Deja Review Pharmacology, 2nd Edition

CHAPTER 2. Antimicrobial Agents

 

ANTIBACTERIAL AGENTS

 

What is a bacteriostatic antibiotic?

An antibiotic that causes reversible inhibition of growth. The bacteria are still present and able to replicate should the bacteriostatic antibiotic be removed. A bacteriostatic antibiotic therefore prevents the exponential growth of bacteria, allowing the host immune system better chances of clearing the bacteria that is present in the body.

What is a bactericidal antibiotic?

An antibiotic that causes irreversible inhibition of growth, therefore directly killing the bacteria

Why should bacteriostatic and bactericidal antibiotics not be given together?

Bacteriostatic drugs will antagonize the effects of bacteriocidal drugs which rely on the active replication and utilization of environmental resources by bacteria.

Which antibiotic inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding tightly to the D-alanyl-D-alanine portion of the cell wall (peptidoglycan) precursor?

Vancomycin

Vancomycin-resistant bacteria change their D-ala-D-ala terminus of the peptide side chain to what?

To D-ala-D-lactate; this change prevents the cross linking reaction necessary for elongation of the peptide side chain, weakening the cell wall and making the bacteria susceptible to lysis

Vancomycin is most commonly used to treat what types of infections?

Gram-positive infections. Vancomycin is only effective against gram-positive bacteria, and is particularly useful for infections due to methicillin resistant Staphylococcus aureus (MRSA) infections.

Does vancomycin have good oral bioavailability?

No. Vancomycin can be given orally to treat Clostridium difficile enterocolitis because the drug stays in the gastrointestinal tract (it is poorly absorbed from the GI tract).

What are the adverse effects of vancomycin?

Hyperemia, or “red man” syndrome (see following questions); ototoxicity (rare, but it must be used with caution when coadministered with other drugs having ototoxicity, such as aminoglycosides); nephrotoxicity (similar situation as described for ototoxicity); phlebitis at site of injection

Release of what substance is responsible for “red man” syndrome?

Histamine

How can vancomycin-induced “red man” syndrome be prevented?

By slowing the infusion rate. Infusion over 1 to 2 hours is normally sufficient. Additionally, antihistamines may be coadministered.

Which antibiotic inhibits the phosphorylation/dephosphorylation cycling of the lipid carrier required in the transfer of peptidoglycan to the cell wall?

Bacitracin (used topically only due to severe nephrotoxicity if given systemically)

Sulfonamide antibiotics antagonize what compound?

Para-aminobenzoic acid (PABA) (see next answer)

What is the mechanism of action of sulfonamide antibiotics?

Sulfonamides are structural analogs of PABA. This class of antibiotics is effective against bacteria that must use PABA to synthesize folate de novo. Sulfonamides work by inhibiting dihydropteroic acid synthase, the enzyme that catalyzes the condensation reaction between PABA and dihydropteridine to form dihydropteroic acid, the first step in the synthesis of tetrahydrofolic acid.

Do humans possess dihydropteroic acid synthase?

No. Therefore sulfonamides are selectively toxic to bacteria and other microorganisms.

Against which microorganisms are sulfonamides effective?

Gram-positive and gram-negative bacteria, Nocardia, Chlamydia trachomatis, some protozoa (malaria), Escherichia Coli, Klebsiella, Salmonella, Shigella, Enterobacter

Are sulfonamide antibiotics bactericidal or bacteriostatic?

Primarily bacteriostatic

What are the adverse effects of sulfonamide antibiotics?

Nausea; vomiting; diarrhea; phototoxicity; hemolysis (in individuals having glucose-6-phosphate dehydrogenase (G6PD) deficiency); hypersensitivity; Stevens-Johnson syndrome (incidence and severity of adverse effects greatly increase immunocompromised in AIDS patients)

Why are sulfonamide antibiotics contraindicated in neonates?

They displace bilirubin from albumin thereby causing kernicterus in neonates.

Give examples of sulfonamide antibiotics:

Sulfamethoxazole; sulfacetamide; sulfisoxazole; sulfadiazine (only available in the United States in combination with pyrimethamine); sulfadoxine in combination with pyrimethamine (the antimalarial “Fansidar”)

Name antibiotics that works synergistically with sulfonamides by preventing the next reaction in folate synthesis:

Trimethoprim or pyrimethamine

What is the mechanism of action of trimethoprim?

Competitive inhibitor of dihydrofolic acid reductase (DHFR), the enzyme that converts dihydrofolic acid to tetrahydrofolic acid

What are the adverse effects of trimethoprim?

Leukopenia; granulocytopenia; thrombocytopenia; megaloblastic anemia

The trimethoprim-sulfamethoxazole combination is most commonly used to treat what type of infections?

Urinary tract infections (UTI) primarily caused by E. coli as well as many upper respiratory infections (URI) such as Pneumocystis jiroveci pneumonia, some nontuberculous mycobacterial infections, most S. aureus strains, Pneumococcus, Haemophilus sp, Moraxella catarrhalis, and Klebsiella pneumoniae infections. However, up to 30% of UTI and URI pathogenic strains are resistant to this antibiotic combination.

Give examples of how bacteria may become resistant to sulfonamide antibiotics:

Increased concentrations of PABA; decreased binding affinity of target enzymes; uptake and use of exogenous sources of folic acid

What is the mechanism of action of fluoroquinolone antibiotics?

Inhibition of two DNA gyrases (bacterial DNA topoisomerase II and IV) which in turn prevents relaxation of supercoiled DNA inhibiting DNA replication and transcription

Give examples of fluoroquinolone antibiotics:

Ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, gatifloxacin. All are fluorinated derivatives of nalidixic acid giving them the ability to be active systemically.

What types of bacteria are susceptible to quinolone antibiotics?

Many gram-positive and gram-negative bacteria. Examples include Shigella, Salmonella, toxigenic E. Coli, Campylobacter, Pseudomonas, Enterobacter, chlamydial urethritis or cervicitis, and atypical mycobacterial infections

What are the adverse effects of fluoroquinolone antibiotics?

Generally are well tolerated, but nausea, vomiting, and diarrhea are the most common adverse effects. Dizziness, insomnia, headache, photosensitivity, QT interval prolongation also occur with certain quinolones. Gatifloxacin causes hyperglycemia in diabetics and hypoglycemia when used in combination with oral hypoglycemics, and therefore is only available for ophthalmic use in the United States.

