Pharmacotherapy of Infectious Disease

Question 1

steps in cell wall synthesis

Answer 1

1. Precursor synthesized (UDP-acetylmuramyl-pentapeptide). 2. Formation of sugar-pentapeptide, is transported out of membrane and subsequent addition and polymerization to linear peptidoglycan strands. 3. Cross-linking of adjacent peptidoglycan (murein) strands by a transpeptidase reaction.

Question 2

Vancomyocin (Vancocin, generic)

Answer 2

Mechanism of Action: inhibitor of cell wall synthesis at step 2. Binds to D-ala-D-ala terminal of the peptidoglycan pentapeptide side chain and prevents polymerization of linear peptidoglycan by peptidoglycan synthase. Powerful gram positive drug. Second line of drug due to high toxicity. However, resistance is starting to appear. Plasmid-based replacement of terminal D-ala with D-ala/D-ser and reduced affinity. Usually IV route, unless GI infection. Eliminated through urine (unchanged) or stool. 5-11 hours with normal renal function 7-9days with renal dysfunction. NEED to know patients creatine clearance. Adverse: Ototoxicity- (tinnitus, high frequency hearing loss and balance problems); fever and chills, flushing “red man” syndrome - (due to destruction of mast cells, release of histamine, cytokines, increases in the presence of anesthetic); nephrotoxicity; thrombophlebitis - vein inflammation due to clot. Treats S. aureus and clostridium difficile

Question 3

Bacitracin

Answer 3

Mechanism of Action - binds to lipid pyrophosphate carrier to inhibit cell wall synthesis (early step 2) to prevent dephosphorylation of lipid carrier. Gram-positve cocci, few gram-negatives, and clostridium difficile. Primarily a topical agent, poor absorption through oral route. Adverse effects (nephrotoxicity) if systemically absorbed.

Question 4

Beta-lactam antibiotics

Answer 4

Resembles termimal D-ala D-ala in the pentapeptide of the peptidoglycan wall. Mechanisms of action 1. Blocks the transpeptidase cross linking of cell wall components (step 3) 2. Binds to penicillin-binding proteins (PBPs) 3. Activates the autolytic enzymes (murein hydrolase) –> results in weakened cell wall, aberrant morphological form, cell lysis, and death. Resistance mechanism - inactivation (opening) of required beta-lacam ring. (Penicillinase, cephalosporinase, B-lacamase)

Question 5

Penicillin

Answer 5

Eliminated through renal excretion, 90% tubular secretion (secretion blocked with probenecid allowing penicillins to work faster) 10% of patients have sensitivity to drug; 6% sensitivity of drug in same class; 1% to drug from another class. (not for type 1 hypersensitivity) Adverse reactions: May see allergic response, nonallergic rashes and eruptions (40-100% from EBV), neural irritant (will not cross BBB unless massive inflammation), Vitamin K deficiency (causes coagulation disorders in newborns, most common to extended spectrum), nephritis, salt loading (hypertension or heart failure) Allergic cross-reactions is significant (~6%) Patients with type 1 reaction should avoid all beta lactam (except aztreonam); patients with only history of rashes are up to 90% likely to not react to another penicillin.

Question 6

Natural Penicillins

Answer 6

Penicillin G - unstable in acid, intramuscular and IV routes. Penicillin V- acid stable, oral administration. Gram positive spectrum of action. (streptococci, meningococci, gram-positive bacilli, spirochetes, syphilis) There is no acceptable alternative penicillin for treatment of penicillin-sensitive syphilis in pregnant women allergic to penicillin.

Question 7

Nafcillin

Answer 7

Anti-staphylococcal penicillins(penicillinase-resistance) - very narrow gram-positive agent –> staphylococcal infections. (injectable only) Elimination (unique to the class) - combination of hepatic and renal mechanisms, rarely requires dosage adjustment in renal failure, however, requires dose adjustment in hepatic failure. potentially will see neutropenia

Question 8

Oxacillin

Answer 8

Anti-staphylococcal penicillins(penicillinase-resistance) - very narrow gram-positive agent –> staphylococcal infections. (oral and injectable forms) Elimination (unique to the class) - combination of hepatic and renal mechanisms, rarely requires dosage adjustment in renal failure, however, requires dose adjustment in hepatic failure.

