Antibacterials: Nucleic Acid Synthesis Inhibitors and Miscellaneous

Question 1

Fluoroquinolones MOA

Answer 1

Enter bacteria via porins –> inhibit bacteria DNA replication via interference with topoisomerase II (DNA gyrase) and topo IV

Broad-spectrum, bacerticidal drugs

Question 2

Fluoroquinolones antibacterial spectrum and clinical applications by generation

Answer 2

1st gen: nalidixic acid

• Moderate gram negative activity
• To treat uncomplicated UTIs

2nd gen: ciprofloxacin

• More gram negative
• Some activity against gram positive and atypical bacteria
• synergistic with beta-lactams
• Traveler’s diarrhea,
• P.aeruginosa infections (CF patients)
• Prophylaxis against meningitis

3rd gen: lecofloxacin

• expanded gram negative activity
• More activity against gram positive and atypical bacteria
• Excellent activity against S.pneumoniae
• Skin infections
• Community acquired pneumonia

4th gen: moxifloxacin, gemifloxacin

• Improved gram positive activity and anaerobic activity
• Community acquired pneumonia

3rd and 4th gen also known as respiratory fluoroquinolones –> used to treat pneumonia when first line agents have failed, patient is inpatient

Question 3

Fluoroquinolones mechanisms of resistance

Answer 3

Bacteria resist drugs due to chromosomal mutations that

• encode subunits of DNA gyrase and topo IV
• regulate expression of efflux pumps

Question 4

Fluoroquinolones PK and interactions

Answer 4

Good oral bioavailability

Iron, zinc, calcium (divalent cations) interfere with absorption

Moxifloxacin excreted in bile, other in urine –> dosage adjustments needed if patient has renal dysfunction

Theophylline, NSAIDs, corticosteroids = enhance toxicity

3rd and 4th gen = raise serum levels of warfarin, caffeine and cyclosporine

Question 5

Fluoroquinolones AE

Answer 5

Connective tissue problems - tendon ruptures, affect growth plates***
—> Black box warning: contraindicated in pregnancy, nursing mothers and under 18s

Peripheral neuropathy

QT prolongation (3rd/4th generation)

High risk of causing superinfections

Question 6

Sulfonamides MOA and resistance

Answer 6

Sulfamethoxazole, sulfadiazine, sulfasalazine

Structural analogs of PABA –> competitive inhibitors of dihydropteroate synthase (compete with PABA) –> cannot form dihydrofolic acid –> inhibit bacterial folic acid synthesis –> inhibit formation of purines/DNA –> bactericidal

Plasmid transfers/random mutations can lead to development of resistance

• enhanced PABA production
• altered dihydropteroate synthase
• decreased cell permeability

Question 7

Sulfonamides antibacterial spectrum, clinical applications and PK

Answer 7

Act against gram positive and gram negative organisms

Topical agents –> ocular, burn infections

Oral agents –> orally absorbable –> to treat simple UTIs

Sulfasalazine (oral non-absorbable) –> used to treat ulcerative colitis, enteritis, IBD***

Can accumulate in renal failure

Acetylated in liver –> can precipitate at neural or acidic pH and cause kidney damage

Question 8

Sulfonamides AE

Answer 8

Crystalluria - nephrotoxicity

Hypersensitivity reactions

Hematopoietic disturbances - esp patients with G6PD deficiency

Kernicterus in newborns and infants < 2 months

Question 9

Sulfonamides contraindications and drug interactions

Answer 9

Contraindicated in newborn and infants <2 months –> kernicterus –> drugs compete with bilirubin for binding sites on albumin

Drugs can displace other drugs from albumin (warfarin, phenytoin, methotrexate)

Don’t give to patients with G6PD deficiency as it can lead to haemolytic anaemia

Question 10

Trimethoprim MOA and antibacterial spectrum

Trimethoprim PK, clinical applications, AE

Answer 10

Structurally similar to folic acid –> Inhibits bacterial dihydrofolate reductase –> inhibits purine, pyrimidine and amino acid synthesis –> bacteriostatic against gram negative and gram positive bacterias

Question 11

Trimethoprim PK, clinical applications, AE

Answer 11

Clinical applications:

• UTIs
• Bacterial prostatitis and vaginitis –> trimethoprim is a weak base and will precipitate in acidic media –> drug will accumulate in high concentration in these tissues***

PK: mostly excreted unchanged through kidneys, reaches high concentration in prostatic and vaginal fluids

AE: contraindicated in pregnancy –> anti-folate so it can cause neural tube defects

Question 12

Cotrimaxazole MOA

Answer 12

Combination of trimethoprim and sulfamethoxazole –> synergistic effects as it inhibits 2 sequential enzymes in tetrahydrofolic acid synthesis

Bactericidal

Question 13

Cotrimaxazole clinical applications, PK and AE

Answer 13

DOC for uncomplicated UTIs

Commonly used to treat opportunistic infections in immunocompromised (HIV patients)

PK:

• Oral administeration generally (can be given IV)
• Well distributed including CSF

AE:

• Common: dermatologic side effects
• More AE in AIDS patients
• Hemolytic anemia
• contraindicated in pregnancy as it is a antifolate

Question 14

Metronidazole MOA and antibacterial spectrum

Answer 14

Antimicrobial, amebicide and antiprotozoal

Bactericidal –> needs anaerobic conditions for activity –> undergoes reductive bioactivation of its nitro group by ferredoxin –> forms cytotoxic products that interfere with nucleic acid synthesis –> damages DNA

Activity against anaerobic bacteria***

Question 15

Metronidazole clinical applications and PK

Answer 15

Activity against anaerobic bacteria***

• Pseudomembranous colitis (caused by anaerobe C.difficile)
  -Anaerobic or mixed abdominal infections
  Brain abscesses
  -H.pylori irradiation - in combination with other drugs

PK:

• can be given oral, IV, rectal or topical
• wide distribution - including CSF
• elimination = hepatic metabolism

Question 16

Metronidazole AE

Answer 16

Disulfarim-like reactions (avoid alcohol)

Headache, dark coloration of urine, metallic taste

Generally not advised in 1st trimester

Question 17

Polymyxin B MOA and antibacterial spectrum

Answer 17

Basic peptides

Activity against gram negatives only***

MOA –> act as cationic detergents –> attach to and disrupt bacterial cell membranes –> also bind to and inactivate endotoxins –> bactericidal

Question 18

Polymyxin B clinical applications and AE

Answer 18

Mostly topical treatment for infected superficial skin lesions –> few AE when used topically

When given systemically –> extremely nephrotoxic

Question 19

Nitrofurantoin MOA, antibacterial spectrum and clinical applications

Answer 19

Urinary antiseptic –> oral agents with antibacterial activity in urine but little or no systemic effect

Reduction of nitrofurantoin by bacteria in urine leads to formation of reactive intermediates that damage bacterial DNA –> bacteriostatic and bactericidal

Active against many gram negative and positive bacteria

Use limited to prophylaxis and treatment of lower UTIs

Question 20

Nitrofurantoin PK, AE, contraindications

Answer 20

Rapid elimination - only achieves adequate concentrations in urine

AE:

• Anorexia, nausea and vomiting
• Neuropathies, hemolytic anemia (G6PD deficient patients)
• signifiant renal insufficiency

Contraindicated in pregnancy at term (38-42 weeks only - can be given safely before this) and in infancy < 1 month due to risk of haemolytic anemia