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

Penicillins
Beta-lactamase inhibitors. Combination drugs

Acquired RESISTANCE OF MICROORGANISMS to Antibiotics, which has reached catastrophic proportions in recent years, is in the overwhelming majority of cases caused by The production of beta-lactamase Enzymes by microbial Cells, which destroy antibacterial agents. Depending on their substrate Specificity (The ability to preferentially hydrolyze a certain Class of antibiotics), beta-lactamases are classified into penicillinases, cephalosporinases, carbapenemases, etc. Depending on the localization of the genes encoding beta-lactamase synthesis, they are divided into chromosomal (genes are part of the microbial Cell chromosome) and plasmid (genes are located in Plasmids, which are additional DNA molecules not linked to the chromosome). Chromosomal beta-lactamases are usually named after the species of microorganism that produces them. Codes (TEM-1, -2, SHV, etc.) are used to designate plasmid enzymes. TEM-1, -2, and SHV are extended-spectrum beta-lactamases capable of destroying Penicillins, F I, F II, and F III.

Certain substances of natural and synthetic origin that possess negligible intrinsic antibacterial activity are capable of irreversibly binding to beta-lactamases, subsequently inhibiting their activity. These substances are known as beta-lactamase inhibitors. They include the natural compound clavulanic acid and the synthetic penicillanic acid sulfones, sulbactam and tazobactam. The addition of beta-lactamase inhibitors to antibacterial drugs enables the latter to fully exert their effects on microorganisms and broadens THE SPECTRUM OF their antimicrobial activity by targeting beta-lactamase-producing bacterial strains.

Clavulanic acid inhibits The activity of ß-lactamases in numerous microorganisms, including Haemophilus influenzae, Escherichia coli, Proteus, Klebsiella (K. pneumoniae), Staphylococcus aureus and Staphylococcus epidermidis, certain Bacteroides, gonococci, and Legionella; however, it has little to no inhibitory effect on the ß-lactamases of members of the Pseudomonadaceae family and most Enterobacteriaceae, including the genus Citrobacter. Clavulanic acid is well absorbed from the gastrointestinal tract, reaches maximum Blood concentration one hour after administration, has a T_1/2 of 1 hour, and penetrates the blood-Brain barrier poorly.

Sulbactam, alongside minimal intrinsic antibacterial activity, has the ability to bind plasmid and certain chromosomal beta-lactamases, including extended-spectrum ones. Furthermore, sulbactam exhibits high in vitro activity against Acinetobacter baumannii, a pathogen that frequently causes severe infectious processes in ICUs.

Modern inhibitor-protected beta-lactam antibiotics include amoxicillin/clavulanate (Amoxiclav, Enhancin, Augmentin), ampicillin/sulbactam (sultamicillin, Unasyn), ticarcillin/clavulanate (Timentin), piperacillin/tazobactam, and cefoperazone/sulbactam (Sulperazon).

Ampicillin/sulbactam, amoxicillin/clavulanate, and cefoperazone/sulbactam are registered in Ukraine.

Amoxicillin/clavulanate (co-amoxiclav, Augmentin, Amoxiclav, Amoklan Forte, Enhancin, Curam) is a combination drug containing amoxicillin and potassium clavulanate. It is prescribed for the Treatment of otitis media, sinusitis, Lower Respiratory Tract infections, Skin, soft tissue, and Urinary Tract infections, pelvic Inflammatory Diseases, Osteomyelitis, septicemia, and Peritonitis. It is administered orally and intravenously (it should not be mixed in the same syringe with Aminoglycosides, as the latter become inactivated).

The combination drug of ampicillin and sulbactam is called sultamicillin (Unasyn) (available for intravenous administration and oral use). The addition of sulbactam significantly enhances the antibacterial activity of ampicillin against Acinetobacter, Proteus, Klebsiella pneumoniae, Enterobacter, staphylococci (Staphylococcus aureus and Staphylococcus epidermidis), and streptococci (S. viridans, S. pyogenes, S. pneumoniae). A comparative characterization of the spectrum of activity of ampicillin/sulbactam and other beta-lactam antibiotics is presented in Table 13.

Table 13. Infection Pathogens: ß-Lactamase Production and Susceptibility to ß-Lactam Antibiotics (I.H. Berezniakov, 2001)

Note: x - the given antibiotic is hydrolyzed by the corresponding enzyme.

