively impermeable to various basic dyes unless the dyes are combined with phenol. Once stained, the cells resist decolorization with acidified organic solvents and are therefore called "acid-fast". (Other bacteria which also contain mycolic acids, such as Nocardia, can also exhibit this feature.)
Mycobacteria Colonies
Mycobacterium tuberculosis
Historical significanceresponsible of 1/3 of deaths in Europe and the Americas during the 17th-18th century; the White Plague Today 2nd cause of death worldwide..
Arctic ocean
ARCTIC
NORTH AMERICA
EUROPE
ASIA
North Pacific Ocean
AFRICA
SOUTH AMERICA AUSTRALIA
TB and HIV/AIDS
* TB is the leading killer of HIV/AIDS patients Worlwide ,35M people have HIV, 40-50% have TB 22% of all TB deaths occur in HIV-infected people TB is the leading AIDS related oppurtunistic infection
*Selwyn,PA et al, JAMA1992; 268: 504-9 Antonucci G, et al, JAMA, 1995, 274:143-8 Havlir D & Barnes P., NEJM, 1999: 340,367
How to spread TB
TB Treatment
FIRST LINE DRUGS
Isoniazid (INH) Rifampicin Ethambutol Pyrazinamide (PZA) Streptomycin
Ethionamide Cycloserine Capreomycin Kanamycin Para-amino Salicylic Acid (PAS) Ciprofloxacin Ofloxacin Amikacin Clofazimine
TB Treatment
* Katzung
FIRST LINE AGENTS : Isoniazid Rifampin PZA Ethambutol Streptomycin Pediatric dosage 5mg/kg 10 mg/kg 25 mg/kg/d 15-25 mg/kg/d 15mg/kg/d Adult dosage 300mg/d 600mg/d 2.5 g
SECOND-LINE AGENTS Amikacin Aminosalicylic acid Capreomycin Ciprofloxacin Clofazimine Cycloserine Ethionamide Levofloxacin Rifabutin Rifapentine
15 mg/kg/d 8-12g/d 15 mg/kg/d 1500 mg/d, div. 200mg/d 500-1000 mg/d, div 500-750mg/d 500mg/d 300mg/d 600mg 1-2x/wk
INH Rif
Ethambutol Steptomycin
I Have Neuritis
Red Man Syndrome
Eye Affected: Retrobulbar Neuritis Song is difficult to hear Ototoxicity
TB Treatment Regimens
Standard Course ( 6 month regimen)
Intensive Phase: INH, Rif, PZA for 2 months then Continuation Phase: INH, Rif for 4 more months
TB Treatment Regimens
When resistance is high: A. INH, Rif, PZA, Ethambutol for 2 months then INH, Rif for 4 months
B. INH, Rif, PZA, Streptomycin for 2 months then INH,Rif for 4 months
TB Treatment Regimens
WHO TREATMENT GUIDELINES
SAT
DOTS
MOA: inhibits mycolic acid synthesis which are essential components of mycobacterial cell walls It is a prodrug which has to be activated by mycobacterial catalase-perosidase KatG. Once activated, it forms a covalent complex with AcpM (acyl carrier protein) and KasA synthetase (a beta keto acyl carrier protein) which blocks mycolic acid synthesis
Pharmacokinetics
Rapidly absorbed from the GIT; available in oral and parenteral forms Peak plasma concentration reached within 1-2 hrs; readily diffuses into all body fluids and tissues Metabolized in the liver by N-acetyltransferase (NAT) . Acetylator status is genetically determined. Rapid vs slow acetylators. Excreted as hydrazone metabolites and unchanged forms in the urine
Clinical uses: Dosage is 5mg/kg/d up to 10 mg/kg/d for serious infections or if malabsorption is a problem. Adult dose is 300mg/d. Dosage of 15mg/kg/dose or 900 mg may be used in a 2x weekly regimen usually in combination with Rifampicin at 600mg Used as a single agent in treating latent TB cases. Dose is 5mg/kg/d or 300 mg daily or 900mg 2x/week for 9 months Pyridoxine 25-50mg/d is recommended to prevent peripheral neuropathies.
Adverse Reactions: Immunologic: fever, skin rashes, drug-induced SLE Direct Hepatotoxicity: Drug induced hepatitis is a contraindication to continuing tx but elevated liver enzymes (expected up to 4x) without other SSx is not. Risk depends on age : rare in those <20 y.o. greater for those aged 50 and up, alcoholics, during pregnancy and the postpartum period.
