Bacteria that produce extended spectrum beta-lactamase (ESBL)

β-Lactams were the first antibiotics to be used in medicine, and essentially gave rise to the era of modern antibacterial chemotherapy. The first antibiotic was benzylpenicillin, which began to be used in clinical practice in 1941. The first semi-synthetic penicillins were synthesized in the late 50s, cephalosporins in the early 60s, and carbapenems in the mid-80s.

Over the years, more than 70 antibiotics of this class have been synthesized, but currently about 30 drugs are actually used in medicine. Over more than half a century of history, many b-lactams have been excluded from practical use, but the remaining ones retain leading positions in many areas of antimicrobial chemotherapy, although their positioning in some infectious diseases has changed. However, to date, antibiotics of this class are the most frequently prescribed both in outpatient practice and in hospital. This review presents a modern view of the place of b-lactam antibiotics in antimicrobial chemotherapy, focusing on the characteristics of antimicrobial activity and resistance of individual drugs and indicating their preferential positioning in treatment regimens (drugs of choice or 1st line). An attempt has also been made to present a balanced comparative description of individual drugs that are similar in their spectrum of antimicrobial activity.

b-Lactams (b-lactam antibiotics) include a large group of drugs that have a b-lactam ring. These include penicillins, cephalosporins, carbapenems, and monobactams. A separate group consists of combination drugs consisting of a b-lactam antibiotic (penicillins, cephalosporins) and a b-lactamase inhibitor (clavulanic acid, sulbactam, tazobactam) and are called “inhibitor-protected b-lactams”.

Antimicrobial activity

b-Lactams have a wide spectrum of antimicrobial action, including gram-positive and gram-negative microorganisms. Mycoplasmas are naturally resistant to b-lactams. b-Lactams do not act on microorganisms localized inside cells into which the drugs do not penetrate well (chlamydia, rickettsia, legionella, brucella, etc.). Most b-lactams have no effect on anaerobes. Methicillin-resistant staphylococci are also resistant to all b-lactams.

Data on the natural activity of b-lactams against clinically significant microorganisms and indicative information on their acquired resistance to individual antibiotics are given in the table.

Beta-lactams

The drugs of choice for the treatment of staphylococcal infections (caused by both Staphylococcus aureus and coagulase-negative staphylococci) are beta-lactam antibiotics, therefore, it is first necessary to determine the sensitivity of staphylococci to these drugs.

Resistance of staphylococci to beta-lactam ABPs is associated either with the production of beta-lactamases or with the presence of an additional penicillin-binding protein, PSB2a. Identifying and differentiating these two resistance mechanisms makes it possible to reliably predict the activity of all beta-lactam antibiotics without directly assessing sensitivity to each of these drugs. In this case, it is necessary to take into account the following patterns:

• Strains of Staphylococcus spp., lacking resistance mechanisms, are sensitive to all beta-lactam ALDs.
• Beta-lactamases (penicillinases) of Staphylococcus spp. capable of hydrolyzing natural and semi-synthetic penicillins with the exception of oxacillin and methicillin. Sensitivity or resistance to benzylpenicillin is an indicator of the activity of natural and semi-synthetic amino-, carboxy- and ureidopenicillins. The remaining beta-lactams with potential antistaphylococcal activity (antistaphylococcal penicillins, cephalosporins of I, II and IV generations and carbapenems) retain activity against beta-lactamase-producing strains.
• Strains of Staphylococcus spp possessing PBP2a are clinically resistant to all beta-lactam ALDs. A marker for the presence of PSB2a is resistance to oxacillin and methicillin. Such strains have historically been called methicillin-resistant Staphylococcus spp (MRSS). Other terms for such strains are MRSA - methicillin-resistant S.aureus and MRSE - methicillin-resistant S.epidermidis.
• Methicillin is currently not used in clinical practice and in laboratory diagnostics; it has been almost completely replaced by oxacillin, and accordingly the term “oxacillin resistance” has appeared, which is a complete synonym for the term “methicillin resistance”.

Thus, testing the susceptibility of Staphylococcus spp. for beta-lactam ABPs should include two tests:

• Determination of sensitivity to benzylpenicillin or detection of beta-lactamase (penicillinase) production.
• Determination of sensitivity to oxacillin or detection of PBP2a or the mecA gene encoding it.

