Antimicrobial Therapy Jeff

7/27/2019 Antimicrobial Therapy Jeff

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Jeffrey Tse Antimicrobial Notes 2013.

ANTIMICROBIAL THERAPY

SHORT NOTES BY JEFFREY TSE, 2013


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Antimicrobial Therapy SummaryMechanism DrugsBlock cell wall synthesis(inhibit peptidoglycan cross-linking )

Penicillins, Cephalosporins, Monobactams,Carbapenems (= all Lactams)

Block peptidoglycan synthesis Vancomycin, BacitracinBlock nucleotide synthesis Sulfonamides, TrimethoprimBlock DNA topoisomerases(control DNA over/underwinding)

Fluoroquinolones

Damage DNA MetronidazoleBlock mRNA synthesis Rifampin (antimycobacterial)Block protein synthesis (30S ribosomal subunit)

Aminoglycosides, Tetracyclines

Block protein synthesis (50S ribosomal subunit)

Macrolides, Chloramphenicol, Clindamycin,Linezolid, Streptogramins (Quinupristin,Dalfopristin)

Damage inner and outer membrane (Bind LPS) Polymyxin (relatively neurotoxic, nephrotoxic)


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Antibacterial therapy-LACTAMSPenicillins[General Mechanism : Bind Penicillin-binding proteins (PBP), block transpeptidase cross-linking of peptidoglycan, activate autolytic enzymes]

Prototype -Lactams: Penicillin G (IV), Penicillin V (oral)Mechanism = Penicillins. Use = Bactericidal for Gram +ve organisms ( Strep. A, Strep. Pneumoniae, Actinomyces ), Gram vecocci (Nisseria, Moraxella), Spirochetes ( Syphilis ). [Not penicillinase resistant]Toxicity = Hemolytic Anemia , Hypersensitivity.Resistance = -Lactamase cleave -Lactam ring.

Penicillinase-resistant Penicillins: Nafcillin, Dicloxacillin, Methicillin ( use NAF for staph )Mechanism = Penicillins. Narrow spectrum , bulky R group Penicillinase-resistant .Use = Staph. Aureus (except MRSA altered PBP target site)Toxicity = Methicillin-interstitial nephritis , Hypersensitivity.

Aminopenicillins : Amoxicillin, Ampicillin Mechanism = Penicillins. Wider spectrum , Penicillinase sensitive ( thus combine with Clavulanicacid to protect against -Lactamase ). AmOxicillin Oral bioavailability > Ampicillin .Use = Haemophilus Influenzae, E. Coli, Listeria Monocytogenes, Proteus Mirabilis, Salmonella ,Shigella , Enterococci . (Amoxicillin HELPSSkill Enterococci )Toxicity = Ampicillin rash , Pseudomembranous Colitis , Hypersensitivity.Resistance = -Lactamase cleaves -Lactam ring.

Anti-pseudomonals: Ticaricillin, Carbenicillin, Piperacillin (TCP: Take Care of Pseudomonas)Mechanism = Penicillins. Wider spectrum .Use = Pseudomonas, Gram ve rods. Penicillinase sensitive ( thus combine with Clavulanic acid toprotect against -Lactamase )Toxicity = Hypersensitivity.

-Lactamase Inhibitors = Clavulanic Acid, Sulbactam, Tazobactam. ( CAST)combine with penicillin to protect against -Lactamase.


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Cephalosporins[General Mechanism : Bactericidal, inhibit cell wall synthesis, less susceptible to penicillinase]

1st generation: Cefazolin, CephalexinUse = Gram +ve cocci , Proteus Mirabilis, E. Coli, Klebsiella Pneumoniae.[PEcKand Gram + cocci]

2nd generation: Cefuroxime, Cefoxitin, CefaclorUse = Gram +ve cocci , Hemophilus Influenzae, Enterobacter Aerogenes, Neisseria , Proteus Mirabilis, E. Coli, Klebsiella Pneumoniae, Serratia Marcescens.[HEN PEcKS]

3rd generation: Ceftriaxone, Cefotaxime, CeftazidimeUse = serious Gram ve infection resistant to other -Lactams.Ceftriaxone Meningitis, Gonorrhea .

Ceftazidime Pseudomonas .

4th generation: CefepimeActivity against Pseudomonas , Gram +ve organisms.