Adverse Reactions: Peripheral Neuropathy: seen in higher doses and is associated more with slow acetylators and patients with other predisposing conditions (AIDS, malnutrition, uremia, alcoholism,DM) ; due to pyridoxine deficiency. Miscellaneous rxns: hematologic, pyridoxine deficiency anemia, tinnitus, GI discomfort, interaction with metabolism of phenytoin (decreases)
A semi-synthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. Has in vitro activity vs g(+) & g(-) cocci, some enteric bacteria, mycobacteria and chlamydia. MOA: binds to the subunit of bacterial DNA dependent RNA polymerase inhibiting RNA synthesis
PK: well absorbed orally; undergoes enterohepatic recirculation and mainly excreted in the feces as deactylated metabolites. A small amount is also excreted in the urine. It is bactericidal for mycobacteria with good penetration into most tissues and phagocytic cells. Widely distributed in all body fluids; but limited CSF penetration except in the presence of meningeal inflammation
Clinical uses: Usually co-administered with other anti-TB meds at doses of 10 mg/kg/d up to 600mg to prevent emergence of drug-resistant strains. Dose for treating leprosy is 600mg daily or 2x week with other drugs for 6 months Elimination of meningococcal carriage: 600mg BID x 2 days As prophylaxis for children with H. influenzae type disease 20mg/kg/d for 4 days Rifampin combination therapy for serious staphylococcal infections i.e. osteomyelitis and prosthetic valve endocarditis
Adverse effects: Gives a harmless orange discoloration to most body fluids Thrombocytopenia, rashes, nephritis Cholestatic jaundice and hepatitis Light chain proteinuria, rarely acute tubular necrosis (ATN)
Adverse effects: Flu-like syndrome ( more with intermittent dosing) CYP 450 inducer (CYPs 1A2,2C9,2C19,2D6 and 3A4) increase elimination of anticoagulants, methadone, cyclosporine, anticonvulsants, protease inhibitors, nonnucleoside reverse transcriptase inhibitors, contraceptives, et al. Results in significant lower serum levels of these drugs.
MOA : inhibits mycobacterial arabinosyl transferases involved in the synthesis of arabinoglycan, an essential component of mycobacterial cell wall. Well-absorbed from the gut, peak plasma levels reached at 2-4 hours. 20% excreted via fecal route and 50% in the urine unchanged. It accumulates during renal failure hence dose adjustments have to be made
Clinical uses: Given in combination with INH and rifampicin, resistance is high when given alone. Dose: 15-25mg/kg, the higher dose is usually given for tx of serious infections (up to 35mg/kg) and TB meningitis.
Adverse effects: Hypersensitivity reactions are rare Most serious: retrobulbar neuritis; red-green color blindness and loss of visual acuity. Dose related: 25mg/kg/d
MOA: unknown Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase. It exerts its activity against mycobacteria residing within the acidic environment of the lysosomes Well absorbed orally and peak serum levels reached at 1-2 hrs. Undergoes hepatic metabolism and renal excretion.
Clinical uses: Acts as a sterilizing agent active against residual intracellular organisms that may cause relapse. Used in combination with INH and Rifampicin as front-line drugs of treatment Its addition to the first line treatment regimen allows course of treatment to be shortened to 6 months
MOA: irreversible inhibitors of protein synthesis; binds to bacterial 30S ribosomal proteins (S12). Poor GI absorption, usually administered IV, can be given IM. Peak serum levels reached within 30 mins to 1 hour Has a postantibiotic effect which is more pronounced with single large dose administration
Clinical Use: Used when an injectable anti-TB drug is needed, used in combination for treatment of severe life-threathening infections and for drug resistant strains. Dose: 15-40 mg/kg/day not to exceed 1.5 g in children
Adverse effects: (dose-related) Ototoxic Nephrotoxic; dose adjustments for those with renal disease. Vertigo
Chemically related to INH, blocks synthesis of mycolic acids Dose initially 250 mg with gradual increase until 1g/d though this is poorly tolerated Severe GI irritation, neurologic symptoms and hepatotoxicity are undesirable effects Pyridoxine may relieve neurologic symptoms