Why are fluoroquinolone antibiotics contraindicated in children?

They have deleterious effects on cartilage development, thereby causing tendonitis and possible tendon rupture.

Are fluoroquinolone antibiotics bactericidal or bacteriostatic?

Bactericidal

Give examples of how bacteria may become resistant to fluoroquinolone antibiotics:

Reduced drug penetration (drug efflux pumps); mutations in DNA gyrases result in decreased binding affinity of bacterial target enzymes for fluoroquinolones

What is the mechanism of action of β-lactam antibiotics?

They weaken the cell wall by inactivating transpeptidases (penicillin-binding protein [PBPs]), thereby inhibiting transpeptidation reactions necessary in the cross-linking of peptidoglycan subunits in the bacterial cell wall.

Name the four main classes of β-lactam antibiotics:

 

  1. Penicillins
  2. Cephalosporins
  3. Carbapenems
  4. Monobactams

 

Give examples of how bacteria may become resistant to β-lactam antibiotics?

Production of β-lactamases (cleaves the β-lactam ring—the most common mechanism); alteration of PBPs; inhibition of drugs to reach PBPs; downregulation of porin structure (only in gram-negative organisms since gram-positive organisms lack the outer cell wall where porins are located); development of efflux pumps in gram-negatives

Which class of β-lactam antibiotics is resistant to β-lactamases?

Monobactams

Give an example of a monobactam antibiotic:

Aztreonam. This is the only monobactam available in the United States.

What organisms are monobactams active against?

Aerobic gram-negative rods, including pseudomonas

Can a monobactam be used in a penicillin-allergic patient?

Yes. This makes monobactams a good choice for patients with a penicillin allergy and a serious gram-negative infection.

Give examples of antibiotics that belong to each of the following penicillin classes:

β-lactamase susceptible; narrow spectrum

Penicillin G (intravenous); penicillin V (oral)

β-lactamase susceptible; broad spectrum

Amoxicillin; ampicillin; piperacillin; ticarcillin

β-lactamase resistant; narrow spectrum

Methicillin; nafcillin; dicloxacillin; oxacillin

Penicillins are synergistic with what other antibiotic drug class in the treatment of enterococcal and pseudomonal infections?

Aminoglycosides. Aminoglycosides are very polar molecules that cannot easily cross the cell wall. With inhibition of cell wall formation by penicillins, aminoglycosides are then able to enter cells and exert their effects.

Name three β-lactamase inhibitors that can be used in combination with penicillins:

 

  1. Clavulanate
  2. Sulbactam
  3. Tazobactam

 

What are the adverse effects of the penicillin antibiotics?

Hypersensitivity; acute interstitial nephritis (common with methicillin); nausea; vomiting; diarrhea; hepatitis (oxacillin); hemolytic anemia; pseudomembranous colitis (ampicillin)

What is the mechanism of methicillin resistance by S. aureusl?

Production of an alternative PBP 2a

Does Streptococcus make β-lactamase?

No (mechanism of resistance is via altered PBPs)

Are β-lactam antibiotics effective in treating Mycoplasma infections?

No (Mycoplasma have no cell walls)

Give examples of medications in each of the following cephalosporin classes:

Note: It is unnecessary to memorize every drug in each generation. Usually there are two to three cephalosporins on formulary, so their use will vary depending on the particular hospital. Licensing exams will not ask you to choose between cephalosporins in the same generation.

First generation

Cefazolin; cephalexin; cefadroxil; cephapirin; cephradine

Second generation

Cefuroxime; cefotetan; cefaclor; cefoxitin; cefprozil; cefpodoxime; cefamandole; cefmetazole; loracarbef; cefonicid

Third generation

Cefotaxime; Ceftazidime; Ceftriaxone; Cefpodoxime; cefdinir; cefditoren; ceftibuten; cefixime; cefoperazone; ceftizoxime; moxalactam

Fourth generation

Cefepime (only representative drug of this generation)

Which cephalosporin has the broadest spectrum of activity and is resistant to β-lactamases?

Cefepime

How does the antibiotic spectrum of activity of cephalosporins vary by generation, that is, how does the coverage of second-generation drugs compare to first generation and so on?

Second generation: increased gram-negative coverage as compared to first generation. Third generation: continued increase in gram-negative coverage and greater ability to cross blood-brain barrier as compared to second generation drugs. Fourth generation: increased β-lactamase resistance as compared to third-generation drugs

Give examples of carbapenem β- lactams:

Imipenem; meropenem; ertapenem; doripenem

Why is cilastatin given concomitantly with imipenem?

Cilastatin (a dipeptidase inhibitor) inhibits renal dihydropeptidases in the renal tubules which inactivate imipenem, thereby allowing imipenem to exert its effects.

What is the difference in microbial coverage between imipenem and ertapenem?

Ertapenem does not cover Acinetobacter species and pseudomonal species.

What is the mechanism of action of aminoglycoside antibiotics?

Binds to 3OS ribosomal subunit to prevent formation of initiation complex, thereby inhibiting bacterial protein synthesis; incorporation of incorrect amino acids in the growing peptide chain

Are aminoglycoside antibiotics bactericidal or bacteriostatic?

Bactericidal

Give examples of aminoglycoside antibiotics:

Gentamicin; tobramycin; streptomycin; amikacin; neomycin

What is streptomycin commonly used to treat?

Tuberculosis infections

Why might the efficacy of an aminoglycoside be increased when given as a single large dose as opposed to multiple smaller doses (two reasons)?

 

  1. Concentration-dependent killing: increasing concentrations of aminoglycosides kill a greater proportion of bacteria more quickly.
  2. Postantibiotic effect: the antibacterial activity of aminoglycosides lasts longer than detectable levels of the drug are found in the bloodstream.

 

Against which organisms are aminoglycosides effective?

Gram-negative aerobes. Aminoglycosides passively diffuse across porins in the outer membrane of gram-negatives and their entry across the inner membrane is oxygen dependent. Use with a (β-lactam increases gram-positive coverage.

Although synergistic in their clinical effects, why can penicillins and aminoglycosides not be given in the same vial?

The penicillins would directly inactivate the aminoglycosides.

What are the adverse effects of the aminoglycoside antibiotics?