Mechanism of action and resistance

The individual properties of individual b-lactams are determined by:

• affinity (affinity) for penicillin-binding proteins (PBPs);
• the ability to penetrate the external structures of microorganisms;
• resistance to hydrolysis by b-lactamases.

The targets of b-lactam antibiotics in the microbial cell are PBP, enzymes involved in the synthesis of the main component of the outer membrane of microorganisms (peptidoglycan); binding of b-lactams to PBP leads to inactivation of PBP, cessation of growth and subsequent death of the microbial cell.

b-Lactams freely penetrate through the capsule and peptidoglycan into the cells of gram-positive microorganisms. b-Lactams do not pass through the outer membrane of gram-negative bacteria, and penetration into the cell occurs through porin channels in the outer membrane.

The access of b-lactam antibiotics to PSB is limited by enzymes - b-lactamases, which inactivate antibiotics. Special substances have been created that protect b-lactam antibiotics from the destructive action of b-lactamases (b-lactamase inhibitors). Dosage forms that combine antibiotics and b-lactamase inhibitors are called “inhibitor-protected b-lactams.”

In addition to natural sensitivity (or resistance), the clinical effectiveness of b-lactams is determined by acquired resistance, the mechanisms of which can be:

• decreased affinity of PBP for b-lactams;
• decreased permeability of the external structures of the microorganism for b-lactams;
• the appearance of new b-lactamases or changes in the expression of existing ones.

Read also[edit | edit code]

• Antibiotics (antimicrobial agents) Choice of antibiotic
• Combination antibiotic therapy
• Prophylactic antibiotic therapy
• Mechanisms of action of antibiotics

• Sulfonamides, trimethoprim/sulfamethoxazole
• Quinolones and urinary antiseptics
• Beta-lactam antibiotics Penicillins
• Cephalosporins
• Carbapenems

• Antituberculosis drugs (antimycobacterial) Isoniazid
• Rifampicin
• Ethambutol
• Streptomycin
• Pyrazinamide
• Other anti-tuberculosis drugs

Contraindications and precautions

Allergic reactions

β-lactams are contraindicated only in cases of documented hypersensitivity to them. Allergic reactions are more often observed with the use of penicillins (5-10%), less often with other b-lactams (1-2% or less). There is a risk of a cross-allergic reaction between b-lactams: with a history of allergy to benzylpenicillin, the likelihood of developing hypersensitivity to semisynthetic penicillins is about 10%, to cephalosporins 2-5%, to carbapenems about 1%. If a history indicates severe hypersensitivity reactions to penicillin (anaphylactic shock, angioedema, bronchospasm), the use of other beta-lactams is not allowed; in case of moderate reactions (urticaria, dermatitis), careful administration of cephalosporins and carbapenems under the guise of H1-histamine receptor blockers is possible.

Pregnancy

If necessary, b-lactams can be used to treat infections in pregnant women, since they have no teratogenic, mutagenic or embryotoxic properties.

Renal dysfunction

Most b-lactams do not have nephrotoxic effects and are safe in therapeutic doses, particularly in patients with kidney disease. In rare cases, interstitial nephritis may develop during the use of oxacillin. Indications of nephrotoxicity of cephalosporins refer exclusively to early drugs (cephaloridine, cephalothin, cephapirin), which are no longer used.

Hepatotoxicity

A transient increase in the level of transaminases and alkaline phosphatase is possible with the use of any b-lactams. These reactions go away on their own and do not require discontinuation of the drug.

Gastrointestinal reactions

Nausea, vomiting and diarrhea may occur with all b-lactams. In rare cases, antibiotic-associated diarrhea caused by C. difficile may develop.

Hematological reactions

The use of some cephalosporins and carboxypenicillins can lead to hemorrhagic syndrome. Some cephalosporins (cefamandole, cefotetan, cefoperazone, cefmetazole) have the ability to cause hypoprothrombinemia due to impaired absorption of vitamin K in the intestine; Bleeding is less common. Malnutrition, renal failure, liver cirrhosis, and malignant tumors predispose to this reaction.

Carbenicillin and ticarcillin should be prescribed with caution before surgery due to the possibility of developing hemorrhagic syndrome associated with impaired platelet membrane function.

Impaired alcohol tolerance

Some cephalosporins (cefamandole, cefoperazone) can cause disulfiram-like reactions when taking alcohol. Patients treated with these antibiotics should be aware of the possibility of such a reaction.