A peptide protein synthesis inhibitor from Streptomyces capreolus Injectable tx for drug-resistant strains Nephrotoxic and ototoxic Injection causes local pain and can cause sterile abscesses
Derived from Streptomyces orchidaceus Inhibits mycobacterial cell wall synthesis specifically the enzyme alanine racemase Toxic effects: peripheral neuropathy and psychological disturbances i.e. depression and psychotic reactions. Pyridoxine at higher doses of 150mg/k/d may relieve neurologic disturbances
A folate synthesis antagonist active almost exclusively vs M tuberculosis Can result in crystalluria since very high concentrations are reached in the urine Toxic effects: peptic ulcers and GI hemorrhage, severe hypersensitivity reactions, hepatosplenomegaly, hepatitis, adenopathy and granulocytopenia
Kanamycin use is obsolete Amikacin for MDR TB, also active vs atypical mycobacteria
Active against M tuberculosis and atypical mycobacteria Ex: Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin Moxifloxacin is the most active vs M tuberculosis Ciprofloxacin has more activity vs atypical mycobacteria
Associated with bone marrow suppression and irreversible optic and peripheral neuropathy. Considered as a drug of last resort
Related to rifampicin Inhibits bacterial RNA polymerase A less potent inducer of CYP 450 enzymes than rifampicin hence may be a suitable alternative esp in HIV pxs Active vs M tuberculosis, M aviumintracellulare and M fortuitum
Same MOA as with all rifamycins Active vs M tuberculosis and M avium Has a complete cross-resistance to rifampicin hence shoud not be used to treat HIV infected patients who have rifampicin resistant organisms As with rifampicin, also a potent inducer of CYP 450
DAPSONE & other SULFONES Mycobacterium leprae Dapsone is the most widely used and is an inhibitor of folate acid synthesis May cause hemolysis esp in patients with G6PD deficiency Toxic effets: Methemoglobinemia, GI sxs, fever, pruritus, rashes
CLOFAZIMINE May be used as an alternative tx to dapsone MOA: unknown , DNA binding? Stored in reticuloendothelial tissues and skin, released slowly; serum half-life 2 months Given to sulfone resistant or intolerant patients May cause skin discoloration ( red-brown to nearly black) Dose is 100mg/d p.o.
Isoniazid
Bactericidal
FIRST LINE ANTIMYCOBACTERIAL DRUGS SUBCLASS PZA MOA Converted to pyrazinoic acid in the acidic environ of macrophage lysosomes EFFECTS Bacteriostatic; may be bactericidal vs actively dividing organisms USE Sterilizing agent in the 1st 2 monts of tx; shorthens duration to 6 months PK, TOX, INTERAXNS Oral. Hepatic clearance. Half life 9 hrs. Metabolites are cleared renally, dose adjustments prn Oral. Mixed clearance. Half life 4 hrs. dose reduction in kidney failure. AE: retrobulbar neuritis
Ethambutol
Bacteriostatic
Given as four drug initial combination tx; used also for atypical mycobacterial infections
FIRST LINE ANTIMYCOBACTERIAL DRUGS SUBCLASS Streptomycin MOA Binds to S12 ribosomal subunit thus preventing bacterial protein synthesis EFFECTS Bactericidal vs susceptible mycobacteria USE Used as an injectable drug for tx of drug resistant strains PK, TOX, INTERAXNS IM, IV. Renal clearance. Halflife 2.5 hrs. Administered daily initially then 2x/wk. AE: Nephrotoxicity, ototoxicity
*Van den Boogaard J, Kibiki G, et al , Antimicrobial Agents and Chemotherapy, Mar 2009;849-862
Diarylquinolines: TMC207 also known as R 207910 or compound J MOA: inhibits mycobacterial ATP synthetase enzyme Undergoing phase II clinical trials
*Van den Boogaard J, Kibiki G, et al , Antimicrobial Agents and Chemotherapy, Mar 2009;849-862
Nitroimidazoles: PA-824 and OPC-67683 PA-824 is a prodrug which has to be activated by mycobacterial glucose-6-phosphate dehydrogenase to inhibit synthesis of proteins and cell wall lipids. OPC-67683 is a mycolic acid biosynthesis inhibitor
*Van den Boogaard J, Kibiki G, et al , Antimicrobial Agents and Chemotherapy, Mar 2009;849-862
Diamines SQ 109 most promising among an array of more than 60,000 compounds MOA: inhibits mycobacterial cell wall synthesis but exact target is still unknown.
*Van den Boogaard J, Kibiki G, et al , Antimicrobial Agents and Chemotherapy, Mar 2009;849-862
Pyrroles: LL3858 has promising activity vs M tuberculosis, atypical mycobacteria and fungi MOA ?