Toxicity = Vitamin K deficiency , Nephrotoxicity of Aminoiglycosides , Hypersensitivity ( crosshypersensitivity with penicillin in 5-10% px), disulfiram-like reaction with ethanol (cephalosporinswith methylthiotetrazole group, eg Cefamandole)


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Monobactam: Aztreonam Mechanism = Bind PBP 3, Inhibit Cell wall synthesis . Synergistic with Aminoglycosides Use = Gram ve rods only (no use for Gram +ve / Anaerobes). For Penicillin allergic px. Px withrenal insufficiency can t tolerate Aminoglycosides .Toxicity = usually non toxic; GI upset. [ NO cross-allergenicity with Penicillins / Cephalosporins]

Carbapenems: Imipenem (+Cilastatin), Meropenem[General mechanism : Broad spectrum (>Penicillins/Cephalosporins), -Lactamase resistant.Imipenem always + Cilastatin, as Imipenem can be hydrolyzed by renal dehydropeptidase I toform nephrotoxic metabolite; Cilastatin = inhibitor of renal dehydropeptidase I)Use = Gram +ve cocci, Gram ve rods, Anaerobes .Meropenem = less risk of seizure + stable to dehydropeptidase I)Toxicity = CNS toxicity (seizures) , GI distress, skin rash. (limit use to life threatening condition)

GLYCOPEPTIDES

Vancomycin, Bleomycin[General Mechanism : Bactericidal. Bind D-ala D-ala portion of cell wall precursors inhibit cellwall mucopeptide formation]Use = Gram +ve only . serious multidrug-resistant organisms ( Staph . Aureus [ MRSA],Enterococci , Clostridium Difficile [Pseudomembranous Colitis])Toxicity = usually WELL tolerated . Nephrotoxicity , Ototoxicity , Thrombophlebitis , Diffuse flusing (red man syndrome) prevented by antihistamine + slow infusion rate. ( NOt a problem)


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PROTEIN SYNTHESIS INHIBITORS(only Aminoglycosides = bactericidal , Linezolid = bactericidal/bacteriostatic , others = bacteriostatic )

30S Inhibitors:

Aminoglycosides : Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin (GNATS cannotKillAnaerobes )[General Mechanism : Bactericidal . Inhibit formation of initiation complex, cause misreading ormRNA (30S). Synergistic with -Lactams . Need O 2 for uptake NOT used for anaerobes ]Use = Severe Gram ve rod infection. Neomycin bowel surgery .Toxicity = Nephrotoxicity (esp when + Cephalosporin), Ototoxicity (esp with loop diuretics),Teratogen . (NOT)Resistance = Transferase enzyme inactive drug by Acetylation, Phosphorylation, Adenylation .

Tetracyclines: Tetracycline, Doxycycline, Demeclocycline, Minocycline [Demeclocycline = ADHantagonist, = Diuretic in SIADH][General Mechanism : Bacteriostatic . Bind 30S, prevent attachment of aminoacyl-tRNA Doxycycline = use in Renal Failure (fecal elimination), but NOT take with milk, antacid,iron-containing preparation divalent cations inhibit absorption in GI.]Use = Mycoplasma Pneumoniae, Borrelia Burgdoferi; Chlamydia , Rickettsia (Tetracyclines canaccumulate intracellularly )Toxicity = Inhibition of bone growth (children) , discolouration of teeth , photosensitivity , GIdistress. CI: pregnancy.Resistance = uptake into cell/ efflux out of cell by efflux pump (plasmid encoded).


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PROTEIN SYNTHESIS INHIBITORS(only Aminoglycosides = bactericidal , Linezolid = bactericidal/bacteriostatic , others = bacteriostatic )

50S Inhibitors:

Macrolides: Erythromycin, Azithromycin, Clarithromycin[General Mechanism : Bacteriostatic . Bind (23S rRNA) of 50S subunit block translocation inhibit protein synthesis]Use = Atypical Pneumonia (Mycoplasma, Chlamydia, Legionella) , URTIs, STDs, Nisseria, Gram +vecocci (Strep. Infection in px allergic to Penicillin ).Toxicity = GI discomfort (most common cause of non-compliance ), Prolonged QT interval (espErythromycin ), acute cholestatic hepatitis , eosinophilia , Skin rash .CI: px on Theophylline , oral Anticoagulants . ( their serum conc.)Resistance = Methylation of 23S rRNA binding site .