Benzylpenicillin

Features of antimicrobial activity

Active mainly against gram-positive and gram-negative cocci: staphylococci (except those producing penicillinase), streptococci, pneumococci, E. faecalis (to a lesser extent), N. gonorrhoeae, N. meningitidis; exhibits high activity against anaerobes, C. diphtheriae, L. monocytogenes, T. pallidum, B. burgdorferi, Leptospira. It is superior to other penicillins and cephalosporins of the 1st and 2nd generation in its effect on the coccal flora.

Acquired resistance

Currently, most strains of staphylococci (both community-acquired and hospital-acquired) produce penicillinase and are resistant to benzylpenicillin. Resistance of Streptococcus pyogenes to benzylpenicillin has not been documented. Resistance of pneumococci to benzylpenicillin in the Russian Federation ranges from 10 to 20% and has increased in recent years. Clinically significant resistance of gonococci is more than 30%.

Main indications

In a non-infectious clinic, the use of benzylpenicillin is justified for streptococcal and meningococcal infections, as well as gas gangrene. In the treatment of bronchopulmonary infections, semisynthetic penicillins have an advantage.

• Infections caused by S. pyogenes (streptococcal tonsillitis, scarlet fever, erysipelas)
• Infections caused by S. pneumoniae (community-acquired pneumonia, meningitis)
• Infections caused by E. faecalis (in combination with gentamicin)
• Treatment and prevention of clostridial infection (drug of choice)
• Meningococcal infection (drug of choice)
• Syphilis (drug of choice)
• Leptospirosis
• Actinomycosis
• As a means of empirical therapy: infective endocarditis of the native valve (in combination with gentamicin)
• abscess pneumonia (in combination with metronidazole)

Dosing

It is used intravenously and intramuscularly in a daily dose of 6 million units (streptococcal infections) to 24-30 million units (central nervous system infections).

Benzathinebenzylpenicillin

Long-acting dosage form of benzylpenicillin. Antimicrobial activity and resistance - see Benzylpenicillin

Features of pharmacokinetics

N,N-dibenzylethylenediamine salt of benzylpenicillin is a prolonged form of benzylpenicillin. When administered intramuscularly, it forms a depot from which the active principle, benzylpenicillin, is slowly released (Tmax is reached after 12-24 hours), which is detected in low concentrations in the blood for a long time (up to 3 weeks). After intramuscular administration at a dose of 1.2 million units, the average blood concentrations after 1 week are 0.1 mg/l, after 2 weeks - 0.02 mg/l, after 3 weeks - 0.01 mg/l.

Connection with plasma proteins is 40-60%. Excreted mainly by the kidneys.

Main indications

• Syphilis
• Streptococcal tonsillitis in children
• Scarlet fever (treatment and prevention)
• Prevention of rheumatism

NATURAL PENICILLINS

Natural penicillins include essentially only benzylpenicillin. However, based on the spectrum of activity, prolonged (benzylpenicillin procaine, benzathine benzylpenicillin) and oral (phenoxymethylpenicillin, benzathine phenoxymethylpenicillin) derivatives can also be classified in this group. All of them are destroyed by β-lactamases, so they cannot be used to treat staphylococcal infections, since in most cases staphylococci produce β-lactamases.

BENZYLPENICILLIN (PENICILLIN)

It is the first natural antibiotic. Despite the fact that many other antibiotics have been introduced in the almost 60 years since its use began, penicillin continues to be one of the important drugs.

Advantages

• Powerful bactericidal effect against a number of clinically significant pathogens (streptococci, meningococci, etc.).
• Low toxicity.
• Low cost.

Flaws

• Acquired resistance of staphylococci, pneumococci, gonococci, bacteroides.
• Highly allergenic, cross-reactive with all penicillins.

Activity spectrum

Pharmacokinetics

It is destroyed in the gastrointestinal tract, so it is ineffective when taken orally. It is well absorbed when administered intramuscularly, peak concentration in the blood is reached after 30-60 minutes. Creates high concentrations in many tissues and body fluids. It penetrates poorly through the BBB and GOB into the prostate gland. Excreted by the kidneys. T1/2 - 0.5 hours.

