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

Penicillins
Biosynthetic Penicillins

Biosynthetic (natural) Penicillins include the sodium, potassium, and procaine salts of benzylpenicillin, phenoxymethylpenicillin, benzathine benzylpenicillin (bicillin-1), bicillin-3, and bicillin-5. Bicillin-1 is the dibenzylethylenediamine salt of benzylpenicillin. Bicillin-3 is a 1:1:1 mixture of bicillin-1, sodium benzylpenicillin, and procaine benzylpenicillin (BP). Bicillin-5 is a 1:4 mixture of procaine BP and bicillin-1. With the exception of phenoxymethylpenicillin, all of these compounds are acid-labile and therefore administered parenterally. Phenoxymethylpenicillin is acid-stable and its dosage forms are administered exclusively via the oral route.

These Antibiotics are degraded by beta-lactamases produced by resistant Gram-positive and Gram-negative Bacteria.

All biosynthetic penicillins share an identical spectrum of activity, the primary feature of which is high potency against Gram-positive and Gram-negative cocci, as well as certain Gram-positive bacteria (Table 5).

Class="center">Table 5. Antibacterial activity of biosynthetic penicillins*

Notes: MIC – minimum inhibitory concentration, defined as The amount of antibiotic that inhibits the growth of 90% of pathogen strains in vitro; * – this table excludes most species of enterobacteria, pseudomonads, rickettsiae, Mycoplasmas, Viruses, and Fungi, which possess a high natural resistance to benzylpenicillin; ** – clinical strains with significantly higher MIC values for the antibiotic have been isolated.

Benzylpenicillin (BP) is the drug of choice for Infections caused by susceptible strains of Neisseria meningitidis (meningitis), the causative agents of gas gangrene, tetanus, Syphilis, leptospirosis, and actinomycosis. When staphylococci are highly susceptible to BP and phenoxymethylpenicillin (which requires laboratory confirmation!), these agents are also preferred. Most strains of S. pneumoniae (pneumococcus) remain susceptible to BP (although its resistance to penicillin reaches 60–70% in certain regions), making it one of the most effective antibiotics for treating pneumococcal (lobar) Pneumonia in such cases. Other streptococci, particularly S. pyogenes (group A ß-hemolytic streptococci), also retain high susceptibility to BP. More than 90% of Staphylococcus spp. strains are resistant to penicillin. N. meningitidis rarely produces beta-lactamases, which is why penicillin remains relevant in the Treatment of meningococcal infections today. This is further supported by the fact that in meningitis, the concentration of BP in the CEREBROSPINAL FLUID reaches 50% of its serum level.

It must be taken into account that prolonged-release formulations of BP (benzathine benzylpenicillin, bicillins-3 and -5, and procaine BP) and phenoxymethylpenicillin do not achieve tissue concentrations sufficient to eradicate severe infections (pneumonia, Sepsis, meningitis) and therefore should not be used in these clinical scenarios.

Recommended dosage regimens for natural penicillins are presented in Table 6.

Table 6. Recommended dosage regimens for natural penicillins

Notes: * – intravenous administration is reserved exclusively for the sodium salt of BP; ** – not recommended for children under 1 year of age.

Indications for the prescription of BP and its salts are determined by the characteristics of their spectrum of activity.

BP (potassium and sodium salts) is indicated for the treatment of infections caused by susceptible microorganisms, predominantly Gram-positive bacteria and Gram-negative cocci, taking into account current trends in the spread of resistant strains. It is used in sepsis, infective endocarditis, septic Arthritis, respiratory tract infections (especially pneumonia), wound and burn infections (During the first days following burn trauma), as well as Skin and soft tissue infections. It is indicated for infections caused by S. pyogenes, such as streptococcal tonsillitis, scarlet fever, and erysipelas. Given the high activity of BP against anaerobic cocci, the antibiotic is effective in purulent processes of the HEAD and Neck (phlegmons, carbuncles), among others. It is utilized in the treatment and Prevention of clostridial infections, leptospirosis, and actinomycosis. It remains the drug of choice for the treatment of syphilis (provided the pathogen is susceptible to BP). For infective endocarditis, BP is combined with gentamicin; for lung abscesses, with metronidazole or ciprofloxacin; and for infections caused by E. faecalis, with gentamicin.

Phenoxymethylpenicillin is used for the same indications as BP in moderately severe infections or for follow-up therapy after completing a course of parenteral treatment.

Bicillins (-1, -3, -5) are used for the seasonal prophylaxis of rheumatic fever and the treatment of syphilis in accordance with current methodological guidelines and instructions. Although BP was previously widely used to treat Gonorrhea, it has now been superseded by third-generation Cephalosporins and fluoroquinolones.