Chloramphenicol[General Mechanism : Bacteriostatic . Block peptide bond formation @ 50S.]Use = Meningitis (Strep. Pneumoniae [ =adult], Haemophilus Influenzae [


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NUCLEOTIDE SYNTHESIS INHIBITORS

Sulfonamides: Sulfamethoxazole (SMX), Sulfisoxazole, Sulfadiazine[General Mechanism : Bacteriostatic . Inhibit Dihydropteroate Synthetase (normally PABA Dihydropteroic acid DHF)]Use = Gram +ve , Gram ve , Nocardia , Chlamydia . Triple sulfas / SMX (+trimethoprim) for UTI andprophylaxis for Pneumocystis Jiroveci pneumonia in HIV.Toxicity = Hemolysis in G6PD def icient, Kernicterus (infants), Nephrotoxicity (tubulointerstitialnephritis), photosensitivity, Hypersensitivity (hives and rashes), induce Steven-Johnson syndrome.CI: displace Warfarin (from albumin ) Warfarin blood conc.Resistance = Altered enzyme (bacterial dihydropteroate synthetase), uptake , PABA synthesis.

Trimethoprim (TMP)[General Mechanism : Bacteriostatic . Inhibit Dihydrofolate Reductase (normally DHF THF)]Use = TMP-SMX for UTIs, Shigella , Salmonella , Pneumocystis Jiroveci pneumonia (prophylaxis inHIV)Toxicity = Megaloblastic anemia, Leukopenia, Granulocytopenia (alleviate with supplementalFolinic acid [Leucovorin rescue]) ( TMP Treats Marrow Poorly! )


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Antibiotics affecting DNA

Fluoroquinolones: Ciprofloxacin / Norfloxacin / Ofloxacin / Enoxacin (2 nd gen), Levofloxacin /Sparfloxacin (3 rd gen), Moxifloxacin / Gatifloxacin (4 th gen), Nalidixic acid (1 st gen = Quinolone,rarely used)[General Mechanism : Bactericidal. Inhibit DNA gyrase (Topoisomerase II)Use = Gram ve rods (include Pseudomonas ) of Urinary /GI tracts , Nisseria , some Gram +ve.Toxicity = GI upset , superinfections, skin rash , HA, dizziness. Tendonitis + tendon rupture (espcalcaneal tendon rare, but maybe sued if not explained to px), leg cramp and myalgia in children .CI: Don t take with antacids, children and pregnancy damage to cartilage.Resistance = DNA gyrase mutation (csome -encoded)

Metronidazole[General Mechanism : Bactericidal. Damage DNA (by forming free radical toxic metabolites)Use = Giardia , Entamoeba , Trichomonas , Gardnerella Vaginalis, Anaerobes (infection belowdiaphragm Bacteroides, C. Difficile), Helicobacter Pylori [+ Bismuth + Amoxicillin (orTetracycline ) for Triple Therapy ] (GET GAPon the Metro !)Toxicity = Disulfiram-like reaction with ethanol , HA. (metallic taste)


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Antimycobacterial (TB) drugs: Rifampin, Isoniazid, Pyrazinamide, Ethambutol ( RIPE for tx )

RifampinMechanism = Inhibit DNA-Dependant RNA Polymerase .Use = MTB. Delay resistance to Dapsone in Leprosy. Meningococcal prophylaxis ,Chemoprophylaxis for contacts of children with Hemophilus Influenzae type B. Toxicity = Hepatotoxicity (minor) , P-450 (drug interactions), Orange body fluid.( 4Rs RNA polymerase inhibition, Revs up microsombal P-450 , Red/Orange body fluids, RapidResistance if used alone )

Isoniazid (INH)Mechanism = Mycolic acid Synthesis . (INH converted to active metabolite by Bacterial CatalasePeroxidase (KatG)) [Different t 1/2 in fast and slow acetylators]Use = MTB. TB prophylaxis (only drug).Toxicity = Neurotoxicity, Hepatotoxicity, Lupus. (Neurotoxic / Lupus prevented by Pyroxidine Vit B 6)

[INH Injures Neurones and Hepatocytes ]

PyrazinamideMechanism = Block Mycobacterial Fatty acid synthase inhibit mycolic acid production .[effective in acidic pH phagolysosomes engulfed TB is here]Use = MTB.Toxicity = Hepatotoxicity , Hyperuricemia .

