Antimicrobials

Question 1

Isoniazid

Answer 1

• MOA-Isoniazid inhibits the synthesis of mycolic acids, which are essential components of the mycobacterial cell wall. Isoniazid is a pro-drug converted by catalase-peroxidase (KatG) to an active metabolite, the nicotinoyl radical, which reacts with NAD to produce adducts that inhibit InhA encoded enoyl acyl carrier protein reductase and the KasA acyl carrier protein synthase to inhibit the synthesis of mycolic acids, which are essential components of the mycobacterial cell wall. A Nicotinoyl-NADP adduct inhibits mycobacterial DHFR as well.
• Tox-High doses of isoniazid increases the risk of peripheral neuritis. Isoniazid also may precipitate convulsions in patients with seizure disorders, and rarely, in patients with no history of seizures. Hepatotoxic metabolites in slow acetylators. Optic neuritis and atrophy also have occurred during therapy with the drug.
• Resistance to isoniazid develops rapidly and is due to polymorphic fast NAT2 acetylation, mutation of the KatG gene that encodes the activating catalase-peroxidase, a missense mutation of the INHA gene involved in mycolic acid synthesis or mutation of KasA.

Question 2

Pyroxidine (in conjunction w/isoniazid

Answer 2

• The prophylactic administration of pyroxidine (vitamin B6) prevents the side effect of peripheral neuritis and is usually co-administered to the patient with isoniazid.
• The two compounds have similar structures and compete for the enzyme, apotryptophanase.

Question 3

Rifampin, Rifabutin. Rifapentine

Answer 3

• first-line agents used in combination with isoniazid in the treatment of tuberculosis.
• Rifampin inhibits bacterial DNA-dependent RNA polymerase by forming a stable complex with the polymerase β-subunit. It is highly effective in combination with isoniazid in the treatment of tuberculosis.
• Rifampin is a strong inducer of hepatic microsomal enzymes to dramatically decrease the half-life of HIV protease inhibitors. For this reason, the similar compound with lower P-450 induction, rifabutin, is currently substituted for rifampin in the treatment of tuberculosis of HIV-infect patients.
• Microbial resistance to rifampin is due to an alteration of the target of this drug, DNA-dependent RNA polymerase. -Well tolerated.

Question 4

Ethambutol

Answer 4

• First-line agent used in combination with isoniazid in the treatment of tuberculosis. Effective for isoniazid-resistant M. tuberculosis.
• MOA-It inhibits mycobacterial wall synthesis by blocking arabinosyl transferase III. The Emb proteins (EmbA, EmbB) are mycobacterial arabinosyltransferases involved in the biogenesis of the mycobacterial cell wall.
• Resistance is due to mutation of embB gene and increased efflux pumps.
• An interesting side effect is optic neuritis which decreases visional acuity and causes an inability to differentiate red from green.

Question 5

Pyrazinamide

Answer 5

• First-line agent used in combination with isoniazid in the treatment of tuberculosis
• MOA-Pyrazinamide is activated by deamination in mycobacteria, pumped out into the acidic exteracellular milieu forming protonated pyrazinoic acid, which enters the bacillus and targets the mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis. Resistance is due to mutations of pyrazinamidase that deaminates the drug. Injury to the liver is the most serious side effect. Inhibits excretion of urate, resulting in hyperuricemia in nearly all patients; acute episodes of gout.

Question 6

Ethionamide

Answer 6

• Second line drug used in the treatment of tuberculosis
• MOA-In the manner of isoniazid, ethionamide is an inactive prodrug that is activated by a mycobacterial redux system (EthaA). A transient intermediate is the active antibiotic. Ethionamide inhibits mycobacterial growth by inhibiting the activity of InhA-encoded enoyl acyl carrier protein reductase of fatty acid synthase II. This is the same enzyme that activated isoniazid inhibits. The results are the same: inhibition of mycolic acid biosynthesis and consequent impairment of cell-wall synthesis.
• Low-level cross-resistance to isoniazid due to mutations in different activation enzymes.
• Tox: anorexia, nausea and vomiting, gastric irritation, and a variety of neurologic symptoms

Question 7

Capreomycin

Answer 7

• Second line drug used in the treatment of tuberculosis
• MOA-Capreomycin is a cyclic peptide produced by Streptococcus capreolus that is very effective when given IM to overcome multidrug resistant mycobacteria. -Tox-However, deafness can result from the use of capreomycin.
• MOA-Little is known about its mechanism of action- may inhibit protein synthesis by binding to the 70S ribosomal unit.

