ANTIMICROBIALS Therapeutic goal: clear tissue of infecting organisms Classification by Organism: o Antibacterial Drugs Narrow spectrum: target few

w types Broad spectrum: target many types Anti-mycobacterial drugs o Antifungal Drugs o Antiviral Drugs Other antivirals Antiretroviral Classification by MOA: o Inhibits bacterial cell wall synthesis o Inhibits protein synthesis o Inhibits nucleic acid synthesis o Interrupts metabolic pathways o Disrupts cell membrane permeability o Inhibits enzymes important in microorganisms function Bacteriocidal drug kills bacteria Bacteriostatic drug inhibits bacterial reproduction so host defenses can kill Selective Toxicity drug is toxic to microorganism but not human host Organism Sensitivity drug is toxic to microorganism causing infection Antimicrobial Resistance microorganism is no longer affected by a particular antimicrobial that was once effective. MOA of Antimicrobial Resistance: o Production of drug-inactivating enzyme o Change in receptor structure o Change in structural features of the microorganism that effects the drug permeability o Development of alternative metabolic pathways

Factors Contributing to Antimicrobial Resistance: o Administration of antimicrobials when not needed (dont treat contamination or colonization) o Lack of/improper adherence to regimens o Dosing that does not maintain adequate drug levels Antimicrobial Selection and Administration: o Match the drug to the bug o Consider the drug spectrum o Combination therapy o Site of infection

o Maintain adequate blood levels (taken around the clock and/or on empty stomach) o Antibiotic combinations Adverse Effects of Antibiotics: o Normal gut flora are killed diarrhea colonization by pathogenic bacteria o Suprainfection infection with second organism o Allergy (penicillin most commonly) Pseudomembranous colitis bowel colonized with Clostridium difficile (severe diarrhea) > Categories of Antimicrobials BETA-LACTAM ANTIBIOTICS o Penetrate cell wall and bind to targets on cytoplasmic membrane o Disrupt synthesis/maintenance of the cell wall bacteria is killed by osmotic pressure o Can be inactivated by beta-lactamasea enzymes degrade the drug o Gram-negative organisms have an additional component to cell wall that most beta-lactam antibiotics cannot penetrate. Penicillins Cephalosporins Carbapenems Azetronam MOA Therapeutic Uses Prophylactic Uses Resistance Distribution PENICILLIN Affects bacterial cell wall Gram-positive bacteria (Strep, Staph) Few gram-negative (Neisseria, syphilis) Some anaerobes (Enterobacter, Psuedomonas) Prevent bacteremia in people at risk for endocarditis

Excretion Adverse Effects Drug Interactions

Have varying resistance to betalactamases Bound to plasma proteins Do not cross blood-brain barrier well except if compromised by infection Kidneys GI symptoms and suprainfections related to loss of normal flora Overdose can cause neurologic problems, seizures Synergistic with aminoglycoside antibiotics but cannot be combined in same IV line

 Beta-Lactamases (Penicillinases) o Enzymes that cut beta-lactam ring, inactivating beta lactam antibiotics o Bacteria that manufacture beta-lactamases may be resistant to all or most beta -lactam antibiotics. Beta-Lactamase Inhibitors o Drugs bind to active site of beta-lactamases, preventing these enzymes from cutting the beta-lactam ring prevents resistance of bacteria to these antibiotics. o Many are irreversible o Can be administered along with beta-lactam antibiotics Some Penicillin-Beta-Lactamase Inhibitor combinations: o Augmentin o Unasyn o Timentin o Zosyn MOA Resistance CEPHALOSPORINS Similar to penicillins in structure and activity 3rd and 4th generations should be reserved for serious infections only to avoid resistant populations Varying resistance to beta-lactamases by generation Widely distributed to body fluids including bone 1st and 2nd generation do not cross blood-brain barrier Most eliminated by kidney Chance of increased bleeding w

Distribution Excretion Adverse Effects Drug Interactions

Chance of increase bleeding with warfarin because of Vit. K metabolism (cefmetazole, cefoperazone, cefotetan) Same 3 can trigger disulfiram-like reaction when combined with alcohol (PUKE!) Activity against Gram Negative Low Higher Higher Highest Resistance to BetaLactamases Low Higher Higher Highest Distribution to CSF Poor Poor Good Good

Generation 1st (e.g., cephalothin) 2nd (e.g., cefamandole) 3rd (e.g. cefotaxime) 4th (e.g. cefepime)