EthambutolMechanism = Block Arabinosyltransferase CHO polymerization of cell wall.

Use = MTB.Toxicity = Optic Neuropathy (protan- and deuteranopia)


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Antifungal Therapy

Echinocandins : Caspofungin, Micafungin Mechanism = Inhibit -glucan inhibit cell wall synthesis Use = Invasive Aspergillosis, Candida Toxicity = flushing , GI upset

Azoles: Fluconazole, Ketoconazole, Itraconazole, Voriconazole, Clotrimazole, Miconazole[Fluconazole can cross BBB]Mechanism = Inhibit P-450 that converts Lanosterol to Ergosterol Inhibit Ergosterol synthesis Use = Systemic mycoses . Fluconazole : Crytococcus Meningitis (in AIDS), Candida infections.Ketoconazole : Candida Albicans , Blastomyces, Coccidiodes, Histoplasma; Hypercortisolism .Clotrimazole/Miconazole : Topical fungal infections.Toxicity = Liver dysfunction (inhibit P-450), Hormone synthesis inhibition ( Gynaecomastia ), feverand chills.

Polyene antimycotics : Nystatin (topical), Amphotericin B Mechanism = Bind ergosterol form membrane pores electrolyte leak [ Amphotericin Bdon t cross BBB ]Use = Nystatin swish and swallow - Oral for oral candidiasis (thrush), Topical for diaper rash/vaginal candidiasis . Amphotericin B Serious Systemic mycoses : Cryptococcus, Aspergillus,Candida , Histoplasma, Blastomyces, Coccidiodes, Mucor. Fungal Meningitis (intrathecal admin).[Require supplement K+ and Mg 2+ for altered renal tubule permeability. ]Toxicity = Fever/chills, hypotension, anemia, arrhythmia, nephrotoxicity ( with hydration), IVphlebitis . (Liposomal Amphotericin toxicity)

Flucytosine (5-Fluorocytosine)Mechanism = converted to 5-Fluorouracil (5-FU) by Cytosine Deaminase Inhibit DNA synthesis .Use = Systemic mycoses (eg Cryptococcus) with Amphotericin B .Toxicity = Bone marrow suppression , nausea/vomiting , diarrhea.


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Antifungal (Dermatophytoses) Therapy

TerbinafineMechanism = Inhibit fungal enzyme (Squalene Epoxidase)Use = Dermatophytoses (esp Onychomycosis finger/toe nails )Toxicity = Visual disturbance, abnormal liver function tests.

GriseofulvinMechanism = Interfere Microtubule function disrupt mitosis . [Deposit in Keratin-containingtissues]Use = Dermatophytoses (inhibit dermatophyte growth), Superficial infections (oral tx)Toxicity = Teratogenic, Carcinogenic , Confusion , HA, P-450 and Warfarin metabolism .

Antiprotozoan TherapyPyrimethamine Toxoplasmosis, Plasmodium FalciparumSuramin + Melarsoprol Trypanosoma BruceiNifurtimox Trypanosoma CruziSodium Stibogluconate Leishmaniasis

ChloroquineMechanism = Block Plasmodium heme polymerase Use = Plasmodium species. [ Primaquine for P. Vivax / P. Ovale (hypnozoites in liver)] Mefloquine(for tx /prophylaxis). Quinine (+ Pyrimethamine / SMX) Resistant species .Toxicity = Bulls eye retinopathy (and keratopathy), G6PD Hemolysis .

Antihelminthic TherapyMebendazole, Ivermectin, Praziquantel , Pyrantel Pamoate, Diethylcarbamazine ImmobilizeHelminths.


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Antiviral Chemotherapy

Immunoglobulins neutralize (blocks) viruses .

Uncoating Inhibitors : Amantadine, Rimantidine Mechanism = Block penetration/uncoating (M2 protein) , release of Dopamine from intact nerve

terminals.Use = Influenza A . Parkinson s DiseaseToxicity = Ataxia, Slurred speech , Dizziness. [ Amantidine blocks influenza A damage cerebell A]Resistance = Mutated M2 protein; 90% Influenza A strains resistant to Amantadine .

Neuraminidase Inhibitors: Zanamivir (inhal), Oseltamivir (oral)Mechanism = Inhibit Influenza Neuraminidase , Release of progeny virus.Use = Influenza A, Influenza B .