Ampicillin/sulbactam is used for ENT infections, upper and lower respiratory tract infections, Genitourinary system infections, intra-abdominal infections (peritonitis, cholecystitis); skin, soft tissue, bone, and joint infections; Sepsis; as well as gonococcal and anaerobic infections.

Timentin is a combination of ticarcillin and clavulanic acid, active against the majority of Gram-positive, Gram-negative, and anaerobic microorganisms. Its activity against P. aeruginosa increases when Timentin is combined with aminoglycosides. It is administered intravenously for Bronchitis, Pneumonia; urinary tract, skin, soft tissue, bone, joint, and pelvic organ infections; abdominal infections, and sepsis.

Specifically, in surgical practice, it is advisable to use Timentin in the following cases: secondary peritonitis of any origin; infected pancreatic necrosis and its purulent-septic complications; surgical infections of other localizations, particularly with clinical signs of sepsis (aerobic-anaerobic infections, Diabetic FOOT, phlegmons, etc.); nosocomial pneumonia, especially in patients on mechanical ventilation (ventilator-associated pneumonia); postoperative peritonitis and nosocomial pneumonia with a high risk of Pseudomonas infection, in which case it is combined with aminoglycosides (netilmicin, amikacin); and Infections caused by S. maltophilia.

The aforementioned drugs (Augmentin, Unasyn, Timentin) are frequently referred to as "protected" ("shielded") penicillins.

Relatively recently, the thus far only "protected" cephalosporin has been developed – Sulperazon, which consists of a third-generation cephalosporin, cefoperazone, and a beta-lactamase inhibitor, sulbactam.

Spectrum of antibacterial activity of Sulperazon.

The drug is highly active against a broad spectrum of microorganisms: 1) Gram-positive Bacteria – S. aureus, including penicillinase-producing and non-producing strains, S. epidermidis, S. pneumoniae, S. pyogenes (group A beta-hemolytic streptococci), S. agalactiae (group B beta-hemolytic streptococci), the majority of beta-hemolytic Streptococcus spp. strains, E. faecalis;

2) Gram-negative bacteria – E. coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., H. influenzae, P. mirabilis, M. morganii, P. rettgeri, Providencia spp., Serratia spp. (including S. marcescens), Salmonella spp., Shigella spp., P. aeruginosa, A. calcoaceticus, N. gonorrhoeae, N. meningitidis, B. pertussis, Y. enterocolitica;

3) anaerobic microorganisms – B. fragilis, Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Clostridium spp., etc. Sulperazon is highly resistant to various beta-lactamases, including extended-spectrum ones (only Sulperazon and carbapenems are active against microorganisms producing these enzymes).

Indications for The Use of Sulperazon:

1. Lower respiratory tract infections: bronchitis, pneumonia, empyema, and lung abscess.

2. ENT infections: pharyngitis, tonsillitis, sinusitis, acute otitis media.

3. Abdominal infections: peritonitis, cholecystitis, cholangitis, etc.

4. Pelvic and urinary tract infections: endometritis, prostatitis, Pyelonephritis, Gonorrhea, cystitis, vulvovaginitis.

5. Skin and soft tissue infections: Pyoderma, furuncle, carbuncle, abscess, lymphadenitis, lymphangitis.

6. Bone and joint infections, including osteomyelitis.

7. Sepsis, meningitis.

8. It can be used for the Prevention of bacterial complications following surgical interventions (in abdominal and pelvic surgery, orthopedics, and cardiac surgery).

The drug is effective in the most severe forms of community-acquired and nosocomial infections caused by microbial associations, including Primary and secondary peritonitis of any origin; infected pancreatic necrosis and its purulent-septic complications; surgical infections of other locations, sepsis, diabetic foot, Phlegmon, and nosocomial pneumonia, including ventilator-associated pneumonia. In cases with a high risk of Pseudomonas aeruginosa infection, it is combined with aminoglycosides (netilmicin, amikacin).

Sulperazone is administered intramuscularly or intravenously at a dose of 2–4 g per day (in severe infections, the daily dose may be increased up to 8 g); the interval between injections is 12 hours (6–12 hours in children).

Adverse reactions associated with the use of Augmentin, Unasyn, Timentin, and Sulperazone are attributed to ampicillin, amoxicillin, ticarcillin, and cefoperazone, which are the components of these drugs.

The CHARACTERISTICS OF THE spectrum of activity of Semisynthetic penicillins are summarized in Figure 2.

Fig. 2. Features of the spectrum of activity of semisynthetic penicillins (V.P. Pishak, I.I. Zamorskyi, 2001).