Nephrotoxicity (acute tubular necrosis); ototoxicity; hypersensitivity; neuromuscular blockade. Adverse effects are also dose dependent, just like efficacy, so close monitoring of drug levels is necessary. Ototoxicity may be irreversible; therefore it is imperative to act before a clinical change in hearing has occurred.

In regards to aminoglycoside ototoxicity, are high-frequency or low-frequency sounds affected first?

High frequency

Give examples of how bacteria may become resistant to aminoglycoside antibiotics?

Inactivation of drug via conjugation reactions (acetylation; adenylation; phosphorylation); inactivation driven by plasmid-encoded enzymes

Which aminoglycoside antibiotic is the most toxic?

Neomycin (used primarily for topical application)

What is the mechanism of action of clindamycin?

Binds to 5OS ribosomal subunit to inhibit translocation of peptidyl-tRNA from acceptor to donor site, thereby inhibiting bacterial protein synthesis

Is clindamycin bactericidal or bacteriostatic?

Bacteriostatic

What is the spectrum of activity of clindamycin?

Gram-positives (eg, penicillin-resistant Staphylococcus); anaerobes (eg, Bacteroides sp)

What major adverse effect is clindamycin associated with?

Pseudomembranous colitis (due to C. difficile)

What is the mechanism of action of macrolide antibiotics?

Binds to 5OS ribosomal subunit to inhibit translocation of peptidyl-tRNA from acceptor to donor site, thereby inhibiting bacterial protein synthesis

Give examples of macrolide antibiotics:

Erythromycin; clarithromycin; azithromycin; telithromycin (a ketolide that is structurally related to the macrolides)

Are macrolide antibiotics bactericidal or bacteriostatic?

Primarily bacteriostatic

Why is a single dose of azithromycin as effective as a 7-day course of doxycycline for chlamydial infections?

Azithromycin has a very long half-life of 68 hours.

Which of the macrolide antibiotics is relatively free of drug-drug interactions?

Azithromycin

Which macrolide related antibiotic can cause hepatotoxicity and blurred vision?

Telithromycin

What are the clinical uses of telithromycin?

Respiratory tract infections

Give examples of how bacteria may become resistant to macrolide antibiotics:

Alteration of binding sites on the 5OS ribosomal subunit; reduced permeability of cell membrane; active efflux; production of esterases by bacteria that hydrolyze the drug

What are the adverse effects of erythromycin?

Nausea; vomiting; diarrhea; anorexia; hepatitis; drug-drug interactions (cytochrome P-450 inhibitor)

What organisms does clarithromycin cover that erythromycin does not?

Mycobacterium avium complex (MAC), M. leprae, Toxoplasma gondii

Which macrolide antibiotic is safe in pregnancy?

Azithromycin

What adverse effect is caused by erythromycin given to infants less than 6 weeks of age for pertussis?

Hypertrophic pyloric stenosis

What is the mechanism of action of tetracycline antibiotics?

Binds to 3OS ribosomal subunit to inhibit the attachment of aminoacyl-tRNA to its acceptor site, thereby inhibiting bacterial protein synthesis

Give examples of tetracycline antibiotics:

Tetracycline; minocycline; doxycycline; demeclocycline; methacycline

What is demeclocycline used for?

Syndrome of inappropriate antidiuretic hormone (SIADH) via inhibition of antidiuretic hormone (ADH) receptors in the renal collecting ducts

Are tetracycline antibiotics bactericidal or bacteriostatic?

Primarily bacteriostatic

What are the adverse effects of tetracycline antibiotics?

Nausea; vomiting; diarrhea; Fanconi syndrome (outdated tetracyclines); phototoxicity; hepatotoxicity; vestibular toxicity; superinfection

Why are tetracycline antibiotics contraindicated in children?

Tooth enamel dysplasia; permanent discoloration of teeth; decreased bone growth via chelation with calcium salts

Oral absorption of tetracycline antibiotics may be decreased by which multivalent cations?

Iron; calcium; magnesium; aluminum

Give examples of how bacteria may become resistant to tetracycline antibiotics:

Efflux pumps or impaired influx; bacterial production of proteins that decrease binding of tetracyclines to ribosome; enzymatic inactivation

Give an example of a glycylcycline antibiotic (derivative of tetracyclines):

Tigecycline

Is tigecycline effective against MRSA?

Yes

Is tigecycline a substrate for the efflux pump mechanism of resistance to tetracyclines?

No

What is the mechanism of action of chloramphenicol?

Binds to 5OS ribosomal subunit to inhibit peptidyltransferase, thereby inhibiting bacterial protein synthesis

What are the adverse effects of chloramphenicol?

Gray baby syndrome in neonates (hypotension, ashen discoloration, vomiting, flaccidity); nausea, vomiting, diarrhea in adults, aplastic anemia; drug-drug interactions (CYP450 inhibitor)

Give examples of streptogramin antibiotics:

Quinupristin; dalfopristin

What is the mechanism of action of streptogramin antibiotics?

Binds 5OS ribosomal subunit to inhibit the attachment of aminoacyl-tRNA to its acceptor site, thereby inhibiting bacterial protein synthesis. Specifically, with the fixed dose combination of dalfopristin/quinupristin, dalfopristin distorts the ribosome promoting quinupristin binding. This blocks the aminoacyl-rRNAs from binding to the ribosome and therefore the transpeptidase reaction.

What is the spectrum of action of streptogramin antibiotics?

MRSA; vancomycin-resistant S. aureus (VRSA); vancomycin-resistant Enterococcus faecium (not Enterococcus fecalis)

What are the adverse effects of the streptogramin antibiotics?

Arthralgias; myalgias; drug-drug interactions (CYP450 inhibitor)

Give an example of an oxazolidinone antibiotic:

Linezolid

What is the mechanism of action of linezolid?

Binds to 5OS ribosomal subunit to prevent formation of initiation complex, thereby inhibiting bacterial protein synthesis

What are the adverse effects of linezolid?

Nausea; vomiting; diarrhea; headache; bone marrow suppression (primarily thrombocytopenia) after 2 weeks of use; weak reversible inhibitor of (monoamine oxidase) MAOA and MAOB; lactic acidosis; peripheral neuropathy; optic neuritis

What is the spectrum of action of linezolid?

Gram-positive organisms such as MRSA; VRSA; vancomycin-resistant E. faecium and E. fecalis

Give an example of a cyclic lipopeptide antibiotic:

Daptomycin

What is the mechanism of action of daptomycin?