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Antiviral TherapyInhibitors of Nucleic acid synthesis

RibavirinMechanism = Inhibit (competitive) IMP dehydrogenase Inhibit Guanine nucleotide synthesis .Use = RSV, Chronic Hep C .Toxicity = Hemolytic anemia , Teratogenic (severe )

Acyclovir, Valacyclovir (prodrug, oral bioavailability), Famciclovir (for VZV)Mechanism = Guanosine analog . Monophosphorylated by HSV/VZV Thymidine Kinase triphosphate formed by enzyme. Inhibit viral DNA polymerase (by chain termination)Use = HSV, VZV, EBV. HSV induced mucocutaneous / genital lesions/ encephalitis . Prophylaxis forimmunocompromised Px. [NO effect on latent HSV / VZV]Toxicity = CNS effects (nausea/vomit/HA/diarrhea severe = hallucination, confusion, rash, hairloss etc)Resistance = Lack Viral Thymidine Kinase .

Ganciclovir, Valganciclovir (prodrug, oral bioavailability)Mechanism = Guanosine analog . Monophosphorylated by CMV viral Kinase triphosphateformed by kinase enzyme. Inhibit viral DNA polymerase Use = CMV (esp in Immunocompromised Px)Toxicity = Leukopenia, Neutropenia, Thrombocytopenia, Renal toxicity . (more toxic to hostenzyme than Acyclovir)Resistance = Lack viral kinase / Mutated CMV DNA polyermase .

FoscarnetMechanism = Pyrophosphate analog. Bind Pyrophosphate-binding site of DNA polyermase Inhibit Viral DNA polymerase .Use = CMV retinitis (in Immunocompromised Px, when Ganciclovir fails ), Acyclovir resistant HSV .Toxicity = Nephrotoxicity Resistance = Mutated DNA polyermase .

CidofovirMechanism = Inhibit Viral DNA polymerase . [Doesn t require phosphorylation by viral Kinase]Use = CMV retinitis (in Immunocompromised Px ), Acyclovir resistant HSV. Long t 1/2 .

Toxicity = Nephrotoxicity (co-admin with Probenecid )


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HIV TherapyHighly Active Anti-Retroviral Therapy (HAART): for Px with AIDS-defining illness , low CD4 cellcount (


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Bacteriostatic vs. Bactericidal AntibioticsBacteriostatic : Macrolides, Clindamycin, Tetracyclines, Chloramphenicol, SMX, TMPBactericidal : Penicillins, Cephalosporins, Vancomycin, Aminoglycosides, Metronidazole,Fluoroquinolones.

Antimicrobial ProphylaxisInfection ProphylaxisMeningococcal infection Ciprofloxacin (preferred), Rifampin, MinocyclineGonorrhea CeftriaxoneSyphilis Benzathine Penicillin G History of recurrent UTIs TMP-SMXEndocarditis + surgical/dentalprocedures

Penicillins

HIV ProphylaxisCell Count Infection ProphylaxisCD4 < 200 TMP-SMX / Pentamide Pneumocystis PneumoniaCD4 < 100 TMP-SMX / Pentamide Pneumocystis Pneumonia +

Toxoplasmosis (not byPentamide)

CD4 < 50 Azithromycin M. Avium complex

Antimycobacterial DrugsBacterium Prophylaxis TxM. Tuberculosis Isoniazid Rifampin , Isoniazid, Pyrazinamide, EthambutolM. Avium-Intracellulare Azithromycin Azithromycin, Rifampin, Ethambutol,

Streptomycin [Any 3 for Triple therapy]M. Leprae - Dapsone (block DHF synthesis), Rifampin ,

Clofazimine (block DNA base, PLA2activity accum lysophospholipid inhibitbacterial prolif.) [ Triple therapy ]

Empiric therapy for community-acquired Pneumonia:Out px MacrolidesIn px FluoroquinolonesICU -Lactam + Fluoroquinolone/Azithromycin

Antibiotics to avoid in PregnancyClarithromycin EmbryotoxicSulfonamides KernicterusAminoglycosides OtotoxicityFluoroquinolones Cartilage damageMetronidazole MutagenesisTetracyclines Inhibit bone growth, Discoloured teethRibavirin TeratogenicGriseofulvin TeratogenicChloramphenicol Gray baby syndrome

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Antimicrobial Therapy Jeff