Adverse reactions

• Allergic reactions: rash, Quincke's edema, fever, eosinophilia. The most dangerous is anaphylactic shock, which has a mortality rate of up to 10%. Prevention measures
  Careful history taking, use of freshly prepared penicillin solutions, observation of the patient for 30 minutes after the first administration of penicillin, detection of hypersensitivity by skin testing (see section VI).
• Locally irritating effect, especially with intramuscular injection of potassium salt.
• Neurotoxicity: convulsions (more often in children), when using high doses of penicillin, especially in renal failure, with endolumbar administration of more than 10 thousand units of penicillin sodium salt or potassium salt.
• Electrolyte imbalance - hyperkalemia when using high doses of potassium salt in patients with renal failure (1 million units contains 1.7 mmol of potassium). In patients with heart failure, administration of large doses of sodium salt may increase edema (1 million units contains 2.0 mmol of sodium).

Drug interactions

Synergistic when combined with aminoglycosides, but they should not be mixed in the same syringe

, since inactivation of aminoglycosides is noted. Combinations with other antibiotics are used, for example, with macrolides for pneumonia, with chloramphenicol for meningitis.

Combination with sulfonamides should be avoided.

Indications

• Infections caused by GABHS: tonsillopharyngitis, erysipelas, scarlet fever, acute rheumatic fever.
• Community-acquired pneumococcal pneumonia.
• Meningitis in children over 2 years of age and in adults.
• Bacterial endocarditis - always in combination with gentamicin or streptomycin.
• Syphilis.
• Leptospirosis.
• Borreliosis (Lyme disease).
• anthrax
• Anaerobic infections: clostridial - gas gangrene, tetanus; non-clostridial (caused by non-spore-forming anaerobes) when the process is localized above the diaphragm.
• Actinomycosis.

Dosage

Adults

For infections of moderate severity and high sensitivity of microflora - 2-4 million units/day in 4 intramuscular injections. For tonsillopharyngitis - 500 thousand units every 8-12 hours for 10 days. For severe infections - 6-12 million units/day, intramuscularly or intravenously every 4-6 hours.

When the infection is localized in a place difficult to reach for penicillin (meningitis, endocarditis) - 18-24 million units/day, in 6 injections intravenously and/or intramuscularly.

Children

Intravenously or intramuscularly - 50-100 thousand units/kg/day in 4 administrations, for tonsillopharyngitis, 500 thousand units every 12 hours for 10 days. For meningitis - 300-400 thousand units/kg/day in 6 injections intravenously and/or intramuscularly.

Release forms

Bottles of 125, 250, 500 thousand and 1 million units of powder for the preparation of a solution for injection in the form of sodium or potassium salt.

PHENOXYMETHYLPENICILLIN

Megacillin

The spectrum of activity does not differ from penicillin, but is more stable when taken orally. Absorbed from the gastrointestinal tract by 60%, and food has little effect on bioavailability. High concentrations of the drug in the blood are not created; taking 0.5 g of phenoxymethylpenicillin orally approximately corresponds to the administration of 300 thousand units of penicillin. T1/2 - about 1 hour.

Adverse reactions

• Allergic reactions (see Benzylpenicillin).
• Dyspeptic and dyspeptic disorders.

Indications

• Streptococcal (GABHS) infections of mild to moderate severity:
• tonsillopharyngitis;
• skin and soft tissue infections.

Dosage

Adults

0.25-0.5 g every 6 hours. For streptococcal tonsillopharyngitis, 0.25 g every 8 hours or 0.5 g every 12 hours, always for 10 days. For the prevention of rheumatic fever, 0.25 g every 12 hours. Take orally 1 hour before meals.

Children

Orally - 30-50 mg/kg/day in 3-4 divided doses. For streptococcal tonsillopharyngitis, 0.25 g every 12 hours, always for 10 days.

Release forms

Tablets of 0.1 g, 0.25 g, 0.5 g and 1.0 g; syrup; granules for preparing a suspension.

BENZATINE PHENOXYMETHYL PENICILLIN

Ospen

It is a derivative of phenoxymethylpenicillin. Compared to it, it is more stable in the gastrointestinal tract and is absorbed faster. Bioavailability is independent of food.

Indications

• Streptococcal (GABHS) infections of mild to moderate severity:
• tonsillopharyngitis;
• skin and soft tissue infections.

Dosage

Adults

Orally - 3 million units/day in 3-4 divided doses, regardless of food.

Children under 10 years old

Orally - 50-100 thousand units/kg/day in 3-4 doses.

Children over 10 years old

Orally - 3 million units/day in 3-4 doses.