MOA Therapeutic Uses

Distribution Adverse Effects Drug Interactions

CARBAPENEMS Beta-lactam antibiotics with extremely broad spectrum Gram positive cocci Gram negative cocci and bacilli Anaerobes Especially valuable in mixed infections Not absorbed from GI tract (IV administration) Suprainfection

Cross allergy with penicillins

NON-BETA-LACTAM ANTIBIOTICS (affect bacterial cell wall too) MOA Therapeutic Uses VANCOMYCIN Affects bacterial cell wall (NOT A BETA-LACTAM!) Gram positive infections in penicillin-allergic patients Synergistic with aminoglycosides Oral preparation can be used for bowel infections (C. diff)

Resistance Distribution Excretion Adverse Effects

Drug Interactions

Poor penetration into CSF If given orally, not absorbed into bloodstream Kidneys Potentially toxic but used to treat serious infections Ototoxicity and nephrotoxicity Rapid infusion causes severe reaction of flushing, tachycardia, and hypotension which can be fatal (infuse over 60 min.) Irritating to the vein, causing thrombophlebitis Synergistic with aminoglycoside antibiotics but cannot be combined in same IV line Multiple drug interactions with hyperlipidemic drugs, muscle relaxants, and ototoxic drugs

BACTERIOSTATIC INHIBITORS OF PROTEIN SYNTHESIS Tetracyclines (tetracycline, doxycycline, minocycline, etc.)

Macrolides (erythromycin, clarithromycin, azithromycin) Clindamycin Chloramphenicol Others

MOA Therapeutic Uses

Resistance Distribution Adverse Effects Problems

TETRACYCLINES Bind to 30S ribosomal subunit and prevent elongation of peptide chain Agents of choice for rickettsial diseases (Rocky Mountain spotted fever) and Chlamydia Acne Periodontal disease Broad spectrum but resistance has developed in many bacterial species, limiting their use Poor CSF penetration Discolors teeth binds to calcium in developing teeth Suprainfection with bowel organisms or Candida Poor absorption when given with antacids/laxatives, milk/dairy, iron. MACROLIDES Inhibit 50S ribosomal subunit Gram-positive bacteria Some gram-negative bacteria Drug of choice for Legionella and Chlamydia Alternative to penicillin in allergic patients Poor CSF penetration Some forms of erythromycin are corrosive to the GI tract and cause erosive esophagitis IV forms can be corrosive to veins and must be diluted and slowly infused Hepatotoxicity is a concern Erythromycin and clarithromycin are strong inhibitors of cytochrome P450!

MOA Therapeutic Uses

Distribution Adverse Effects

MOA Therapeutic Uses

CLINDAMYCIN Inhibits 50S ribosomal subunit (dont use with macrolide) Anaerobes Gram-positive anaerobes

Distribution Adverse Effects

Poor penetration of brain Suprainfection with C. diff IV infusion must be slow Reserve for serious infections!

BACTERIOCIDAL ANTIBIOTICS ALTERING PROTEIN SYNTHESIS Aminoglycosides (tobramycin, gentamycin, amakacin, others) MOA Distribution Adverse Effects Administratio n AMINOGLYCOSIDES Bind to 30S ribosomal subunit. Promote formation of abnormal proteins whose abnormal functioning kills the bacteria cell. Gram-negative bacteria (Psuedomonas, Klebsiella, Serratia) Can be used topically to sterilize gut, skin (neomycin), or eye Charged drugs that are not absorbed used IV Ototoxic and nephrotoxic adjust for renal impairment

Therapeutic Uses

For many patients, once daily infusion is as good as divided doeses because it produces very high levels that kill bacteria even after blood level declines Low levels in between the daily dose allows washout from body cells in between doses and lowers risk of toxicity

SULFAMETHOXAZOLE-TRIMETHROPRIM (BACTRIM) SULFAMETHOXAZOLE-TRIMETHROPRIM (BACTRIM) MOA Blocks bacterial enzymes that are important for synthesis of building blocks of DNA, RNA, and proteins Combo of sulfa drug and inhibitor of a bacterial enzyme, blocking different steps in the pathway synergistic Therapeutic Broad spectrum Uses Gram-negative Gram-positive UTO and Pneumocystis carinii pneumonia of AIDS Adverse Hypersensitivity reactions Effects Rash Stevens-Johnson syndrome

 Blood dyscrasias (from trimethoprim component) Crystalluria (kidney/bladder stones) CNS effects headache, psychosis