Binds to components of the bacterial cell membrane and causes rapid intracellular depolarization, thereby inhibiting DNA, RNA, and protein synthesis

What is the spectrum of action of daptomycin?

MRSA; VRSA; vancomycin-resistant E. faecium and E.fecalis, therefore daptomycin is an effective alternative to vancomycin

Which antibiotic, that works by inhibiting protein synthesis, can also be used in patients to increase GI motility?

Erythromycin (activates motilin receptors)

Give the mechanism of action for each of the following first-line antituberculosis medications:

Rifampin

Inhibition of DNA-dependent RNA polymerase

Isoniazid

Inhibition of mycolic acid synthesis

Pyrazinamide

Unknown; activated by susceptible bacterial strains which in turn lowers pH of the surrounding environment

Ethambutol

Inhibition of RNA synthesis Ethambutol

Which of the previous four antituberculosis medications is bacteriostatic?

Give the adverse effects for each of the following antituberculosis medications:

Rifampin

Flu-like syndrome; hepatitis; elevated liver function tests (LFTs); drug-drug interactions (cytochrome P-450 inducer); proteinuria; thrombocytopenia; red-orange discoloration of tears, sweat, urine

Isoniazid

Drug-induced systemic lupus erythematosus (SLE); hepatitis; peripheral neuropathy; hemolytic anemia in G6PD deficiency; seizures

Pyrazinamide

Phototoxicity; increased porphyrin synthesis; hepatitis; arthralgias; myalgias; hyperuricemia

Ethambutol

Optic (retrobulbar) neuritis; decreased visual acuity; red-green color blindness; hyperuricemia

How can isoniazid-induced peripheral neuropathy be prevented?

Supplementation of vitamin B6 (pyridoxine)

ANTIFUNGAL AGENTS

 

Name two medications in the polyene antifungal drug class:

Amphotericin B; nystatin

What is the mechanism of action of the polyene antifungals?

Forms artificial pores by binding to ergosterol in fungal membranes, thereby disrupting membrane permeability

How do fungi become resistant to polyene antifungals?

Reduction in the amount of membrane ergosterol

What types of fungi are affected by amphotericin B?

Candida; Aspergillus; Histoplasma; Cryptococcus; Rhizopus; Sporothrix

Amphotericin B is synergistic with what other antifungal drug in the treatment of candidal and cryptococcal infections?

Flucytosine

Flucytosine is converted by fungal cytosine deaminase to what active compound?

5-Fluorouracil which is subsequently converted selectively in fungal cells into two other compounds which inhibit DNA and RNA synthesis

Does amphotericin B have good central nervous system (CNS) penetration?

No, amphotericin B must be given via intrathecal route if adequate cerebrospinal fluid (CSF) levels are warranted

Which polyene antifungal is said to cause a “shake and bake” adverse reaction?

IV infusion of amphotericin B can cause fevers, chills, rigors, and hypotension, the so called “shake and bake” adverse reaction.

How can the “shake and bake” adverse reaction caused by amphotericin B be prevented?

Test dose prior to initiation of intravenous therapy; pretreatment with antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), meperidine, and glucocorticoids

Pretreatment with meperidine prior to amphotericin B infusion is used to prevent what specific adverse reaction?

Rigors

What is the major dose-limiting adverse effect of amphotericin B?

Nephrotoxicity (also causes anemia via decreased erythropoietin, hypokalemia, hypomagnesemia, decreased glomerular filtration rate [GFR], renal tubular acidosis)

How can the nephrotoxicity caused by amphotericin B be minimized?

Load with normal saline solution; use of amphotericin B in combination with another medication so that the dose of amphotericin B can be decreased; use of liposomal amphotericin B formulations

Give examples of the azole antifungal drug class:

Fluconazole; itraconazole; ketoconazole; voriconazole; miconazole; clotrimazole; posaconazole; ravuconazole

What is the mechanism of action of the azole antifungals?

Prevents the synthesis of ergosterol from lanosterol by inhibiting cytochrome P-450-dependent 14-α-demethylation

Fluconazole is the drug of choice for what types of fungal infections?

Mucocutaneous candidiasis; coccidioidomycosis; prevention and treatment of cryptococcal meningitis

Itraconazole is the drug of choice for what types of fungal infections?

Sporotrichoses; blastomycoses

Which antifungal is the drug of choice for paracoccidioides infections?

Ketoconazole

What antifungal can be formulated into a topical shampoo gel to treat dermatophytosis of the scalp?

Ketoconazole

What is another name for dermatophytosis of the scalp?

Tinea capitis

What adverse effect of ketoconazole is also an adverse effect of spironolactone?

Gynecomastia (via inhibition of androgen synthesis)

Voriconazole can be used to treat what types of fungal infections?

Invasive aspergillosis; invasive candidiasis; candidemia

Is absorption of ketoconazole increased or decreased by alkalinization of gastric pH?

It is decreased. Do not use antacids in combination with ketoconazole.

Some physicians may tell patients to drink what in order to enhance the oral absorption of ketoconazole?

Coca-Cola, Pepsi-Cola, etc. Carbonated beverages that contain phosphoric and/or citric acid are acidic and therefore enhance oral absorption.

The International Normalized Ratio (INR) of a patient stabilized on warfarin therapy will be increased or decreased when an azole antifungal medication is initiated?

Increased (azole antifungals inhibit hepatic cytochrome P-450 enzymes thereby inhibiting the metabolism and increasing the blood levels of warfarin)

Which laboratory tests may become elevated in patients being treated with azole antifungals?

Liver function tests (LFTs) used to monitor for hepatotoxicity

Which antifungal medications act by inhibiting the synthesis of β-(l-3)-d-glucan?

Caspofungin; anidulafungin; micafungin

β-(1-3)-d-Glucan is an integral part of the fungal cell membrane or fungal cell wall?

Fungal cell wall

Caspofungin can be used to treat what types of fungal infections?

Invasive aspergillosis; invasive candidiasis; candidemia

Which antifungal, active only against dermatophytes, acts by depositing in newly formed keratin and disrupting microtubule structure?

Griseofulvin

Griseofulvin is active against dermatophytes when used orally or topically?

When used orally

What is the major dose-limiting adverse reaction of griseofulvin?

Hepatotoxicity

Griseofulvin is contraindicated in patients with which disease?