Question 9

Dicloxacillin

Answer 9

Anti-staphylococcal penicillins(penicillinase-resistance) - very narrow gram-positive agent –> staphylococcal infections. (oral forms) Elimination (unique to the class) - combination of hepatic and renal mechanisms, rarely requires dosage adjustment in renal failure, however, requires dose adjustment in hepatic failure.

Question 10

Methicillin

Answer 10

Anti-staphylococcal penicillins(penicillinase-resistance) - very narrow gram-positive agent –> staphylococcal infections. (not available in the US due to nephrotoxicity)

Question 11

Ampicillin (Omnipen, Principen, generics, oral and injectable forms)

Answer 11

Aminopenicillin Extended/broad spectrum of action (HELPS) (Haemophilus influenzae, escherichia coli, listeria monocytogenes, proteus mirabilils, salmonella) Drugs of choice for preventing endocarditis with surgical or dental procedures. Reaches therapeutic levels in CSF in meningitis to be effective. Sometimes can produce a serious rash in sensitive patients.

Question 12

Amoxicillin (Amoxil, Trimox, generics, oral forms)

Answer 12

Aminopenicillin Extended/broad spectrum of action (HELPS) (Haemophilus influenzae, escherichia coli, listeria monocytogenes, proteus mirabilils, salmonella) Drugs of choice for preventing endocarditis with surgical or dental procedures

Question 13

Ticarcillin (Ticar, injectable preps)

Answer 13

Antipseudopenicillins Extended/broad spectrum of action (pseudomonas, enterobacter, klebsiella)

Question 14

Piperacillin (Pipracil, injectable preps)

Answer 14

Antipseudopenicillins Extended/broad spectrum of action (pseudomonas, enterobacter, klebsiella)

Question 15

Carbenicillin (Pyopen)

Answer 15

Antipseudopenicillins Extended/broad spectrum of action (pseudomonas, enterobacter, klebsiella)

Question 16

Clavulanate

Answer 16

Beta-Lactamase Inhibitors; suicide inhibitors Use when resistance by beta-lactamases is expected, eliminated through renal route. Want suicide inhibitors to have same pharmacokinetics as antibiotic.

Question 17

Sulbactam

Answer 17

Beta-Lactamase Inhibitors; suicide inhibitors Use when resistance by beta-lactamases is expected, eliminated through renal route. Want suicide inhibitors to have same pharmacokinetics as antibiotic.

Question 18

Tazobactam

Answer 18

Beta-Lactamase Inhibitors; suicide inhibitors Use when resistance by beta-lactamases is expected, eliminated through renal route. Want suicide inhibitors to have same pharmacokinetics as antibiotic.

Question 19

Cephalosporins

Answer 19

(4 generations) Moving from 1st to 4th - increase activity against gram-negatives - decrease activity against gram-positives - increase resistance to beta-lactamases - increase distraction to body tissues and fluids, especially during inflammation Complete cross-reactivity within class should be assumed; cross reactivity between penicllins and cephalosporins is incomplete. (a patient with anaphylaxis to any beta-lactam should not be given another beta-lactam)

Question 20

Ceftriaxone (IM, IV)

Answer 20

Third generation agents - cephalosporins

Question 21

Ceftazidime (IM, IV)

Answer 21

Third generation agents - cephalosporins

Question 22

Ceftizoxime (IM/IV)

Answer 22

Third generation agents - cephalosporins

Question 23

Cefpodoxime proxetil (PO)

Answer 23

Third generation agents - cephalosporins

Question 24

Cefotaxime (IM, IV)

Answer 24

Third generation agents - cephalosporins

Question 25

Cefixime (PO)

Answer 25

Third generation agents - cephalosporins

Question 26

Ceftibuten (PO)

Answer 26

Third generation agents - cephalosporins

Question 27

Cefditoren pivoxil (PO)

Answer 27

Third generation agents - cephalosporins

Question 28

Cefdinir (PO)

