Miscellaneous

Question 1

What is the mechanism of action of tetracyclines/tetracycline analogs?

Answer 1

inhibit bacterial protein synthesis by reversibly binding to the 30S ribosome, blocking binding of amino-acyl tRNA to the acceptor (A) site on the mRNA-ribosomal complex. This prevents the addition of amino acid residues to the elongating peptide chain and inhibits protein synthesis. Bacteriostatic.

Question 2

What are the tetracyclines?

Answer 2

tetracycline, doxycycline, minocycline

Question 3

What are the tetracycline analogs?

Answer 3

tigecycline, eravacycline, omadacycline

Question 4

What are the sulfonamides?

Answer 4

trimethoprim-sulfamethoxazole

Question 5

What is the mechanism of action of trimethoprim-sulfamethoxazole?

Answer 5

The sulfonamides were the 1st effective antimicrobial agents to be used systemically in the treatment and prevention of bacterial infections. Produce sequential blockade of microbial folic acid synthesis.
1. Sulfamethoxazole: competitively inhibits the incorporation of p-aminobenzoic acid (PABA) into folic acid by inhibiting dihydropteroate synthetase, which inhibits the formation of dihydrofolic acid.
2. Trimethoprim competitively inhibits the activity of bacterial dihydrofolate reductase to prevent the reduction of dihydrofolate to tetrahydrofolate.
3. Together they produce sequential inhibition of the synthesis of folate, which is necessary for microbial production of DNA, producing a synergistic bactericidal effect against gram-positive and gram-negative aerobic bacteria.

Question 6

What are the polymyxins?

Answer 6

colistin (polymyxin E), polymyxin B

Question 7

What is the mechanism of action of polymyxins?

Answer 7

cationic detergents that bind to the anionic lipopolysaccharide molecules of the outer cell membrane of gram-negative bacteria causing displacement of calcium and magnesium, which normally stabilize the cell membrane  changes in cell wall permeability, leakage of cellular contents, and subsequent cell death. Concentration dependent bactericidal activity.

Question 8

What are the lincosamides?

Answer 8

clindamycin

Question 9

What is the mechanism of action of clindamycin?

Answer 9

Inhibits protein synthesis by exclusively binding (reversibly) to the 50S ribosomal subunit. Primarily bacteriostatic but can display time-dependent bactericidal activity.

Question 10

What are the nitroimidazoles?

Answer 10

metronidazole

Question 11

What is the mechanism of action of metronidazole?

Answer 11

One of the most useful agents in the treatment of anaerobic and polymicrobial infections. Prodrug that is activated by a reductive process. Selective toxicity towards anaerobic and microaerophilic bacteria is due to presence of electron transport components such as ferredoxins within these bacteria. Ferredoxins are small Fe-S proteins that donate electrons to metronidazole to form a highly reactive nitro radical anion. These damage bacterial DNA (inhibit nucleic acid synthesis)  cell death. Metronidazole is rapidly bactericidal in a concentration dependent manner.
1. Does not treat aerobes because increased levels of oxygen inhibit metronidazole-induced cytotoxicity since oxygen competes with metronidazole for generated electrons.

Question 12

What are the mechanisms of resistance of tetracyclines/tetracycline analogs?

Answer 12

1. Decreased accumulation of tetracycline within the bacteria due to either altered permeability or the presence of tetracycline-specific efflux pumps (overexpression if mutation in repressor gene).
2. Decreased access of the tetracycline to the ribosome due to the presence of ribosomal protection proteins.
3. Enzymatic inactivation of the tetracycline.
4. Cross-resistance except in minocycline.
5. Tigecycline, eravacycline, and omadacycline retain activity against many tetracycline resistant bacteria because they are NOT affected by efflux pumps or ribosomal protection.

Question 13

What are the mechanisms of resistance of trimethoprim-sulfamethoxazole?

Answer 13

1. Bacterial resistance mediated by point mutations in dihydropteroate synthase and/or altered production or sensitivity of bacterial dihydrofolate reductase.

Question 14

What are the mechanisms of resistance of polymyxins?

Answer 14

1. Alteration of outer cell membrane: decreased lipopolysaccharide content, reduction in calcium and magnesium content, decreased outer membrane proteins.
2. Cross-resistance between polymyxin B and colistin.

Question 15

What are the mechanisms of resistance of clindamycin?

Answer 15

Alteration of the ribosomal binding site – ribosomal methylation by erm-coded enzymes. Cross resistance with macrolides and streptogramins.

Question 16

What are the mechanisms of resistance of metronidazole?

Answer 16

1. Altered growth requirements: organism grows in higher local oxygen concentrations causing decreased activation of metronidazole.
2. Altered levels of ferredoxin: reduced transcription of ferredoxin gene.