Acute intermittent porphyria

Name the three major dermatophytes:

 

  1. Epidermophyton
  2. Trichophyton
  3. Microsporum

 

Which antifungal inhibits ergosterol synthesis by inhibiting squalene epoxidase?

Terbinafine

Terbinafine is used to treat what types of fungal infections?

Dermatophytic infections

Oral terbinafine is used to treat what specific types of dermatophytic infections?

Onychomycosis of the toenail; onychomycosis of the fingernail

Oral terbinafine can cause what major dose-limiting adverse reaction?

Hepatotoxicity

ANTIVIRAL AGENTS

 

What enzyme adds the first phosphate to acyclovir?

Viral thymidine kinase

True or False? Monophosphorylated acyclovir is converted to the triphosphate form by viral enzymes.

False (host cell kinases are responsible for these reactions)

How does acyclovir triphosphate work as an antiviral agent?

Inhibits viral DNA replication by competing with deoxyguanosine triphosphate for viral DNA polymerase; incorporated into the viral DNA molecule and acts as a chain terminator

How does acyclovir triphosphate work as a chain terminator?

Lacks the ribosyl 3’ hydroxyl group

How do viruses become resistant to acyclovir?

Downregulation of viral thymidine kinase; lacking thymidine kinase altogether; altered specificity of viral thymidine kinase; altered specificity of viral DNA polymerase

Acyclovir is effective in treating which virus types?

Herpes simplex virus (HSV) 1 and 2; varicella-zoster virus (VZV). Acyclovir is 10 × more potent against HSV than VZV

Is acyclovir effective in treating postherpetic neuralgia?

No (only effective against acute neuritis)

What is the oral bioavailability of acyclovir?

15%-30%. There is minimal systemic distribution after topical application.

What is the half-life of acyclovir in adults?

2.5-3 hours

Why is it necessary to maintain adequate hydration in patients receiving IV acyclovir therapy?

To prevent crystalluria or interstitial nephritis. Slow infusion additionally helps to avoid these adverse reactions.

What is the name of the prodrug that is converted to acyclovir and L-valine by first-pass metabolism?

Valacyclovir

What is the advantage of valacyclovir over acyclovir?

Higher oral bioavailability of 54%-70%

Famciclovir is a prodrug that is metabolized to what active metabolite?

Penciclovir

What is the bioavailability of penciclovir after oral administration of famciclovir?

70%

Is famciclovir effective in viral strains resistant to acyclovir secondary to mutated DNA polymerase?

Yes

Is famciclovir effective in viral strains resistant to acyclovir secondary to lack of thymidine kinase?

No

What is the mechanism of action of ganciclovir?

Phosphorylated to a substrate which competitively inhibits binding of deoxyguanosine triphosphate to DNA polymerase, thereby inhibiting viral DNA synthesis

Does ganciclovir have chain-terminating ability?

No

Ganciclovir is effective in treating which virus types?

HSV; VZV; human herpes virus (HHV)-6 and 8; cytomegalovirus (CMV). Activity against CMV is 100 × greater than acyclovir. It may be used intraocularly for CMV retinitis.

What is the advantage of valganciclovir over its parent drug ganciclovir?

Valganciclovir (the valine ester) has up to 60% better oral availability than ganciclovir.

What is ganciclovir’s dose-limiting adverse effect?

Myelosuppression; thrombocytopenia; anemia; leukopenia

What are the adverse effects of ganciclovir?

Crystalluria; mucositis; rash; fever; hepatotoxicity; seizures; diarrhea; nausea; hematotoxicity

What is cidofovir used for?

CMV retinitis most commonly. It also has activity against HSV-1 and 2, varicella zoster virus (VZV), Epstein-Barr virus (EBV), HHV-6 and 8, adenovirus, poxviruses, polyomaviruses, and human papilloma virus (HPV).

What antiviral agent is a pyrophosphate analogue that acts as an inhibitor of viral RNA and DNA polymerase and HIV reverse transcriptase?

Foscarnet

Does foscarnet require activation by thymidine kinase?

No

Foscarnet is effective in treating which virus types?

Acyclovir-resistant HSV and VZV; ganciclovir-resistant CMV

Does foscarnet cause hematotoxicity?

Yes

What are the major adverse effects of foscarnet?

Hematotoxicity; fever; seizures; electrolyte abnormalities; nausea; vomiting; diarrhea

What types of electrolyte abnormalities can foscarnet cause?

Hyper- or hypocalcemia; hyper- or hypomagnesemia; hyper- or hypophosphatemia; hypokalemia

True of False? Amantadine is effective in treating both influenza A and B.

False (it is effective against the influenza A virus only)

What is the antiviral mechanism of action of amantadine?

Blocks the uncoating of influenza A virus, thereby preventing penetration of the virus into host cells

What other noninf ectious disease processes is amantadine used for?

Parkinson disease; drug-induced extrapyramidal symptoms. It also increases dopamine levels in the synaptic cleft by either inhibiting reuptake into presynaptic neurons or by increasing release from presynaptic neurons. It may have anticholinergic effects.

What are the adverse effects of amantadine?

Seizures; insomnia; nervousness; livedo reticularis; orthostatic hypotension; peripheral edema; dry nose; xerostomia; nausea; anorexia

What is livedo reticularis?

A purplish discoloration of the skin caused by dilation of capillaries and venules secondary to stasis or changes in underlying blood vessels

Name two drugs that inhibit neuraminidase of both influenza A and B, thereby decreasing the likelihood of viral penetration into host cells:

Oseltamivir; zanamivir

Which neuraminidase inhibitor has an oral inhalational route of administration?

Zanamivir

Ribavirin is effective in treating which virus types?

Respiratory syncytial virus (RSV); influenza A and B; hepatitis C virus (HCV)

Ribavirin is used in conjunction with what other drug to treat HCV?

Interferon-alpha (IFN-α)

What are the adverse effects of ribavirin?

Anemia; neutropenia; thrombocytopenia; anorexia; headache; conjunctivitis; nausea; pharyngitis; lacrimation; alopecia; rash; flu-like syndrome; teratogenicity (pregnancy category X)

Name the major adverse effects of IFN-α:

Flu-like symptoms; depression; alopecia; insomnia; nausea

What is the name of the only available nucleotide reverse transcriptase inhibitor?