Answer 28

Third generation agents - cephalosporins

Question 29

Streptomycin

Answer 29

Aminoglycosides - 30S protein syntesis inhibitor Hydrophilic, polycationic amine-containing carbohydrate. Aminoglycoside structure binds to anionic sites in outer anionic bacterial membrane as well as anionic phospholipids of mammalian renal proximal tubular cells (nephrotoxicity). Tuberculosis, plague and tularemia MOA - phase 1 positive molecule enters bacteria through negative pores. In an aerobic event, the internalized aminoglycoside changes the permeability of the membrane (disrupted by low O2). Phase 2, inhibition of protein synthesis through various binding sites on ribosomal subunit 30S. (Post antibiotic effect - these effects sustain long after the ab is excreted). concentration-dependant action. Spectrum of action - aerobic gram-negative The drug concentrates in bone, renal cortical and endo- and peri-lymph of the ear. However, there is a low margin of safety: Nephrotoxicity (reversible and additive with other drugs), hypersensitivity, ototoxicity (presents in hearing and balance problems) - cochlear toxicity, neuromuscular blockade

Question 30

Neomycin (Neo-Fradin, Myciguent)

Answer 30

Aminoglycosides - 30S protein syntesis inhibitor Hydrophilic, polycationic amine-containing carbohydrate. Aminoglycoside structure binds to anionic sites in outer anionic bacterial membrane as well as anionic phospholipids of mammalian renal proximal tubular cells (nephrotoxicity). Bowel sterilization and skin infections. MOA - phase 1 positive molecule enters bacteria through negative pores. In an aerobic event, the internalized aminoglycoside changes the permeability of the membrane (disrupted by low O2). Phase 2, inhibition of protein synthesis through various binding sites on ribosomal subunit 30S. (Post antibiotic effect - these effects sustain long after the ab is excreted). concentration-dependant action. Spectrum of action - aerobic gram-negative The drug concentrates in bone, renal cortical and endo- and peri-lymph of the ear. However, there is a low margin of safety: Nephrotoxicity (reversible and additive with other drugs), hypersensitivity, ototoxicity (presents in hearing and balance problems) - vestibular toxicity, neuromuscular blockade

Question 31

Gentamicin (Garamycin, Genoptic)

Answer 31

Aminoglycosides - 30S protein syntesis inhibitor Hydrophilic, polycationic amine-containing carbohydrate. Aminoglycoside structure binds to anionic sites in outer anionic bacterial membrane as well as anionic phospholipids of mammalian renal proximal tubular cells (nephrotoxicity). MOA - phase 1 positive molecule enters bacteria through negative pores. In an aerobic event, the internalized aminoglycoside changes the permeability of the membrane (disrupted by low O2). Phase 2, inhibition of protein synthesis through various binding sites on ribosomal subunit 30S. (Post antibiotic effect - these effects sustain long after the ab is excreted). concentration-dependant action. Spectrum of action - aerobic gram-negative The drug concentrates in bone, renal cortical and endo- and peri-lymph of the ear. However, there is a low margin of safety: Nephrotoxicity (reversible and additive with other drugs), hypersensitivity, ototoxicity (presents in hearing and balance problems) - cochlear toxicity, neuromuscular blockade

Question 32

Tobramycin (TOBI, Tobrex)

Answer 32

Aminoglycosides - 30S protein syntesis inhibitor Hydrophilic, polycationic amine-containing carbohydrate. Aminoglycoside structure binds to anionic sites in outer anionic bacterial membrane as well as anionic phospholipids of mammalian renal proximal tubular cells (nephrotoxicity). MOA - phase 1 positive molecule enters bacteria through negative pores. In an aerobic event, the internalized aminoglycoside changes the permeability of the membrane (disrupted by low O2). Phase 2, inhibition of protein synthesis through various binding sites on ribosomal subunit 30S. (Post antibiotic effect - these effects sustain long after the ab is excreted). concentration-dependant action. Spectrum of action - aerobic gram-negative The drug concentrates in bone, renal cortical and endo- and peri-lymph of the ear. However, there is a low margin of safety: Nephrotoxicity (reversible and additive with other drugs), hypersensitivity, ototoxicity (presents in hearing and balance problems) - vestibular toxicity, neuromuscular blockade

Question 33

Amikacin (Amikin)