Question 17

Spectrum of activity of tetracyclines

Answer 17

1. Gram-positive aerobes: minocycline and doxycycline most active – streptococcus pneumoniae (PSSP), enterococcus spp, staphylococcus aureus (MSSA).
2. Gram-negative aerobes: many Enterobacteriaceae are relatively resistant.
3. Anaerobes: actinomyces, Propionibacterium spp.
4. Miscellaneous organisms: atypical bacteria such as legionella pneumophila, Chlamydophila pneumoniae, and psittaci.

Question 18

Spectrum of activity of tetracycline analogs

Answer 18

1. Gram-positive aerobes: enterococcus faecalis (VSE and VRE), staphylococcus aureus (MSSA and MRSA)
2. Gram-negative aerobes: eravacycline has come activity against ESBL, AmpC, and KPC producing bacteria
3. Tetracycline analogs are NOT active against proteus mirabilis or pseudomonas aeruginosa!
4. Anaerobes: Bacteroides spp.
5. Miscellaneous organisms: atypical bacteria (eravacycline and omadacycline).

Question 19

Spectrum of activity of TMP-SMX

Answer 19

1. Gram-positive aerobes: S. aureus (MRSA, CA-MRSA)
2. Gram-negative aerobes: Stenotrophomonas maltophilia; NOT active against P. aeruginosa
3. Anaerobes: INACTIVE
4. Other organisms: pneumocystis carinii/jirovecii (DRUG of CHOICE)

Question 20

Spectrum of activity of polymyxins

Answer 20

1. Gram-positive aerobes: INACTIVE
2. Gram-negative aerobes: Acinetobacter spp, pseudomonas aeruginosa (including MDR strains).
3. NOT active against Burkholderia spp, Proteus spp, Providencia spp, Serratia spp, and Brucella spp
4. Anaerobes: INACTIVE

Question 21

Spectrum of activity of clindamycin

Answer 21

1. Gram-positive aerobes: streptococcus pneumoniae (PSSP) and staphylococcus aureus (MSSA and CA-MRSA).
2. Anaerobes: most useful for above the diaphragm – clostridium spp (NOT C. diff), Bacteroides spp
3. Atypical bacteria: pneumocystis carinii/jirovecii, toxoplasmosis gondii, plasmodium falciparum and vivax (malaria).

Question 22

Spectrum of activity of metronidazole

Answer 22

1. Antianaerobic agent most reliably active against Bacteroides fragilis.
2. Gram-negative aerobes: bacteroides fragilis, Bacteroides distasonic, ovatus, thetaiotamicron, bivius (B fragilis group DOT organisms).
3. Gram-positive anaerobes: clostridium spp (including C diff.)
4. INACTIVE against all common aerobic bacteria.

Question 23

PK parameters of tetracyclines

Answer 23

1. Doxycycline, minocycline have best oral bioavailability, then tetracycline, demeclocycline, and then omadacycline. Absorption of the oral tetracyclines and omadacycline is impaired by the concurrent ingestion of dairy products, aluminum hydroxide gels, calcium, magnesium, iron, zinc, and bismuth subsalicylate due to chelation with divalent or trivalent cations.
2. Only small amounts diffuse into CSF, not useful for meningitis.
3. Demeclocycline and tetracycline required dosage adjustment in renal insufficiency. Doxycycline and minocycline mainly metabolized, no need for dosage adjustment. Tetracycline analogs mainly eliminated by biliary/fecal excretion of unchanged drug and its metabolites. None require dosage adjustments in renal insufficiency. Tigecycline and eravacycline need dosage adjustments in severe hepatic impairment.
4. Tetracyclines and tetracycline analogs not removed during hemodialysis.

Question 24

PK parameters of TMP-SMX

Answer 24

1. Optimal synergistic ratio of TMP to SMX is 1:20 and is achieved by using a fixed oral or IV combo of 1:5 (TMP: SMX). Well absorbed after oral administration. Concentrates in CSF in presence of inflamed meninges. Also concentrates in urine, uninflamed prostatic tissue.
2. Doses should be adjusted in patients with CrCl < 30 ml/min.

Question 25

PK parameters of polymyxins

Answer 25

1. Colistin displays extensive interpatient variability and a narrow therapeutic window – TDM may be needed. 2. Not absorbed from GI tract. Poor penetration into CSF. 3. Polymyxin B and colistin are primarily eliminated by nonrenal routes and do NOT require dosage adjustment in renal dysfunction. ~50% of CMS is excreted unchanged in urine by glomerular filtration (CMS is a prodrug). CMS requires dosage adjustment in presence of renal insufficiency when the creatinine clearance is <80 ml/min.

