Carbapenem

See Also

Indications

Bacterial Coverage
1. Gram Positive Bacteria
  1. Streptococcus
  2. Staphylococcus Aureus (MSSA, but not MRSA)
2. Gram Negative Bacteria
  1. Enterobacteriaceae
  2. Listeria
3. Anaerobic Bacteria
  1. Enterococcus
  2. Bacteroides
  3. Pseudomonas (some species are resistant)
Conditions
1. ESBL Aerobic Gram Negative Rods
2. Multi-drug allergy patients (e.g. Penicillin and Cephalosporin allergies) with susceptible infections
3. Carbapenems are best reserved for critically ill patients with Severe or Complicated Infections
  1. Skin and Soft Tissue Infections
  2. Respiratory tract infections
  3. Intraabdominal infections
  4. Urogenital infections
  5. Endocarditis
  6. Sepsis
  7. Meningitis
  8. Anthrax (off-label use of Meropenem)

Mechanism
Carbapenems

See Beta Lactam
Broad-spectrum, Beta LactamAntibiotics with bactericidal activity
1. Carbapenems have the broadest spectrum of activity of any of the Beta Lactam Antibiotics (Penicillins, Cephalosporins)
Structure
1. See Beta Lactam
2. Fused Beta Lactam ring (provides for Beta Lactamase resistance)
3. Small size allows them to pass through Gram Negative Bacteria porin channels
Attaches to Penicillin binding Proteins (PRBs) on Bacterial cell wall (similar to other Beta Lactams)
1. Interferes with peptidoglycan synthesis (key component of the Bacterial cell wall)
2. Results in a weak Bacterial cell wall and Bacterial cell lysis
Carbapenems are stable against most Beta Lactamases
1. AmpC Beta Lactamases
2. Extended Spectrum Beta Lactamases
Carbapenems are a major cause of Antibiotic Resistance (related to their broadest spectrum of activity)
1. Serine Carbapenemases (e.g. Klebsiella producing Carbapenemases)
2. Metallo Beta-Lactamases
3. Oxacillinases (OXA-48)

Pharmacokinetics

All Carbapenems have poor oral absorption and are administered via Parenteral Route
Renal excretion (unchanged in urine)
Renal dihydropeptidase (DHP-1) breaks down Imipenem
1. Cilastin is added to Imipenem as a dihydropeptidase inhibitor
2. Other Carbapenems are not affected by dihydropeptidase

Adverse Effects

Gastrointestinal Effects (Diarrhea, Nausea or Vomiting)
1. More common with Imipenem-Cilastin
Skin Rash (including injection site reactions)
Pruritus
Liver Function Test abnormalities
1. Serum Aminotransferase increase is common
  1. Transient mild-moderate increases
  2. Most common with Imipenem-Cilastin
2. Cholestatic liver injury is rare
Antibiotic Drug Resistance
Clostridioides difficile
Seizures
1. Higher risk in elderly, underlying CNS disorders or Epilepsy, impaired Renal Function or high doses
2. Also seen with Imipenem-Cilastin (Primaxin) when combined with Ganciclovir
3. Carbapenems are associated with a higher risk of Seizure than other Beta Lactams
Thrombocytopenia
1. May oocur with Meropenem (Merrem) in patients with renal dysfunction

Drug Interactions

Valproic Acid
1. Significant decrease in Valproic Acid levels

Medications
Imipenem-Cilastin (Primaxin)

Unknown safety in pregnancy and Lactation
Background
1. Imipenem alone is rapidly inactivated by renal DHP-1
2. Cilastin is added to Imipenem to prolong its half life by slowing renal excretion
Dosing
1. Infuse over 20-30 minutes (over 40 to 60 minutes if dose >500 mg or Nausea occurs)
2. Adult
  1. High dose (intermediately sensitive Bacteria)
    1. CrlCl >=90 ml/min: 1000 mg IV/IM every 6 hours
    2. CrCl 60-90 ml/min: 750 mg IV/IM every 8 hours
  2. Low dose (suscepible Bacteria, empiric Febrile Neutropenia coverage)
    1. CrlCl >=90 ml/min: 500 mg every 6 hours or 1000 mg every 8 hours IV/IM
    2. CrCl 60-90 ml/min: 500 mg IV/IM every 6 hours
3. Child (3 months and older)
  1. Avoid in renal Impairment if weight <30 kg
  2. Dose: 15 to 25 mg/kg IV every 6 hours (maximum: 4 g/day)
4. Infant (birth to 3 months)
  1. Avoid in renal Impairment
  2. Age <1 week: 25 mg/kg every 12 hours
  3. Age 1 to 4 weeks: 25 mg/kg every 8 hours
  4. Age 1 to 3 months: 25 mg/kg every 6 hours
Indications: Complicated Infections
1. Avoid in Meningitis and other CNS Infections
2. Sepsis
3. Pneumonia
4. Endocarditis
5. Intraabdominal Infections
6. Bone and joint infections
7. Pelvic or gynecologic infections
8. Urinary Tract Infections
9. Skin and Soft Tissue Infections
10. Empiric Febrile Neutropenia coverage (not FDA approved)

Medications
Meropenem (Merrem)