Answer 33

Aminoglycosides - 30S protein syntesis inhibitor Hydrophilic, polycationic amine-containing carbohydrate. Aminoglycoside structure binds to anionic sites in outer anionic bacterial membrane as well as anionic phospholipids of mammalian renal proximal tubular cells (nephrotoxicity). Serious infections of Escherichia coli, Enterobacter, klebsiella, proteus, pseudomonas, and serratia MOA - phase 1 positive molecule enters bacteria through negative pores. In an aerobic event, the internalized aminoglycoside changes the permeability of the membrane (disrupted by low O2). Phase 2, inhibition of protein synthesis through various binding sites on ribosomal subunit 30S. (Post antibiotic effect - these effects sustain long after the ab is excreted). concentration-dependant action. Spectrum of action - aerobic gram-negative The drug concentrates in bone, renal cortical and endo- and peri-lymph of the ear. However, there is a low margin of safety: Nephrotoxicity (reversible and additive with other drugs), hypersensitivity, ototoxicity (presents in hearing and balance problems) - vestibular toxicity, neuromuscular blockade.

Question 34

Minocycline (Minocin, Minocin IV, Vectrin)

Answer 34

Long-lasting (>12 hrs) Tetracycline - organic bases, unstable in solution MOA - inhibition of protein synthesis - binds to 30S ribosome subunit, inhibits amino acid-tRNA complex binding to the acceptor site on 50S subbing. Selective toxicity related to specific energy-dependant transport and accumulation systems found in bacteria. Impaired by food and metal ions (except doxycycline and minocycline- improves with food) Eliminated through renal elimination (except doxycycline which is excreted in the feces) Enterohepatic circulation may be extensive resulting in relatively long biological half lives. Broad spectrum of action (mycoplasma pneumonia, chlamydia, rickettsia and vibros, secondary drug for syphilis, sometimes prophylaxis of chronic bronchitis and acne) Resistance is increasing due to decreased uptake and increases efflux. Adverse effects: gastrointestinal disturbances, teeth and bone accumulation, photosensitivity, vestibular toxicity with minocycline and doxyclycine, nephrotoxity, hepatotoxicity.

Question 35

Doxycycline (Doryx, Periostat, Vibramycin)

Answer 35

Long-lasting (>12 hrs) Tetracycline - organic bases, unstable in solution MOA - inhibition of protein synthesis - binds to 30S ribosome subunit, inhibits amino acid-tRNA complex binding to the acceptor site on 50S subbing. Selective toxicity related to specific energy-dependant transport and accumulation systems found in bacteria. Impaired by food and metal ions (except doxycycline and minocycline- improves with food) Eliminated through renal elimination (except doxycycline which is excreted in the feces) Enterohepatic circulation may be extensive resulting in relatively long biological half lives. Broad spectrum of action (mycoplasma pneumonia, chlamydia, rickettsia and vibros, secondary drug for syphilis, sometimes prophylaxis of chronic bronchitis and acne) Resistance is increasing due to decreased uptake and increases efflux. Adverse effects: gastrointestinal disturbances, teeth and bone accumulation, photosensitivity, vestibular toxicity with minocycline and doxyclycine, nephrotoxity, hepatotoxicity.

Question 36

Oxytetracycline (Urobiotic-250)

Answer 36

Short acting (half life about 8 hours) Tetracycline - organic bases, unstable in solution MOA - inhibition of protein synthesis - binds to 30S ribosome subunit, inhibits amino acid-tRNA complex binding to the acceptor site on 50S subbing. Selective toxicity related to specific energy-dependant transport and accumulation systems found in bacteria. Impaired by food and metal ions (except doxycycline and minocycline- improves with food) Eliminated through renal elimination (except doxycycline which is excreted in the feces) Enterohepatic circulation may be extensive resulting in relatively long biological half lives. Broad spectrum of action (mycoplasma pneumonia, chlamydia, rickettsia and vibros, secondary drug for syphilis, sometimes prophylaxis of chronic bronchitis and acne) Resistance is increasing due to decreased uptake and increases efflux. Adverse effects: gastrointestinal disturbances, teeth and bone accumulation, photosensitivity, vestibular toxicity with minocycline and doxyclycine, nephrotoxity, hepatotoxicity.