Tenofovir

Give examples of nucleoside reverse transcriptase inhibitors (NRTIs):

Zidovudine (AZT); stavudine (d4T); lamivudine (3TC); didanosine (ddl); abacavir (ABC); emtricitabine (FTC)

What adverse effect(s) are associated with all NRTIs?

Lactic acidosis with hepatic steatosis

What is the general mechanism of action of NRTIs?

Interference with HIV viral RNA-dependent DNA polymerase resulting in inhibition of HIV viral replication

What two NRTIs are thymidine analogs?

Zidovudine; stavudine

What NRTI is an adenosine analog?

Didanosine

What NRTI is a guanosine analog?

Abacavir

What two NRTIs are cytosine analogs?

 

  1. Emtricitabine
  2. Lamivudine

 

Which NRTI should not be rechallenged if hypersensitivity is expected?

Abacavir (symptoms include fever, rash, nausea, vomiting, malaise, fatigue, and respiratory dysfunction)

Which NRTI can cause hyperuricemia?

Didanosine

Which two NRTIs can cause pancreatitis?

 

  1. Didanosine
  2. Stavudine (dose-limiting effect)

 

Which two NRTIs can cause peripheral neuropathy?

 

  1. Didanosine
  2. Stavudine (dose-limiting effect)

 

What is didanosine’s dose-limiting adverse effect?

Pancreatitis

What is stavudine’s dose-limiting adverse effect?

Peripheral neuropathy

What are the main adverse effects of AZT?

Anemia and neutropenia (dose-limiting effect/potentiated by vitamin B12); headache; nausea; insomnia; body aches; lactic acidosis

What is the dose-limiting adverse effect of AZT?

Hematotoxicity

What antiretroviral agent can cause Fanconi syndrome?

Tenofovir. Fanconi syndrome is impairment of the proximal tubule resulting in increased phosphate and calcium losses.

What NRTI can cause altered LFTs, lipoatrophy, hyperlipidemia, and ascending paresis?

Stavudine

Name three nonnucleoside reverse transcriptase inhibitors (NNRTIs):

 

  1. Delavirdine
  2. Efavirenz
  3. Nevirapine

 

What is the mechanism of action of efavirenz?

Binds directly to reverse transcriptase and blocks the RNA-and DNA-dependent DNA polymerase activity of reverse transcriptase

What is the class adverse effect(s) of the NNRTIs?

Rash

Which NNRTI can cause hepatitis and hepatic necrosis?

Nevirapine

Which NNRTI can cause abnormal dreams, impaired concentration, dizziness, and altered LFTs?

Efavirenz

Which NNRT can produce a false-positive urine test for Cannabis?

Efavirenz (in about 50% of patients)

Do NNRTIs require metabolic activation?

No

Do NRTIs require metabolic activation?

Yes

What is the name of the drug that inhibits fusion of the HIV-1 virus with CD4 cells by binding to and blocking the conformational change in gp41 required for membrane fusion and entry into CD4 cells?

Enfuvirtide (fusion inhibitor)

What are the adverse effects of enfuvirtide?

Pain, induration, erythema, and nodules at the injection site; nausea; vomiting; diarrhea; fatigue

Give examples of protease inhibitors:

Atazanavir; indinavir; lopinavir; fosamprenavir; nelfinavir; ritonavir; saquinavir; tipranavir; amprenavir; darunavir

What adverse effect(s) are associated with the protease inhibitors?

Hepatotoxicity; fat maldistribution; insulin resistance; osteonecrosis; increased bleeding in hemophiliac patients

Are protease inhibitors metabolized by P-450 enzymes?

Yes

Do protease inhibitors inhibit or induce P-450 enzymes?

They inhibit P-450 enzymes.

What is HIV protease responsible for?

Cleaves the Gag-Pol polyprotein of HIV (the gag region of the gene codes for structural proteins whereas the Pol region of the gene codes for protease, reverse transcriptase, and integrase)

The combination of atazanavir and indinavir can cause what possible adverse effect?

Hyperbilirubinemia

Patients with sulfonamide allergy should use caution when taking which two protease inhibitors?

 

  1. Tipranavir
  2. Fosamprenavir

 

Which protease inhibitor can cause an altered taste sensation?

Ritonavir

Which two protease inhibitors can cause asthenia (lack of strength)?

 

  1. Lopinavir
  2. Ritonavir

 

Which protease inhibitor can cause kidney stone formation?

Indinavir

Which protease inhibitor can cause numbness around the mouth?

Ritonavir

What type of prophylaxis is given to a person stuck with a potentially HIV contaminated needle?

Zidovudine and lamivudine for 1 month (protease inhibitor should be added for high-risk exposures)

How is maternal-fetal HIV transmission prevented in mothers?

Zidovudine beginning at 14-34 weeks’ gestation and continued until start of labor; during labor and delivery, zidovudine until the umbilical cord is clamped

How is maternal-fetal HIV transmission prevented in neonates?

Zidovudine started 8-12 hours after birth and continued for 6 weeks

ANTIPROTOZOAL AGENTS

 

Amebiasis is generally treated with what drug combination?

Metronidazole and diloxanide

What is the mechanism of action of metronidazole?

Mixed amebicide (effective against both luminal and systemic forms of disease); nitro group of metronidazole acts as an electron acceptor, thereby forming reduced cytotoxic compounds that lead to inhibition of protein synthesis and DNA strand breakage

What are the adverse effects of metronidazole?

Nausea; vomiting; metallic taste sensation; disulfiram-like reaction

Give examples of medications that can cause a disulfiram-like reaction:

Metronidazole; chlorpropamide; cefotetan; cefamandole; cefoperazone

What is the antimicrobial spectrum of metronidazole?

Entamoeba histolytica; Giardia lamblia; Trichomonas vaginalis; bacterial anaerobes; C. difficile

Metronidazole is contraindicated in which trimester of pregnancy?

First trimester during organogenesis since teratogenicity has not been effectively ruled out

Can metronidazole cross the blood-brain barrier (BBB)?

Yes

What is the mechanism of action of diloxanide?

Luminal amebicide (effective against luminal forms of disease) used in the treatment of asymptomatic amoebic cyst passers

What are the adverse effects of diloxanide?

Contraindicated in pregnancy and children less than 2 years old; dry mouth; pruritus; flatulence

What are the four species of Plasmodium

 

  1. Malariae
  2. Falciparum
  3. Vivax
  4. Ovale

 

What is the most dangerous/life-threatening Plasmodium species?