Question 8

Treatment of mycobacterium avium complex (MAC)

Answer 8

Most clinicians treat MAC (Mycobacterium avium Complex) infections with clarithromycin or azithromycin plus ethambutol.
Clarithromycin has shown good efficacy against a broad range of atypical mycobacteria that do not cause TB.

Question 9

Streptomycin

Answer 9

-First line drug used in the treatment of mycobacterial infections
-MOA-Binds to S12 ribosomal subunit inhibiting protein
synthesis
-used in TB when injectable drug needed, or in treatment of drug-resistant strains
-Parenteral administration, renal elimination
-Tox-Ototoxicity, nephrotoxicity

Question 10

Amikacin

Answer 10

• MOA-inhibit protein synthesis via binding to 30S ribosomal subunit concentrationdependent action; also exert postantibiotic effects
• Used against Aerobic gram-negative bacteria, H influenzae, M catarrhalis, and Shigella species. Often used in combinations with beta-lactams Gonorrhea, tuberculosis (streptomycin, IM)
• Given by IV, renal clearance with half-lives 2–4 h, once-daily dosing effective with less toxicity
• Tox-Nephrotoxicity (reversible), ototoxicity(irreversible), neuromuscular blockade

Question 11

Azithromycin & Clarithromycin

Answer 11

• MOA-Bind to 50S ribosomal subunit
• Usez-Community-acquired pneumonia, pertussis, corynebacteria, and chlamydial infections
• Oral admin (clarithyromycin,IV for azithromycin, Hepatic clearance, azithromycin long half-life (>40 h)
• Tox-GI upsets, hepatic dysfunction, QT elongation CYP450 inhibition (not azithromycin)

Question 12

Aminosalicyclic acid/PAS

Answer 12

• Used in the treatment on multi drug resistant M. tuberculosis
• PAS has been shown to be a pro-drug and it is incorporated into the folate pathway by dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits DHFR enzymatic activity.
• Tox-Gastrointestinal side-effects (nausea, vomiting, diarrhoea) are common; the delayed-release formulation is meant to help overcome this problem. It is also a cause of drug-induced hepatitis. Patients with glucose-6-phosphate dehydrogenase deficiency should avoid taking aminosalicylic acid as it causes haemolysis. Thyroid goitre is also a side-effect because aminosalicylic acid inhibits the synthesis of thyroid hormones.
• Drug interactions include elevated phenytoin levels. When taken with rifampicin, the levels of rifampicin in the blood fall by about half.

Question 13

Amphotericin B

Answer 13

• MOA-Amphotericin B is a polyene that forms pores by binding to ergosterol in the fungal cell membrane. Small molecules like K+ escape to cause death of the fungal cell.
• This drug is insoluble in water must be given intravenously after complexing with deoxycholate (Fungizone).
• A high incidence of nephrotoxicity limited the use amphotericin B until the recent introduction of a lipid-bound formulation (Ambisome). Nephrotoxicity is much less prevalent with Ambisome compared to the deoxycholate preparation. This has led to a resurgence in the use of amphotericin B to treat deep mycoses.
• Fungi with amphotericin B resistance replace ergosterol with certain precursor sterols.

Question 14

Flucytosine

Answer 14

• MOA-Flucytosine is 5-fluorocytosine. The fungal cell deaminates it to form 5-fluorouracil. 5-FU must then be metabolized to 5-fluorodeoxyuridine- monophosphate, which inhibits thymidylate synthase and, hence fungal DNA synthesis.
• Resistant fungus can lack the permease necessary for cytosine transport or have decreased levels cytosine deaminase.
• Flucytosine is administered primarily in combination with amphotericin B because the latter drug produces membrane pores and overcome permease deficiency in resistant fungi.
• Tox-May depress the bone marrow and lead to leukopenia and thrombocytopenia.

Question 15

Ketoconazole

Answer 15

• MOA-Ketoconazole is an imidazole antifungal. All azoles inhibit C-14 alpha-demethylase, a fungal cytochrome P-450 enzyme that converts lanosterol to ergosterol, the principal sterol used in fungal membrane synthesis and cause accumulation of 14α-methyl-sterols. These methylsterols may disrupt the close packing of acyl chains of phospholipids, impairing the functions of certain membrane-bound enzyme systems such as ATPase and enzymes of the electron transport system and thus inhibiting growth of the fungi. However, ketoconazole also blocks human steroid biosythesis of testosterone, estradiol and cortisol by inhibiting several key cytochrome P-450s in the steroidogenic pathway. It also inhibits the liver P-450-mediated metabolism of many drugs such as warfarin and cyclosporine.
• Tox-Hepatic dysfunction, many drug-drug CYP450 interactions