FLUOROQUINONES Ciprofloxacin, levoflaxacin, oxofloxacin, others MOA Therapeutic Uses Adverse Effects FLUOROQUINONES Inhibit enzyme important in bacterial DNA replication Aerobic organisms Most gram-negative Some gram-positive Irreversible joint disease in children under 18 Rarely, tendon rupture in adults Photosensitivity Candida suprainfections, especially oropharynx Infrequent but serious CNS effects Dont take with aluminum, iron, calcium, or zinc Can increase plasma levels of theophylline and warfarin

METRONIDAZOLE (FLAGYL) MOA Therapeutic Uses Adverse Effects METRONIDAZOLE Prodrug activated only in anaerobic cells Anaerobic organisms, including parasites and bacteria C. diff., Bacteroides, Entameba histolytica Darkened urine CNS effects Caution during pregnancy, avoid during lactation Cytochrome P450 interactions

ANTIBIOTICS FOR TUBERCULOSIS o Target mycobacteria

o Always treated with 2 or more drugs to avoid emergence of resistant strains o Treatment is prolonged (6-10 months) because bacteria grow slowly. o Patients with HIV are very susceptible to TB and other mycobacteria o Reactive skin test in previously negative patient indicates new exposure and treatment is needed. o TB infections can be followed by latent phase where disease is inactive, but should be treated to avoid re-emergence of active disease. o Patients with newly reactive skin tests or in latent phase can be treated with monotherapy isoniazid or rifampin.

Isoniazid Rifampin Pyrazamide o Often combined with other 3 drugs o Hepatotoxic follow liver values Ethambutol o Distributed widely but doesnt penetrate brain o Can cause optic neuritis. o Allergic reactions o NOT HEPATOTOXIC! MOA Therapeutic Uses Distribution ISONIAZID Inhibits the formation of the mycobacterial cell wall highly specific for TB Used alone to treat latent TB Used with at least one other drug for active TB Distributed to all body tissues and fluids Crosses blood-brain barrier to achieve therapeutic levels Hepatotoxic, especially in elderly Contraindicated for people with pre-existing liver disease Alcohol increases risk of hepatotoxicity Increased phenytoin levels Risk of peripheral neuropathy reduced by giving pyridoxine

Adverse Effects

Administratio n

Therapeutic Uses Distribution

RIFAMPIN Used with at least one other drug for active TB Distributed to CSF

Adverse Effects

Hepatic metabolism Hepatotoxic and increases hepatotoxicity of other drugs Induces cytochrome P450 enzymes decreases levels of birth control pills, seizure meds, and others Turns body fluids RED!

ANTIFUNGALS Amphotericin B Ketoconazole MOA Therapeutic Uses Adverse Effects AMPHOTERICIN B Binds to sterols in the fungal membrane and increases permeability fungal cell swells and bursts Systemic fungal infections Toxic to mammalian cells because of the cholesterol in cell membranes AMPHOTERRIBLE! Infusion reactions phlebitis and systemic symptoms Nephrotoxic ANTIVIRALS Acyclovir KETOCONAZOLE Inhibits synthesis of a sterol component of fungal cell membrane Oral alternative to amphotericin B for systemic fungal infections Can be used topically for fungal skin infections Strong inhibitor of cytochrome P450 enzymes use with extreme caution in hepatically metabolized drugs Rare hepatic necrosis

MOA Therapeutic Uses Adverse Effects

 Ganciclovir Drugs for influenza MOA Therapeutic Uses Resistance Adverse Effects Other ACYCLOVIR Suppresses synthesis of viral DNA but must be activated by viral enzyme, thymidine kinase Active against all herpes viruses (most strains of CMV are resistant) Topical, oral, IV Commonly due to thymidine kinase deficiency Nephrotoxic

Valtrex is a prodrug of acyclovir bt is more bioavailable Immunizations for chicken pox and shingles (herpes zoster)

Therapeutic Uses Excretion Adverse Effects

GANCICLOVIR Active against all herpes viruses including CMV Reserved for treatment in CMV in immunocompromised patients Excreted unchanged in urine (decreased dose for patients with renal impairment) Poor oral bioavailability Granulocyptopenia and thrombocytopenia Teratogenic and embryotoxic

INFLUENZA ANTIVIRALS o First line of defense is immunization Amantadine (prophylaxis during epidemics and as treatment) Rimantadine (prophylaxis during epidemics and as treatment) Neuraminidase inhibitors o Oseltamivir (Tamiflu) oral drug for prophylaxis or to shorten duration of flu o Zanamivir (Relenza) inhaled, not approved for prophylaxis o Both must be taken very soon after first flu symptoms appear o Resistance may be a problem HUMAN IMMUNODEFICIENCY VIRUS (HIV) o HIV drugs have overlapping toxicities and many interactions with each other and other drugs

o Always treated with combination of drugs known as ART (AntiRetroviral Therapy), ARV (Anti-Retrovirals) or HAART (Highly Active AntiRetroviral Therapy) o Do not skip doses! Classes o o o o of HIV Drugs: Nucleoside reverse transcriptase inhibitors (NRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Attachment inhibitors Fusion CCR5 antagonists o Integrase inhibitors