Unknown safety in pregnancy and Lactation
Dosing
1. Adult (and child weighing >50 kg)
  1. High Dose: 2000 mg IV every 8 hours
    1. Indicated in Meningitis (not FDA approved)
  2. Medium Dose: 1000 mg IV every 8 hours
    1. Indicated in complicated intra-abdominal and Pseudomonas infections
    2. Also used in Hospital Acquired Pneumonia, complicated UTI, Malignant Otitis Externa (not FDA approved)
  3. Low Dose: 500 mg IV every 8 hours
    1. Indicated in Skin and Soft Tissue Infections
  4. Adjust dose in impaired Renal Function
    1. CrCl 10 to 25 ml/min: Give indicated dose every 12 hours
    2. CrCl 26 to 50 ml/min: Give 50% of indicated dose every 12 hours
    3. CrCl <10 ml/min: Give 50% of indicated dose every 24 hours
2. Child over age 3 months (and weight<50 kg)
  1. High Dose: 40 mg/kg IV every 8 hours
    1. Indicated in Meningitis
  2. Medium Dose: 20 mg/kg IV every 8 hours
    1. Indicated in complicated intra-abdominal and Pseudomonas infections
  3. Low Dose: 10 mg/kg IV every 8 hours
    1. Indicated in Skin and Soft Tissue Infections
3. Infant age 2 weeks to 3 months (for complicated intra-abdominal infection)
  1. Gestational age <32 weeks: 20 mg/kg IV every 8 hours
  2. Gestational age >32 weeks: 30 mg/kg IV every 8 hours
4. Infant age <2 weeks (for complicated intra-abdominal infection)
  1. Gestational age <32 weeks: 20 mg/kg IV every 12 hours
  2. Gestational age >32 weeks: 20 mg/kg IV every 8 hours

Medications
Ertapenem (Invanz)

Administration
1. Administer IV doses over 30 minutes (and do not combine with dextrose solutions)
2. Dilute IM doses with Lidocaine (if not allergic)
Dosing
1. FDA approved duration up to 14 days IV and up to 7 days IM
2. Adult (and age >12 years)
  1. Dose: 1 g IM/IV every 24 hours (or 1 hour prior to surgical incision)
  2. Renal Dosing
    1. CrCl <30 ml/min: 500 mg IV every 24 hours
    2. Hemodialysis: 500 mg IV every 24 hours
      1. Give additional 150 mg after Dialysis if dose within 6 hours prior to Dialysis
3. Child (3 months to 12 years)
  1. Dose: 15 mg/kg IV or IM every 12 hours (max total daily dose: 1 gram/day)
Indications: Complicated Infections
1. Avoid in Pseudomonas and Acinetobacter infections (inactive)
2. Community Acquired Pneumonia
3. Diabetic Foot Infections
4. Intraabdominal and Pelvis Infections
5. Skin and Soft Tissue Infections
6. Urinary Tract Infections
Safety
1. Unknown safety in pregnancy
2. Safe in Lactation

Medications
Doripenem (Doribax)

Adult Dosing
1. Standard Dose: 500 mg IV every 8 hours for 5 to 14 days
2. Renal Dosing
  1. CrCl 30-50 ml/min: 250 mg IV every 8 hours
  2. CrCl 10-30 ml/min: 250 mg IV every 12 hours
Indications
1. Avoid in Bacterial Pneumonia (increased mortality)
2. Primarily used in severe aerobic Gram-Negative Bacterial infections (esp. Pyelonephritis and intraabdominal infections)
3. May have greater Pseudomonas activity than other Carbapenems
Safety
1. Pregnancy Category B
2. Unknown safety in Lactation

Medications
Combinations

Recarbio (Imipenem-Cilastin AND Relebactam)
1. Indicated in complicated UTI or intra-abdominal infections where other options have been exhausted
2. Unknown safety in pregnancy and Lactation
3. Adult dosing
  1. CrCl >=90 ml/min: 1.25 g IV every 6 hours administered over 30 minutes
  2. CrCl 60 to 89 ml/min: 1 g IV every 6 hours administered over 30 minutes
  3. CrCl 30 to 59 ml/min: 0.75 g IV every 6 hours administered over 30 minutes
  4. CrCl 15 to 29 ml/min: 0.5 g IV every 6 hours administered over 30 minutes
  5. CrCl <15 ml/min: Avoid unless Hemodialysis planned for within 48 hours
    1. Administer after Hemodialysis
Vabomere (Meropenem AND Vaborbactam)
1. Indicated in complicated UTI where other options have been exhausted
2. Adult dosing
  1. CrCl >=50 ml/min: 4 g IV every 8 hours administered over 3 hours
  2. CrCl 30 to 49 ml/min: 2 g IV every 8 hours administered over 3 hours
  3. CrCl 15 to 29 ml/min: 2 g IV every 12 hours administered over 3 hours
  4. CrCl <15 ml/min: 1 g IV every 12 hours administered over 3 hours
    1. Administer after Hemodialysis

Medications
Oral Carbapenems

Sulopenem Etzadroxil and Probenecid

References

LiverTox (2017), accessed online 1/2/2023
1. https://www.ncbi.nlm.nih.gov/books/NBK548705/
Hamilton (2020) Tarascon Pharmacopeia
(2012) Presc Lett, Resource #231205, Comparison of Carbapenem Antibiotics
Zhanel (2007) Drugs: 67(7): 1027-52 [PubMed]