Question 16

Fluconazole, itraconazole, posaconazole and voriconazole

Answer 16

• MOA-Fluconazole, itraconazole (cannot enter CSF), posaconazole and voriconazole are triazoles. They have the same MOA as ketoconazole but do not inhibit the human steroidogenic P-450 enzymes.
• Fluconazole, posaconazole and itraconazole inhibit other mammalian P-450 enzymes, however, and this raises the plasma concentrations of many other drugs.
• Posaconazole is a synthetic structural analog of itraconazole with the same broad antifungal spectrum but with up to 4-fold greater activity in vitro against yeasts and filamentous fungi.
• Voriconazole also inhibits mammalian cytochrome P-450 enzymes; good for invasive aspergillosis and Pneumocystitis jirovecii (common opportunistic infections in AIDS).
• Itraconazole- serious hepatotoxicity has rarely led to hepatic failure and death. If symptoms of hepatotoxicity occur, the drug should be discontinued and liver function assessed. Itraconazole causes a dose-dependent inotropic effect that can lead to congestive heart failure in patients with impaired ventricular function.
• Fluconazole- nausea and vomiting.

Question 17

Amantadine & Rimantadine

Answer 17

• Used in the treatment of viral infections of the respiratoy system
• MOA-inhibit viral uncoating by interfering with the viral-encoded M2 protein.
• Tox-Toxic effects of these agents include GI irritation, dizziness, ataxia, and slurred speech. Rimantadine’s activity is no greater than that of amantadine, but it has a longer half-life and requires no dosage adjustment in renal failure.

Question 18

Oseltamivir & Zanamivir

Answer 18

• Used in the treatment of viral infections of the respiratoy system
• MOA-inhibit neuraminidase to cause aggregation of the virions on the cell surface and inhibit release into the respiratory tract.
• Tox-Oseltamivir: Gastrointestinal effects
• Zanamivir: Bronchospasm in asthmatics

Question 19

Third Generation Cephalosporins: Cefpodoxime proxetil, cefotaxime, ceftazidime, ceftriaxone, ceftizoxime

Answer 19

-overcome the β-lactamase resistance of most strains of S. pneumoniae and have extended spectrum that includes gram-positive and gram-negative organisms that can also cause pneumonia.
-MOA-Cephalosporins bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to those of the penicillins. Cephalosporins are bactericidal against susceptible
organisms.
-Structural differences from penicillins render cephalosporins less susceptible to penicillinases produced by staphylococci, but many bacteria are resistant through the production of other betalactamases
that can inactivate cephalosporins. Resistance can also
result from decreases in membrane permeability to cephalosporins and from changes in PBPs. Methicillin-resistant staphylococci are also resistant to cephalosporins.
-One of these third gen cephalosporins is ineffective against Steptoccoccus pneumoniae; Ceftizoxime. However, it is effective against Pseudomonas aeruginosa, a gram-negative bacteria that causes pneumonia in a hospital setting.
-Oral use for older drugs, Mostly IV for newer drugs, renal elimination, Short half-lives, Third-generation drugs enter CNS
-Tox-Hypersensitivity reactions (~2% incidence), assume complete cross-reactivity between cephalosporins, partial with penicillins. GI distress

Question 20

Other Cephalosporins: Cefepime(4th Gen), Cefuroxime(2nd Gen)

Answer 20

-If the third-generation drugs are ineffective, the fourth-generation, cefepime, is even more resistant to β-lactamases, including the inducible, chromosomally encoded type I β-lactamases which destroy the third gen cephalosporins.
-Cefepime is very effective against Pseudomonas aeruginosa.
-2nd Gen cefuroxime more active vs S pneumoniae and
H inflenzae; B fragilis (cefotetan)
-MOA-Cephalosporins bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to those of the penicillins. Cephalosporins are bactericidal against susceptible
organisms.
-Structural differences from penicillins render cephalosporins less susceptible to penicillinases produced by staphylococci, but many bacteria are resistant through the production of other betalactamases
that can inactivate cephalosporins. Resistance can also
result from decreases in membrane permeability to cephalosporins and from changes in PBPs. Methicillin-resistant staphylococci are also resistant to cephalosporins.
-Oral use for older drugs, Mostly IV for newer drugs, renal elimination, Short half-lives
-Tox-Hypersensitivity reactions (~2% incidence), assume complete cross-reactivity between cephalosporins, partial with penicillins. GI distress

Question 21

Macrolide Antibiotics: Erythromycin, telithromycin, clarithromycin, azithromycin, clindamycin

