Carboxypenicillins: structural features and spectrum
These are broad-spectrum antibiotics that are inferior in potency to aminopenicillins. Their main chemical feature is the presence of a carboxyl group in the side chain.
This structure gives the drugs a negative charge, which ensures resistance to certain chromosomal bacterial β-lactamases. However, due to the absence of an amino group, the antibiotic molecules diffuse poorly through the porin channels of gram-negative microorganisms. That is why high doses are required to create an effective intracellular concentration.
Spectrum of activity:
- Susceptible: many members of the family Enterobacteriaceae, as well as Pseudomonas and Enterobacter.
- Resistant (gaps in spectrum): Klebsiella spp., Proteus vulgaris, C. diversus, Enterococcus faecalis.
Characteristics of carboxypenicillins
The main indication for prescribing these drugs is infections caused by Pseudomonas aeruginosa.
- Carbenicillin
A derivative of 6-aminopenicillanic acid. The drug is destroyed in the acidic environment of the stomach and is poorly absorbed in the gastrointestinal tract, so it is administered exclusively parenterally (intramuscularly or intravenously) 4–6 times a day. It does not cross the blood-brain barrier (BBB), binds to plasma proteins by approximately 50%, and is excreted mainly by the kidneys. It is inactivated by β-lactamases.
In addition to allergic reactions typical of penicillins (anaphylactic shock, urticaria, angioedema), carbenicillin has specific toxic effects:
- Hypernatremia: the drug is available as a disodium salt, which creates an excess sodium load and increases the risk of heart failure.
- Hypokalemia: potassium cations are excreted in the distal renal tubules along with the unabsorbable anion of the antibiotic.
- Bleeding: occurs due to decreased platelet aggregation.
- Carfecillin
It is a phenyl ester of carbenicillin. Its main advantage is acid stability and good absorption in the gastrointestinal tract. This allows the drug to be administered orally 3 times a day.
- Ticarcillin
It surpasses carbenicillin in activity, especially against Pseudomonas aeruginosa. Like carbenicillin, it is poorly absorbed in the gastrointestinal tract, so it is prescribed parenterally 4–6 times a day.
Ureidopenicillins
This group includes azlocillin, piperacillin, and mezlocillin.
Their spectrum of activity is largely similar to that of carboxypenicillins, but they have several important advantages:
- 4–8 times more active against Pseudomonas aeruginosa.
- Possess higher activity against Klebsiella and gram-positive flora.
Like carboxypenicillins, they are destroyed by staphylococcal and gram-negative bacterial β-lactamases. Administered parenterally only.
Clinical use and comparative activity
Both groups are combined based on their main clinical advantage—the ability to eradicate Pseudomonas aeruginosa. Target pathogens also include Proteus and E. coli.
Main indications for prescription:
- Sepsis.
- Wound infections.
- Pneumonia.
- Urinary tract infections.
- Intra-abdominal and pelvic infections.
Activity ranking against Pseudomonas aeruginosa (in descending order of efficacy):
- Azlocillin and Piperacillin (highest activity).
- Mezlocillin and Ticarcillin (moderate activity).
- Carbenicillin (lowest activity in the series).
Briefly: answers to topical questions
What are the pharmacokinetic parameters of carbenicillin?
The pharmacokinetic parameters of carbenicillin are characterized by poor gastrointestinal absorption and predominant renal excretion.
- Absorption — the drug is acid-labile and destroyed in the stomach, so it is administered parenterally (intramuscularly or intravenously).
- Distribution — the antibiotic does not cross the blood-brain barrier, and its plasma protein binding is about 50%.
- Elimination — is carried out predominantly by the kidneys.
- Dosing regimen — the drug is administered 4–6 times a day.
Which beta-lactamase inhibitors are antipseudomonal penicillins combined with?
Antipseudomonal penicillins are combined with $\beta$-lactamase inhibitors such as clavulanic acid and tazobactam.
The pharmaceutical industry produces the following fixed combinations:
- Piperacillin — combined with tazobactam; this combination has the widest spectrum of antimicrobial activity.
- Ticarcillin — combined with clavulanic acid.
The inhibitors themselves have weak antibacterial properties, but they bind to bacterial enzymes and irreversibly inactivate them, preventing the hydrolysis of the primary antibiotic.
What is the mechanism of antibacterial action of antipseudomonal penicillins at the cellular level?
The mechanism of action of antipseudomonal penicillins is based on the disruption of bacterial cell wall synthesis and is bactericidal in nature.
The process includes the following stages:
- Enzyme inhibition — the antibiotic binds to penicillin-binding proteins and inhibits transpeptidase.
- Synthesis disruption — the formation of functional peptidoglycan on the outer surface of the cytoplasmic membrane is blocked.
- Autolysis activation — an excess of peptidoglycan precursors serves as a signal to trigger the self-destruction system via autolytic enzymes.
- Lysis — decreased cell wall strength and destruction of peptidoglycan lead to bacterial cell death.
To memorize the activity ranking against Pseudomonas aeruginosa (from strongest to weakest), use the mnemonic: "Active Person Makes Time Carefully". Azlocillin = Piperacillin > Mezlocillin = Ticarcillin > Carbenicillin.
Class and exam questions
Why are carboxypenicillins prescribed in very high doses?
Due to the absence of an amino group in their chemical structure, they penetrate poorly through bacterial porin channels. To achieve the required intracellular concentration, the drug dose must be significantly increased.
Can these antibiotics be taken in tablet form?
Most drugs in the group (carbenicillin, ticarcillin, all ureidopenicillins) are destroyed in the stomach or poorly absorbed, so they are administered parenterally. An exception is carfecillin, which is acid-stable and administered orally.
How does carbenicillin affect blood electrolyte levels?
It is available as a disodium salt, which can lead to hypernatremia (dangerous in heart failure). In addition, it is excreted by the kidneys as a non-reabsorbable anion, "dragging" potassium along with it in the distal tubules, which causes hypokalemia.
What else to study on this topic
- Mechanisms of bacterial resistance to $\beta$-lactam antibiotics
- Structural features of porin channels in Gram-negative bacteria
- Pharmacokinetics of penicillins: plasma protein binding and excretion pathways
- Pathogenesis of allergic reactions to $\beta$-lactams
- Effect of antibiotics on platelet aggregation
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