Antibiotics (Properties, Administration, Interactions) - Posokhova K.A., Viktorov O.P. 2005

Penicillins
Carbapenems (Thienamycins)

Carbapenem Antibiotics include imipenem, meropenem, ertapenem, and panipenem. Among all beta-lactam antibiotics, they possess the broadest spectrum of antibacterial activity.

Imipenem. The MECHANISM OF ACTION of the drug, similar to other beta-lactam antibiotics, involves binding to Enzymes responsible for Cell wall synthesis, namely penicillin-binding Proteins (PBPs). Imipenem is the unique beta-lactam antibiotic that binds to all PBPs, with a particularly high affinity for PBP2. Given that a bacterial cell contains only about 20 molecules of this enzyme (unlike PBP1 and PBP3, which number up to 1.5–2 thousand), it becomes clear why microorganisms are eradicated so rapidly under METABOLISM/18.html">The Influence of imipenem.

Today, imipenem stands as one of the broadest-spectrum antibiotics, covering the majority of aerobic and anaerobic Gram-positive and Gram-negative Bacteria, including most beta-lactamase-producing species. It exerts robust activity against most members of Enterobacteriaceae (E. coli, Proteus spp., K. pneumoniae, Enterobacter spp., Serratia spp., Citrobacter spp.), H. influenzae, Acinetobacter spp., S. pneumoniae, S. pyogenes, E. faecalis, S. aureus, S. epidermidis, and the majority of anaerobes (B. fragilis, C. perfringens, Peptostreptococcus spp.).

Certain methicillin- and oxacillin-resistant strains of S. aureus, specific group D streptococci (E. faecium), Corynebacterium spp., Mycobacterium spp., Flavobacterium spp., C. difficile, St. maltophilia, Chlamydia spp., and Mycoplasma spp. are resistant to imipenem. Although imipenem is not classified as an anti-pseudomonal agent, approximately 80% of Pseudomonas aeruginosa strains remain susceptible to it.

Imipenem and amikacin demonstrate a synergistic effect against P. aeruginosa strains that are resistant to either imipenem or amikacin alone. The anaerobic activity of imipenem is comparable to that of metronidazole and meropenem, while surpassing that of cefoxitin and clindamycin.

The post-antibiotic effect (PAE) of imipenem against Gram-negative bacteria is of significant importance. It means that even after certain antibiotics disappear from the Blood or Tissues, the surviving bacteria remain unable to multiply for several hours. While all other beta-lactam antibiotics exhibit a PAE solely against Gram-positive bacteria, imipenem displays a PAE against E. coli, P. aeruginosa, E. cloacae, and K. pneumoniae.

Pharmacokinetics. The small size of the imipenem molecule, combined with the presence of both positively and negatively charged regions, ensures its exceptionally rapid cellular penetration. The antibiotic is metabolized in the renal tubular epithelial Cells by dehydropeptidase-1, an enzyme that hinders its excretion in the urine (which is precisely what drives the nephrotoxicity of the drug at high doses). Clinically, imipenem is used in a 1:1 combination with cilastatin, a substance lacking antibacterial activity but inhibiting the aforementioned dipeptidase. This inhibits imipenem's biotransformation and nephrotoxicity while accelerating its urinary excretion. This combination drug is known as Tienam or Primaxin. The serum half-life (T_1/2) of imipenem is approximately 1 hour.

Indications for imipenem include monotherapy for septicemia, neutropenic fever, endocarditis; severe intra-abdominal, respiratory, genitourinary, and gynecological infections; as well as Skin, soft tissue, bone, and joint infections. The drug demonstrates high efficacy in treating nosocomial infections.

The exceptionally broad spectrum of antimicrobial activity and low level of microbial resistance make it feasible to use imipenem as empirical antibacterial monotherapy, including for severe infections in intensive care units. Indications for use and dosing regimens for imipenem are presented in Table 18.

In most cases, imipenem is administered intravenously (via a 30–60 minute infusion) at a total daily dose of 2–3 g, divided into 3–4 administrations. For intramuscular administration, the daily dose is 1.0–1.5 g (with an injection interval of up to 12 hours). It belongs to the Class of time-dependent antibiotics (see Table 1).

Adverse effects associated with imipenem may include weakness, tremor, encephalopathy with seizure activity, arterial hypotension, nausea, vomiting, superinfections (including Candida species), diarrhea, pseudomembranous colitis, phlebitis, thrombophlebitis (upon intravenous administration), thrombocytosis, eosinophilia, and elevated serum Liver enzymes. Mixing imipenem-cilastatin with Aminoglycosides in the same syringe must be avoided due to physical incompatibility. Overall, imipenem is well tolerated. Reported side effects occur in 0.1–3.0% of cases, while dysbiosis phenomena are observed in 16% of patients. Intramuscular administration is less frequently complicated than intravenous infusion.

Table 18. Indications and Dosing Regimens for Imipenem

Note: * - intramuscular administration of imipenem is used for moderately severe infections; ** - imipenem is combined with parenteral macrolides; *** - imipenem is combined with amikacin.

Other carbapenems (meropenem, ertapenem, panipenem) exhibit similar antibacterial activity, although meropenem is more potent against members of the Enterobacteriaceae family. Strains with a meropenem MIC of < 4 mg/L are classified as susceptible, those with an MIC of 8 mg/L as intermediate, and those with > 16 mg/L as resistant. Since meropenem is not hydrolyzed by renal dehydropeptidase, it does not require co-administration with cilastatin.

Meropenem is the drug of choice for treating nosocomial meningitis, given that—unlike Tienam—it does not lower the seizure threshold, does not provoke convulsions, and can be safely administered to patients with underlying Central Nervous system pathology. Effective Treatment of meningitis necessitates the prompt removal of foreign bodies (drains, shunts, catheters, etc.). Combined parenteral administration of meropenem with intrathecal polymyxin B has also been recommended. Meropenem is administered intravenously via bolus injection or infusion (over 15–30 minutes).