Carbapenems and Monobactams

Question 1

Carbapenems

Answer 1

• Gains entry to Gram-negative organisms by specific
porin (OprD)

• Improved binding to PBPs
• Improved resistance to ß-lactamases
• provides broadest spectrum (“Gorillacillin”)

• Not hydrolyzed or only very slowly hydrolyzed by
most penicillinases and cephalosporinases (AmpC and
ESBLs)

• Is hydrolyzed by Ambler Class B ß-lactamases (Zn
containing) (carbapenemases)

Question 2

Imipenem / Cilastatin (Primaxin®)

Wide spectrum -

Answer 2

Wide spectrum

• Most Gram-positives

• excluding MRSA, MRSE
• Covers E. faecalis (not E. faecium)
• Unpredictable against PRSP

• Most Gram-negatives
- (including P. aeruginosa resistant to piperacillin,
ceftazidime; and most Acinetobacter)
- Retains activity against AmpC ß-lactamases and
ESBLs
- Neisseria gonorrhoeae, N. meningitidis

• Most anaerobes, except C. difficile
• Not active against Mycoplasma and Chlamydia

Question 3

Imipenem / Cilastatin (Primaxin®)

Answer 3

• imipenem hydrolyzed in renal tubules by
dehydropeptidase 1 producing toxic metabolites and ↓
renal levels of imipenem

• (cilastatin a dehydropeptidase inhibitor)

• t 1/2 imipenem 1 hr / Cilastatin 1 hr
• (4hr and 16 hr if CrCl < 10ml/min )

• q6h dosing

Question 4

Meropenem, Doripenem

Answer 4

• carbapenems similar to imipenem
• stable to dihydropeptidase 1 (DHP1)
• *more rapid entry into cell due to configuration
• high affinity for PBPs
• excellent stability to β-lactamases

Question 5

Ertapenem

Answer 5

Similar activity to meropenem/doripenem BUT NOT active against:

• P. aeruginosa
• Acinetobacter

• Long t 1/2 4hrs permits once daily dosing

Question 6

Carbapenem Resistance

Answer 6

• Change in Opr D

• Production of carbapenemase ß-lactamase (IMP-1,
NDM-1)

• Change in penicillin binding proteins
• Development of efflux pumps
• Often may be a combination of mechanisms

Question 7

Adverse Effects

Answer 7

• Carbapenems generally well tolerated

• many adverse effects similar to penicillins
  
  • rash or drug fever 2.7%, diarrhea 4%

• Cross reactivity of carbapenems with penicillins in
patients with reported penicillin allergy
- 4.3% for any hypersensitivity
- 2.4% for IgE mediated reaction ( Clin Infect Dis
2014;59:1113-22 )

• ** Seizures ** (1-2% for imipenem; 0.1-0.3% for others)
- renal failure, elderly, CNS lesions, history of seizures
- dosage reduction in renal failure
- imipenem not recommended for the treatment of
meningitis

• Nausea & vomiting (1%) if given too rapidly

• Rare - elevated liver enzymes, nephrotoxicity,
eosinophilia, +Coombs test, thrombocytopenia

Question 8

Drug Interactions

Answer 8

• Uncommon

• Using carbapenems with valproic acid results in very
subtherapeutic valproic acid levels

Question 9

Aztreonam

Answer 9

• High affinity for PBP3 of Gram-negatives
• Broad spectrum against Gram-negative bacteria
• No activity against Gram-positives or anaerobes

• Hydrolyzed by carbapenemases, ESBLs, and AmpC
β-lactamases when they are produced in large
amounts

• Most B. cepacia, S. maltophilia, and A. baumannii
are resistant

Question 10

Aztreonam

Adverse Effects

Answer 10

• skin rashes, ↑ serum transaminases x 2

• no skin rashes or anaphylaxis in 41 patients with
positive skin tests to penicillin

• no hematologic, G.I., renal, or neurotoxic effects
• widely distributed and crosses into CSF
• t 1/2 1.3 – 2 hr
• q6-12h dosing

Question 11

Sodium Content of Select Antibiotics

Answer 11

see slide 17

see slide 18