Question 26

PK parameters of clindamycin

Answer 26

1. Oral bioavailability approaches 90%. Penetrates bone, does NOT penetrate CSF. Primarily metabolized by the liver to metabolites with varying antimicrobial activity. Enterohepatic circulation of clindamycin and its metabolites can lead to prolonged antimicrobial presence in the stool  why it’s a big inducer of C. diff. NOT removed by hemodialysis.

Question 27

PK parameters of metronidazole

Answer 27

1. One of the few drugs you can use ORALLY to treat a CNS infection. 2. Almost completely absorbed after oral administration. DOES penetrate the CSF and brain tissue. 3. Metabolized by liver, 6-15% excreted in feces. 4. Removed during hemodialysis.

Question 28

Clinical uses of tetracyclines

Answer 28

1. Primarily for outpatient CAP (doxycycline) or infections due to unusual organisms. 2. Mild-moderate outpatient community-acquired pneumonia (doxycycline). Chlamydial infections and nongonococcal urethritis (doxycycline).

Question 29

Clinical uses of tetracycline analogs

Answer 29

NOT for proteus spp or pseudomonas spp. Complicated skin/skin structure infections, intraabdominal infections.

Question 30

Clinical uses for TMP-SMX

Answer 30

1. DRUG of CHOICE for acute, chronic or recurrent infections of the urinary tract. 2. Acute or chronic bacterial prostatitis. 3. Pneumocystis carinii/jirovecii pneumonia (DRUG OF CHOICE) 4. Stenotrophomonas maltophilia infections.

Question 31

Clinical uses of polymyxins

Answer 31

1. Infections caused by gram-negative bacteria (including P. aeruginosa and A. baumannii) that are resistant to other available antibiotics. 2. Polymyxin B preferred for systemic infections; colistin preferred for UTIs.

Question 32

Clinical uses of clindamycin

Answer 32

1. Infections due to anaerobes OUTSIDE the CNS – pulmonary infections, diabetic foot infections. 2. Mild-moderate skin and soft tissue infections due to CA-MRSA. 3. Alternative agent for treatment of infections due to gram-positive aerobes in patients allergic to penicillin.

Question 33

Clinical uses of metronidazole

Answer 33

1. Infections due to anaerobes – brain abscesses. Many serious anaerobic infections are polymicrobial and additional antibiotics are necessary for coverage of aerobic bacteria. 2. Pseudomembranous colitis due to C. diff. – alternative agent for non-severe C. diff colitis, can use oral or parenteral therapy. 3. Trichomonas vaginalis; diarrhea due to giardia.

Question 34

Major AEs of tetracyclines/tetracycline analogs

Answer 34

1. GI: N/V (most with tigecycline) – recommended to sit up for 30 min after ingestion due to esophageal irritation. 2. Dermatologic: photosensitivity (most with demeclocycline). 3. Pregnancy category D: all tetracyclines and tetracycline analogs are not recommended to be used during pregnancy/lactation and in children <8yrs of age because they cause permanent discoloration of primary dentition (yellow/gray-brown) in children with developing teeth and form a complex in bone-forming tissue, leading to decreased bone growth.

Question 35

Major AEs of TMP-SMX

Answer 35

1. Hematologic: leukopenia; hypersensitivity reactions: rash; Renal insufficiency, crystalluria, hyperkalemia 2. Pregnancy category C: should NOT be used in pregnant women or lactating women because it may cause kernicterus in the newborn due to bilirubin displacement from protein binding site.

Question 36

Major AEs of polymyxins

Answer 36

1. Nephrotoxicity and neurotoxicity

Question 37

Major AEs of clindamycin

Answer 37

1. GI: N/V, diarrhea; clostridium difficile colitis (pseudomembranous colitis or antibiotic-associated diarrhea) – clindamycin one of the worst inducers. 2. Hepatotoxicity.

Question 38

Major AEs of metronidazole

Answer 38

1. GI – metallic taste. 2. CNS: peripheral neuropathy, seizures. 3. Mutagenicity and carcinogenicity: may be teratogenic – avoid during 1st trimester and during breastfeeding.

Question 39

Major drug interactions with tetracylines

Answer 39

Aluminum hydroxide gels, calcium, magnesium, iron, zinc, bismuth subsalicylate --> chelation with divalent/trivalent cations.

Question 40

Major drug interactions with TMP-SMX

Answer 40

warfarin – potentiated anticoagulant effects.

Question 41

Major drug interactions with metronidazole

Answer 41

warfarin – increased anticoagulant effect; alcohol – disulfiram reaction.

Question 42

What is the potential therapeutic advantage of the tetracycline analog antibiotics?

Answer 42

structural modifications impart enhanced activity against many tetracycline-resistant bacteria