ART, ARV, or HAART therapy o Combination of 3 to 4 drugs that target different aspects of viral life cycle o Can reduce viral load so that it is undetectable in blood, but does not cure o Currently start therapy when CD4+ cells drop below 500 cells/mm3 but some recommend earlier o Pregnant patients should receive treatment while pregnant as it will reduce viremia and reduce transmission to fetus o RT inhibitors can be given during labor if woman was not treated during pregnancy and to child after labor Nucleoside Reverse Transcriptase Inhibitors (NRTIs) o Zidovudine, ddi, ddc, 3tc, d4t, and others NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) MOA Inhibit viral enzyme, reverse transcriptase, that converts viral RNA into DNA by terminating the growing DNA strand. Adverse MOA activity can also inhibit human DNA polymerases Effects so these drugs can be toxic to dividing cells Can cause mitochondrial toxicity in liver (hepatomegaly and fatty liver) and elsewhere leading to lactic acidosis Bone marrow depression Anemia Neurtropenia GI toxicity Peripheral lipoatrophy (i.e. facial loss of fat) Peripheral neuropathy Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

o Nevirapine, delavirdine, efavirenz NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) MOA Bind to active site of the reverse transcriptase enzyme More specific for viral reverse transcriptase Do not affect human DNA polymerases the way nucleoside RT inhibitors do Adverse All have cytochrome P450 interactions but of different Effects kinds (nevirapine is an inducer, delavirdine and efavirenz inhibit) Many drug interactions Rash can be severe Stevens-Johnson syndrome Severe hepatotoxicity Avoid St. Johns wort

Protease Inhibitors (PIs) o Indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, fosamprenavir, atazanavir, tipranavir, and lopinavir o Several dosage forms and one combination MOA PROTEASE INHIBITORS (PIs) Inhibit viral protease, which is responsible for the final step in maturation of an infective virus and because of inability to cut the long viral proteins into functional units, the virus remains immature and non-infective Hyperglycemia/diabetes Fat redistribution Hyperlipidemia Increased bleeding in patients with hemophilia Reduced bone mineral density Elevation of serum transaminases (liver enzymes) ECG changes with atazanavir (prolonged QT) All are metabolized by cytochrome p450 enzymes, so concurrent administration with inducers or inhibitors

Adverse Effects

can affect half-lives and drug-levels GI side effects Avoid St. Johns wort and garlic preparations

Entry Inhibitors o Two types: Fusion Inhibitors (Enfuvirtide Fuzeon) Attachment Inhibitors MOA ENFUVIRTIDE - FUSION INHIBITORS Binds to gp41, a viral envelope protein Resistance occurs when viral gene encoding gp41 mutates to alter its shape so the drug cannot bind Inhibits entry of HIV into CD4 positive cells Injection-site reactions Risk of bacterial pneumonia is increased Only fusion inhibitor currently on market Must be given subq twice a day Reserved for patients who failed more standard HAART with RT inhibitors and protease inhibitors Expensive Hard to manufacture

Adverse Effects Other

Attachment Inhibitors MOA Adverse Effects MARAVIROE- ATTACHMENT INHIBITORS Blocks the CCR5 receptor so HIV does not attach to the CD4 cell (CCR5 antagonist) Cough Fever Rash Muscle, joint, stomach pain Dizziness Liver toxicity Use caution in people with cardiovascular disease Pregnancy category B Dosage adjusted depending on whether it is combined with a CYP 450 inducer or inhibitor

Other

Integrase Inhibitors MOA RALTEGRAVIR INTEGRASE INHIBITORS Blocks integrase which normally aids in integration of viral genetic information into the host cell DNA which then turns into a viral factory. One chance for this to be effective. Diarrhea Nausea Headache Pregnancy category C Elimination by metabolis Given twice daily

Adverse Effects Other

Resistance and Adherence o Replication rate of HIV is between 1 and 10 billion virions/day o High probability of introducing base-pair errors by HIV reverse tanscriptase o HIV can mutate into a drug-resistant form quickly o Combining antiretroviral drugs that work at different points in replication cycle minimizes resistance o Recommended > 95% adherence to prevent resistance