Falciparum

What are the three stages of the malarial parasite life cycle primarily targeted by antimalarial drugs?

 

  1. Erythrocytic stage
  2. Exoerythrocytic stage
  3. Gametocytic stage

 

What is the oldest antimalarial drug still in use?

Quinine (“Jesuit Bark”)

Quinine has been replaced by which antimalarial drug?

Chloroquine (more potent and less toxic than quinine)

What drugs are effective against the exoerythrocytic forms of malaria?

Primaquine; atovaquone + proguanil (Malarone)

What drug is effective against the gametocytic (hepatic) forms of malaria?

Primaquine

Is primaquine effective against erythrocytic forms of malaria?

No

Give examples of antimalarial drugs that are effective against the erythrocytic forms of malaria:

Hydroxychloroquine; chloroquine; mefloquine; pyrimethamine; quinine; atovaquone + proguanil; artemisinin

What drug is effective against relapsing forms of P. vivax and P. ovale malarias?

Primaquine. To prevent recurrence of infection, hepatic forms of these parasites must be eliminated.

What are the adverse effects of primaquine?

Hemolytic anemia in patients with G6PD deficiency; methemoglobinemia; agranulocytosis

What is the drug of choice for acute attacks of malaria caused by chloroquine-sensitive strains of P. falciparum and P. vivax?

Chloroquine

Does chloroquine have a large or small Vd?

Large

What is the mechanism of action of chloroquine?

It concentrates within parasite food vacuoles and raises pH leading to inhibition of growth; inhibits hemoglobin metabolism and utilization by parasites; concentrates within parasite vacuoles and raises pH leading to inhibition of growth; binds to ferriprotoporphyrin IX leading to membrane damage; inhibits DNA and RNA polymerase

What continents contain the largest repositories of chloroquine-resistant P. falciparuml

Africa, Asia

What are the adverse effects of chloroquine?

ECG changes (quinidine-like effects); headaches; pruritus; mucosal pigmentary changes (blue-black); photosensitivity; nausea; vomiting; diarrhea; aplastic anemia; agranulocytosis; neutropenia; thrombocytopenia; retinopathy; tinnitus; reduced hearing

Chloroquine is contraindicated in patients with what disease states?

Porphyria; psoriasis

What are the major adverse effects of quinine?

Cinchonism (nausea, vomiting, diarrhea, tinnitus, vertigo); hemolytic anemia; digoxin toxicity

What other medication can cause cinchonism?

Quinidine

Is quinine acidic or basic?

Basic

How can the urinary excretion of quinine (or chloroquine) be enhanced?

Acidification of the urine

Name two newer antimalarials that are chemically related to quinine:

 

  1. Halofantrine
  2. Lumefantrine

 

What can be used to acidify the urine?

Ammonium chloride

What is the mechanism of action of pyrimethamine?

Inhibits nucleic acid and protein metabolism in the parasites; plasmodial dihydrofolate reductase (DHFR) inhibitor

The antimalarial effects of pyrimethamine can be potentiated by combining it with which drugs?

Sulfonamides (synergistic blockade of folic acid synthesis).

How is folate-deficient megaloblastic anemia reversed in patients taking pyrimethamine?

Leucovorin

What is the mechanism of action of leucovorin?

As a reduced form of folic acid, leucovorin supplies human cells with the necessary cofactor blocked by DHFR inhibitors.

What kind of compounds are the antimalarial drug artemisinin and its derivatives?

Sesquiterpene lactones (the active ingredient in a 2000-year-old Chinese herb—Qing Hao).

What is the antimalarial mechanism of action of artemisinin?

It is thought that it is activated by heme to irreversibly decompose generating free radicals that form adducts mostly with proteins and lipids.

Give examples of antimalarial drugs used in artemisinin combination therapies (ACT):

Pyrimethamine/sulfadoxine (Fansidar), mefloquine, amodiaquine

What is the name of the most promising antimalarial vaccine?

RTS-S/AS02A or Mosquirix

Which genetic diseases/conditions may help protect against malarial infections?

Sickle cell trait; G6PD deficiency

Trypanosoma cruzi is responsible for causing what disease?

American trypanosomiasis (Chagas disease)

  1. brucei gambienseand T.brucei rhodesiense are responsible for causing what disease?

African trypanosomiasis (sleeping sickness)

What drug is used as a suppressive agent in patients with acute T. cruzi infections?

Nifurtimox

What is the mechanism of action of nifurtimox?

Forms intracellular oxygen-free radicals which are toxic to the parasite because of its lack of catalase (oxygen radical scavenger)

What drug is used to treat African sleeping sickness with CNS involvement?

Eflornithine for West African trypanosomiasis; melarsoprol for East African trypanosomiasis

What are the adverse events of melarsoprol?

Hypersensitivity; abdominal pain; vomiting; hemolytic anemia in patients with G6PD deficiency; encephalopathy

What two drugs are used in the early stages of African sleeping sickness?

 

  1. Pentamidine (first choice for West African sleeping sickness)
  2. Suramin (first choice for East African sleeping sickness)

 

Does pentamidine cross the BBB?

No. Therefore it cannot be used for late trypanosomiasis with CNS involvement.

What are the two routes of administration of pentamidine?

 

  1. IV
  2. Aerosol

 

What fungus is pentamidine commonly used to treat?

Pneumocystis carinii

What drug combination is used for prophylaxis against P. carinii?

Trimethoprim-sulfamethoxazole

What is the treatment of choice for T. gondii?

Pyrimethamine + sulfadiazine

How do humans become infected with T. gondii?

Ingestion of undercooked, infected meat; contact with infected cats

Can pregnant mothers transmit T. gondii to the fetus?

Yes (remember TORCH syndromes)

What are the three types of leishmaniasis infections?

 

  1. Visceral
  2. Cutaneous
  3. Mucocutaneous

 

What is the drug of choice for treating leishmaniasis?

Stibogluconate (pentavalent antimony compound)

ANTIHELMINTHIC AGENTS

 

What is another name for the nematodes?

Roundworms

What is another name for the trematodes?

Flukes

What is another name for the cestodes?

Tapeworms

What drug is commonly used to treat trematode infections?

Praziquantel

What is the mechanism of action of praziquantel?

