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:
- Penicillins
- Cephalosporins
- Carbapenems
- 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:
- Clavulanate
- Sulbactam
- 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)?
- Concentration-dependent killing: increasing concentrations of aminoglycosides kill a greater proportion of bacteria more quickly.
- 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
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