The dosage of natural penicillins varies depending on the severity, type, and localization of the infection focus. Specifically, streptococcal and pneumococcal infections are treated with low doses of BP (1–4 million IU daily), lung abscesses and enterococcal infections require up to 10 million IU, while gas gangrene, meningitis, and endocarditis require 20–30 million IU daily.

Biosynthetic penicillins have low toxicity and are well tolerated by patients. However, adverse effects and complications associated with antibiotic therapy may occasionally occur.

Allergic reactions are the most frequent, occurring in 10% of patients. They present as various types of skin rashes, including urticaria, which may be accompanied by fever and lymphadenopathy; angioedema occurs rarely. Urticaria typically appears 7–10 days after starting BP treatment. Hypersensitivity reactions can also develop following the very first administration of BP, resulting from prior sensitization (due to past penicillin therapy, consumption of foods containing trace amounts of antibiotics, Blood transfusions containing traces of BP, occupational exposure among medical personnel or pharmacists, etc.). Allergenic properties are exhibited not only by the BP molecule itself, but also by its degradation products (6-aminopenicillanic acid, penicilloyl, penicilloic acid, etc.). Therefore, patients must be administered exclusively freshly prepared BP solutions, as even brief storage leads to partial degradation of BP into substances with significantly stronger allergenic properties than the parent molecule.

To prevent allergic reactions, a meticulous medical history must be obtained from the patient. If the patient has a history of an allergic reaction to penicillins, the administration of these antibiotics is strictly contraindicated.

Skin testing is occasionally performed by intradermal injection of 10,000–20,000 IU of BP. This Procedure can provoke serious allergic reactions, including anaphylactic Shock; conversely, a negative test result does not guarantee the absence of allergic reactions, and the test itself contributes to patient sensitization.

Safe alternatives are in vitro tests, such as serological tests (which detect only IgM and IgG), radioimmunoassays (IgG and IgE), and others.

It is crucial to bear in mind the possibility of cross-allergy among all beta-lactam antibiotics. Notably, in the presence of penicillin hypersensitivity, allergic reactions to cephalosporins occur in 10% of patients. If a patient has a history of severe allergic reactions to penicillin (anaphylactic shock, bronchospasm, angioedema), the administration of other beta-lactam antibiotics is contraindicated. If the patient experienced only mild reactions to penicillin in the past (rhinitis, urticaria, eosinophilia, etc.), cephalosporins or carbapenems may be administered under absolute clinical necessity. In such cases, the physician must be fully equipped to provide comprehensive emergency care should an allergic reaction develop.

Penicillin administration can occasionally trigger an endotoxic shock-like reaction. In the early era of antibiotic therapy, this phenomenon was described as the Jarisch-Herxheimer reaction, which occurred in syphilis patients upon receiving BP due to the release of endotoxins (lipopolysaccharides) resulting from the treponemicidal action of the antibiotic.

The administration of sodium and potassium salts of BP can cause electrolyte imbalances. Every 1,000,000 IU of these BP preparations contains approximately 0.039 g of sodium and 0.066 g of potassium, respectively. Such sodium loads are undesirable in patients with Heart Failure. In heart failure cases, the potassium salt is preferred, but only if renal function is intact, as its use in patients with renal impairment can precipitate dangerous hyperkalemia.

Massive doses of BP, especially in patients with impaired renal function, can trigger neurotoxic reactions, including encephalopathy with various clinical manifestations such as hyperreflexia, visual and auditory hallucinations, myoclonic seizures, and coma. These reactions may occur even with moderate doses of BP in the treatment of meningitis due to increased blood-Brain barrier (BBB) permeability (normally, BP penetrates the BBB poorly when the Meninges are intact). Encephalopathy can also develop following intrathecal administration (direct injection into the subarachnoid space), a route exclusively used for the sodium salt of BP. Consequently, the daily dose of BP for intrathecal administration should not exceed 10,000 IU in adults and 5,000 IU in children.

Other adverse reactions include interstitial nephritis (associated with intravenous administration of 20–40 million IU of BP daily), hemolytic anemia, neutropenia (at doses exceeding 10 million IU of BP daily), thrombocytopenia, and others. Given that penicillins, and BP in particular, are time-dependent antibiotics, modern therapeutic efficacy is best achieved not by administering megadoses, but by increasing the dosing frequency—in the case of BP, often via repeated intravenous drip infusions. Therefore, the aforementioned adverse effects associated with daily penicillin doses exceeding 10 million IU can generally be considered negligible under these regimens.

Drug Interactions. The results of interactions between biosynthetic penicillins and other medicinal products are presented in Table 7.

Table 7. Interactions of biosynthetic penicillins with other medicinal products (V.P. Yakovlev, S.V. Yakovlev, 2003; with amendments)