Increases cell permeability to calcium, thereby increasing contractions with subsequent paralysis of musculature

What is the mechanism of action of mebendazole?

It irreversibly blocks glucose uptake; inhibits microtubule polymerization

What are the adverse effects of mebendazole?

Diarrhea; abdominal pain; contraindicated during pregnancy

What is the mechanism of action of albendazole?

It interferes with microtubule polymerization; inhibits adenosine triphosphate (ATP) production thereby depleting energy availability

What is the mechanism of action of thiabendazole?

Inhibits helminth-specific mitochondrial fumarate reductase

What types of cutaneous adverse effects are caused by thiabendazole?

Stevens-Johnson syndrome; erythema multiforme

What is the mechanism of action of pyrantel?

Depolarizing neuromuscular blocker thereby causing paralysis of musculature

What types of helminths are affected by praziquantel?

Trematodes; cestodes

What types of helminths are affected by mebendazole?

Nematodes

What types of helminths are affected by pyrantel?

Nematodes

What is the drug of choice for treating Enterobius vermicularis?

Mebendazole

What is the common name for E. vermicularis?

Pinworm

What is the drug of choice for treating Onchocerca volvulus (onchocerciasis or river blindness)?

Ivermectin

What is the mechanism of action of ivermectin?

Acts at helminthic gamma-aminobutyric acid (GABA) receptors, thereby enhancing influx of chloride and causing hyperpolarization and paralysis

Why does onchocerciasis potentially lead to blindness?

A bacteria (Wolbachia sp.) that colonizes many parasitic worms, including the nematode that causes onchocerciasis, is an important factor in the inflammatory response that leads to blindness.

What is another name for onchocerciasis?

River blindness

What drug is commonly used to treat cestode infections?

Niclosamide

What is the mechanism of action of niclosamide?

Inhibits mitochondrial phosphorylation of ADP to ATP, thereby depleting energy availability

Is niclosamide active against the ova of cestodes?

No; only active against cestode’s scolex and segments

CLINICAL VIGNETTES

 

A 48-year-old female marine animal trainer develops a reddish granuloma on her hand. Her past medical history is significant only for gastroesophageal reflux disease (GERD) which is well controlled with a PPI (omeprazole). Moreover, she is very conscious as to maintain fitness in keeping with her required scuba licensing; thus, she regularly takes calcium tablets with her meals. She is diagnosed with a Mycobacterium marinum infection and begins treatment with minocycline. However, 6 weeks after treatment her condition has not resolved and she has developed new granulomas. What is the most likely reason for treatment failure in this patient?

This vignette underscores the importance of taking a good patient’s history. Here the patient’s occupation, gender, age, fitness requirements, and medication history are crucial. Her unique occupation gives the patient exposure to microorganisms that are uncommonly causes of infection in the lay human population. In terms of her medications, even supplements have significant side effects and drug interactions, and must be asked about as part of your history. Calcium salts such as those used to increase calcium intake in menopausal women will chelate tetracyclines like minocycline, decreasing their oral bioavailability. Therefore, this patient should have been instructed not to take her calcium supplement tablets 2 hours before or after a dose of her antibiotic.

A 76-year-old man is brought to the intensive care unit (ICU) after being found unresponsive on the floor of his home. It is unknown how long the patient had remained immobile on the floor. Respiratory effort was diminished and the patient was intubated and placed on a ventilator. The intern on call placed the patient on a tobramycin nebulizer to suppress ventilator-associated pneumonia. The next morning, the attending physician sees this and immediately terminates this treatment. Why is tobramycin contraindicated in this patient?

Prolonged immobility leads to dehydration and muscle breakdown with release of creatine phosphokinase (CPK), both of which can cause acute renal failure. Aminoglycosides, such as tobramycin, are nephrotoxic and will cause further damage to the kidneys. All aminoglycosides should be used with caution in the elderly. Another consideration is ototoxicity. Since this patient is unresponsive, we are unaware of his baseline hearing status. A small amount of damage in an individual who is already hard of hearing could have dramatic consequences.

A 24-year-old female medical student participates in an exchange program in rural South Korea. Despite chemoprophylaxis (mefloquine), she develops cyclic shaking chills and fever and is diagnosed with malaria. Treatment is begun with chloroquine, but the student fails to respond. Resistance to chloroquine is suspected, and the treatment is switched to quinidine plus a tetracycline with complete resolution of her symptoms. Two months after her return to the United States, she has a reoccurrence of the malarial symptoms. Why has this therapy failed to resolve her illness?

The student has most likely contracted P. vivax, an endemic strain of malaria on the Korean peninsula. Chloroquine (and mefloquine) resistance is an increasing problem worldwide. A quinidine plus tetracycline (eg, doxycycline) combination is an effective treatment regimen for eradication of chloroquine-resistant malaria. However, it is important to remember that P. vivax has liver repositories which the above antimalarial will not treat effectively. Reactivation of these hypnozoites can lead to recurrence of infection months to years later. Once the original acute attack P. vivax malaria is resolved, primaquine is the drug of choice to eradicate the liver forms and must be added to the drug regimen in cases of P. vivax or P. ovale.

Note: Licensing exams will not expect you to determine whether a specific geographic area is endemic with chloroquine resistant strains of malaria. You should know treatment alternatives for drug-resistant strains, as well as when addition of primaquine is necessary to eradicate hepatic repositories of the malaria parasite (ie, therapy is specie-specific).

During the second week of a trip to Belize, a traveler experienced some diarrhea, which was sufficient to remind him of previous admonitions about consuming food dispensed by street vendors. Fortunately, his symptoms seem to subside and he recovered in a few days. About a month after his return, the traveler developed severe pain in the right upper quadrant of his abdomen. When the abdominal pain persisted, he went to a gastroenterologist. The gastroenterologist performed an x-ray study of the intestine after a barium enema, a CT scan, and a serological test for E. histolytica. The results of these tests revealed pseudopolyps consistent with inflammatory bowel disease, the CT scan showed abscesses in the liver and a hemagglutination titer of 1:2000 for E. histolytica. What antiprotozoal drug should be given to this patient?

The drug of choice for this active amebic infection picture is metronidazole. It is absorbed rapidly from oral doses with a half-life in serum of about 8 hours. It has potent activity against E. histolytica. The drug is well tolerated and adverse effects are not common, but nausea, headaches, and dry mouth can occur.