Question 37

Tetracycline (Achromycin V, Sumycin)

Answer 37

Short acting (half life about 8 hours) Tetracycline - organic bases, unstable in solution MOA - inhibition of protein synthesis - binds to 30S ribosome subunit, inhibits amino acid-tRNA complex binding to the acceptor site on 50S subbing. Selective toxicity related to specific energy-dependant transport and accumulation systems found in bacteria. Impaired by food and metal ions (except doxycycline and minocycline- improves with food) Eliminated through renal elimination (except doxycycline which is excreted in the feces) Enterohepatic circulation may be extensive resulting in relatively long biological half lives. Broad spectrum of action (mycoplasma pneumonia, chlamydia, rickettsia and vibros, tularemia, helicobacter pylori, borrelia burgdoferi (lyme disease), secondary drug for syphilis, sometimes prophylaxis of chronic bronchitis and acne) Resistance is increasing due to decreased uptake and increases efflux. Adverse effects: gastrointestinal disturbances, teeth and bone accumulation, photosensitivity, vestibular toxicity with minocycline and doxyclycine, nephrotoxity, hepatotoxicity.

Question 38

Chloramphenicol (Chloromycetin)

Answer 38

MOA - binds to 50S subunit to prevent peptide bond formation Broad spectrum of action - toxicity limits use to severe infections that have not responded to safer drugs. (cannot use in neonates) Inactivation by conjugation before excretion - alternative biotransformation pathways are noted in neonates and young children but are inadequate to handle normal dosing. Adverse: bone marrow suppression - dose related anemia (daily dose >4g), Idiosyncratic aplastic anemia (not dose related) (due to disrupted mitochondrial protein synthesis); Gray baby syndrome (abdominal distention, vomiting, cyanosis, irregular respiration, hypothermia, vasomotor collapse. Black box warning - hospitalize patients and monitor hematological toxicity - blood dyscrasias (hematologic abnormalities) Indications - meningitis (haemophilus infulenzae, neisseria meningitidis, streptococcus pneumoniae)

Question 39

Erythromycin

Answer 39

Macrolides or erythromiycins MOAs - bind to 50S subunit - inhibits translocation and blocks acceptor site. Broad spectrum of action - relatively few primary indications (mycoplasma pneumonia, corynebacterium diphtheria, legionaries disease, chlamydia, neisseria) Resistance by changing rRNA near binding site. Adverse: ototoxicity - high dose effect Drug interactions - Never co-adminsiter with other drugs noted to prolong QT interval. May increase change of cardiac death. (associated with concurrent use of erythromycins and drugs that inhibit CYP3A4 - calcium channel blockers, antifungals, and typical antidepressants)

Question 40

Clarithromycin (Biaxin)

Answer 40

Short acting (~4 hours) Macrolides or erythromiycins MOAs - bind to 50S subunit - inhibits translocation and blocks acceptor site. Broad spectrum of action - relatively few primary indications (mycoplasma pneumonia, corynebacterium diphtheria, legionaries disease, chlamydia, neisseria) Resistance by changing rRNA near binding site. Adverse: ototoxicity - high dose effect Drug interactions - Never co-adminsiter with other drugs noted to prolong QT interval. May increase change of cardiac death. (associated with concurrent use of erythromycins and drugs that inhibit CYP3A4 - calcium channel blockers, antifungals, and typical antidepressants)

Question 41

Azithromycin (Zithromax)

Answer 41

Long lasting (40+ hours) Macrolides or erythromiycins MOAs - bind to 50S subunit - inhibits translocation and blocks acceptor site. Broad spectrum of action - relatively few primary indications (mycoplasma pneumonia, corynebacterium diphtheria, legionaries disease, chlamydia, neisseria) Resistance by changing rRNA near binding site. Adverse: ototoxicity - high dose effect Drug interactions - Never co-adminsiter with other drugs noted to prolong QT interval. May increase change of cardiac death. (associated with concurrent use of erythromycins and drugs that inhibit CYP3A4 - calcium channel blockers, antifungals, and typical antidepressants)

Question 42

Telithromycin (Ketek)

Answer 42

Macrolides or erythromiycins MOAs - bind to 50S subunit - inhibits translocation and blocks acceptor site. Broad spectrum of action - relatively few primary indications (mycoplasma pneumonia, corynebacterium diphtheria, legionaries disease, chlamydia, neisseria) Resistance by changing rRNA near binding site. Adverse: ototoxicity - high dose effect Drug interactions - Never co-adminsiter with other drugs noted to prolong QT interval. May increase change of cardiac death. (associated with concurrent use of erythromycins and drugs that inhibit CYP3A4 - calcium channel blockers, antifungals, and typical antidepressants)