Answer 21

• Erythromycin, clarithromycin, azithromycin, clindamycin are especially effective against gram-positive cocci like S. pneunomiae.
• MOA-These macrolide antibacterial agents bind to the 50S subunit of bacterial ribosomes and inhibits the translocation of the nascent polypeptide from the A site to the P site, thus inhibiting bacterial protein synthesis.
• The advanced macrolides, clarithromycin and azithromycin, have the same MOA as erythromycin, but they achieve higher intracellular drug concs.
• Aspiration pneumonia- Clindamycin for lung abscess.
• Unlike the other macrolides that inhibit CYP3A4, azithromycin does not inhibit this Cyt P-450 and has fewer drug interactions.
• Telithromycin- new ketolide that is effective against macrolide-resistant S. pneumonia and other bacteria by not inducing methylation of 50s subunit and with less drug efflux.
• Resistance to macrolides usually results from: (1) drug efflux by an active pump mechanism: (2) ribosomal protection by inducible or constitutive production of methylase enzymes, which modify the ribosomal target and decrease drug binding; (3) macrolide hydrolysis by esterases produced by Enterobacteriaceae; and (4) chromosomal mutations that alter a 50S ribosomal protein (found in B. subtilis, Campylobacter spp., mycobacteria, and gram-positive cocci).
• Tox-Among the allergic reactions observed are fever, eosinophilia, and skin eruptions. Cholestatic hepatitis is the most striking side effect. Epigastric distress may be severe. Erythromycin has been reported to cause cardiac arrhythmias, including QT prolongation with ventricular tachycardia.

Question 22

Floroquinolones: Levofloxacin, gatifloxacin, moxifloxacin

Answer 22

• Levofloxacin and moxifloxacin are respiratory fluoroquinolones that have broad activity against streptococci (S. pneumoniae) and mycobacteria (TB).
• MOA-Inhibition of bacterial DNA gyrase (gram negative like E coli) or topoisomerase IV (gram positive like streptococcus), which is similar to mammalian topoisomerases.
• Gatifloxacin was recently removed from the market due to induction of hypoglycemia.
• Tox-Fluoroquinolones generally are well tolerated. The most common adverse reactions involve the GI tract, with 3% to 17% of patients reporting mostly mild nausea, vomiting, and/or abdominal discomfort, can produce arthropathy in several species of immature animals. Traditionally, the use of fluoroquinolones in children has been contraindicated for this reason.

Question 23

Penicillins: Piperacillin-tazobactam, imipinem, meropenem, Ticarcillin-clavulinic acid

Answer 23

• Piperacillin/ticarcillin has in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria. Piperacillin is normally used together with a beta-lactamase inhibitor such as tazobactam/clavulinic acid (effective against plasmid extended spectrum but not inducible chromosomal β-lactamases), the combination has activity against many anaerobes, including Pseudomonas aeruginosa.
• Aztreonam is a monobactam active only vs gram-negative bacteria: Klebsiella, Pseudomonas, and Serratia spp
• MOA-Imipenem and meropenem, like other β-lactam antibiotics, bind to penicillin-binding proteins, disrupts bacterial cell wall synthesis, and cause death of susceptible microorganisms. They are very resistant to hydrolysis by most β-lactamases, including the cephalosporin-resistance organisms that express chromosomal or plasmid extended-spectrum β-lactamases.
• Not many species are resistant to imipenem and meropenem except for some strains of Pseudomonas aeruginosa due to porin modfications.
• Imipenem is given with cilistatin to inhibit degradation by dipeptidase in the proximal renal tubule, but meropenem is not degraded by renal dipeptidase.
• Tox- nausea, vomiting, seizures with high doses.

Question 24

Trimethoprim-sulfamethoxazole

Answer 24

• Antimicrobial drug combination: causes synergistic sequential blockade of folic acid synthesis.
• Active against many gram-negative bacteria, including Aeromonas, Enterobacter, H influenzae, Klebsiella, Moraxella, Salmonella, Serratia, and Shigella.
• Tox: mainly due to sulfonamide; includes hypersensitivity, myelotoxicity, kernicterus, and drug interactions caused by competition for plasma protein binding.

Question 25

Beta-lactamase inhibitors: tazobactam, clavulanic acid, sulbactam

Answer 25

Clavulanic acid, sulbactam, and tazobactam inhibit penicillinases and are often used along with penicillinase-sensitive beta-lactam drugs.

• They are most active against plasmid-encoded beta-lactamases such as those produced by gonococci, streptococci, E coli, and H influenzae.
• They are not good inhibitors of inducible chromosomal betalactamases formed by Enterobacter, Pseudomonas, and Serratia.