Question 43

Rifampin

Answer 43

MOA - lethal to intra- and extracellular forms of pathogen. Inhibits DNA-dependant RNA polymerase (binds to beta subunits and prevents attachment of enzyme to DNA). Inhibits RNA synthesis. Resistance typically caused by alteration of beta-subunit. Adverse - Hepatotoxicity (esp. in isoniazid high-acetylator), immunosuppressive effects (most common with intermittent therapy - compliance) Drug can cause permanent discolorations of soft contact lenses, sweating stains, etc. Used in treatment of tuberculosis and Hansen’s disease.

Question 44

Dapsone

Answer 44

Inhibits folic acid synthesis Slow but complete absorption, wide distribution, retained in tissue, enterohepatic circulation prior to biotransformation. Adverse: Hemolytic anemia, nonhemolytic anemia, sulfone syndrome (severe hypersensitivity reaction- fever, malaise, exfoliative dermatitis, jaundice, hepatic necrosis)

Question 45

Clofazimine (Lamprene) Restricted access in US

Answer 45

Unknown mechanism of action (may bind DNA altering function, anti-inflammatory action may be important) Adverse: reddish brown pigmentation of skin and tissues, gastrointestinal intolerance, anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation)

Question 46

Steps in Viral Infection and Replication

Answer 46

1. Attachment and penetration 2.Uncoating 3. Transcription of viral genome 4. Translation of viral proteins 5. Posttranslational modifications 6. Assembly of virion components 7. Release 3 and 4 are best therapeutically

Question 47

Acyclovir (Zovirax) Valacyclovir (Valtrex)

Answer 47

Inhibits viral DNA synthesis Lethal synthesis required: -Presence of viral nucleoside kinase to convert to monophosphate form -Presence of host enzymes to convert monophosphate to triphosphate form -Presence of virus-induced DNA polymerase that is sensitive to inhibition by triphosphate form or can incorporate the triphosphate form into the new viral DNA where it terminates synthesis (Valacyclovir is converted to acyclovir in a first pass hydrolysis reaction) Adverse: reversibel renal dysfunction, neurological and renal toxicity with high dose or intravenous infusion.

Question 48

Cidofovir (Vistide)

Answer 48

MOA -Lethal synthesis to activated cidofovir diphosphate requires only host enzymes. Cidofovir diphosphate incorporated into DNA slows or stops DNA polymerase activity. Levels in infected and non infected cells are similar. Adverse: BBW - nephrotoxicity - probenecid given currently slows uptake into proximal tubule cells reducing toxicity. Indications: Herpers, CMV, VZV, EBV

Question 49

Foscarnet (Foscavir)

Answer 49

MOA - competitive inhibitor of viral DNA polymerase (no lethal synthesis required). Inhibitor of reverse transcriptase. Not effective in HIV. Adverse: CNS disturbances and bone marrow depression; BBW - appropriate use only, renal toxicity, seizures. If there is increase in BP - indicative of renal toxicity.

Question 50

Ganciclovir (Cytovene) Valganciclovir (Valcyte)

Answer 50

Inhibits viral DNA synthesis Lethal synthesis required: -Presence of viral nucleoside kinase to convert to monophosphate form -Presence of host enzymes to convert monophosphate to triphosphate form -Presence of virus-induced DNA polymerase that is sensitive to inhibition by triphosphate form or can incorporate the triphosphate form into the new viral DNA where it terminates synthesis Adverse effects: Bone marrow suppression, teratogenic, mutagenic and oncogenic potential. BBW - hematological toxicities, carinogenic and teratogenic activity, spermatogenesis (not a contraceptive). Appropriate oral and IV use only.

Question 51

Pentamidine (Pentam 300)

Answer 51

MOA - binds to DNA and inhibits DNA replication; Inhibits dihydrofolate reductase. Antiparasitic by nature. Generally administered intramuscularly or by aerosol. Adverse: respiratory stimulation followed by depression, renal dysfunction (transient), blood dyscrasias, fall in blood pressure, hypoglycemia or hyperglycemia (diabetics)