Release forms

Tablets of 250 thousand and 500 thousand units; suspension 750 thousand units/5 ml.

PROLONGED-LONG DRUGS PENICILLIN

Long-acting penicillin preparations (depot penicillins) include benzylpenicillin procaine (novocaine salt of benzylpenicillin), which has an average duration of action (about 24 hours), benzathine benzylpenicillin, which has a long-term effect (up to 3-4 weeks), as well as their combination preparations.

These drugs are slowly absorbed when administered intramuscularly and do not create high concentrations in the blood.

Adverse reactions

• Allergic reactions (see Benzylpenicillin)
• Soreness, infiltrates at the site of intramuscular injection.
• Hoigne's syndrome is ischemia and gangrene of the extremities due to accidental injection into an artery.
• Nicholau syndrome is an embolism of the blood vessels of the lungs and brain when injected into a vein.

Prevention of vascular complications:

strict adherence to the injection technique - intramuscularly into the upper outer quadrant of the buttock using a wide needle, with the patient in a horizontal position. Before insertion, it is necessary to pull the syringe plunger towards you to make sure that the needle is not in the vessel.

Indications

• Infections caused by microorganisms highly sensitive to penicillin:
• streptococcal (GABHS) tonsillopharyngitis;
• syphilis.

BENZYLPENICILLIN PROCAINE

When administered intramuscularly, the therapeutic concentration in the blood is maintained for 12-24 hours, but the concentrations are lower than when an equivalent dose of benzylpenicillin sodium or potassium salt is administered. T1/2 - 24 hours.

Used for mild pneumococcal pneumonia, streptococcal tonsillopharyngitis (an alternative to benzylpenicillin if frequent injections are not possible). It has a local anesthetic effect and is contraindicated if you are allergic to procaine (Novocaine).

Dosage

Adults

Intramuscularly - 600 thousand-1.2 million units/day in 1-2 injections. For the prevention of anthrax - 1.2 million units every 12 hours for 2 months.

Children

Intramuscularly - 50-100 thousand units/kg/day in 1-2 injections. For the prevention of anthrax - 25 thousand units/kg every 12 hours for 2 months.

Release forms

Bottles of 300 thousand, 600 thousand and 1.2 million units of powder for the preparation of solution for injection.

BENZATINE BENZYLPENICILLIN

Bicillin-1, Extensillin, Retarpen

It acts longer than benzylpenicillin procaine, up to 3-4 weeks. After intramuscular administration, peak concentrations are observed after 24 hours in children and after 48 hours in adults. T1/2 - several days.

In recent years, pharmacokinetic studies have been carried out on domestic drugs containing benzathine benzylpenicillin (bicillin-3, bicillin-5). It has been shown that when used, the therapeutic concentration in the blood serum is maintained for no more than 14 days, which requires their more frequent administration than, for example, extensillin.

Dosage

Adults

1.2-2.4 million units once; for syphilis - 2.4 million units/day every 5-7 days (2-3 injections); for the prevention of rheumatic fever and recurrent erysipelas - 1.2-2.4 million units once a month. The drug is administered strictly intramuscularly.

Children

Intramuscularly - 1.2 million units once; for the prevention of rheumatic fever - 600 thousand-1 million units once a month.

Release forms

Bottles of 300 thousand, 600 thousand, 1.2 million and 2.4 million units of powder for the preparation of solution for injection.

Bicillin-3

Ingredients: benzylpenicillin potassium salt, benzylpenicillin procaine and benzathine benzylpenicillin in equal quantities. Has no advantages over benzathine benzylpenicillin.

Dosage

Adults and children

Intramuscularly - 1.2 million units once.

Release forms

Bottles of 300 thousand, 600 thousand, 900 thousand and 1.2 million units of powder for the preparation of solution for injection.

Bicillin-5

Ingredients: 1 part benzylpenicillin procaine, 4 parts benzathine benzylpenicillin. Has no advantages over benzathine benzylpenicillin.

Dosage

Phenoxymethylpenicillin

Features of antimicrobial activity

The spectrum of antimicrobial activity is similar to benzylpenicillin. Predominant activity against gram-positive (staphylococci, streptococci) and gram-negative (N. gonorrhoeae, N. meningitidis) cocci, Treponema spp., H. influenzae, Corynebacterium spp.

Acquired resistance - see Benzylpenicillin

Main indications

• Streptococcal tonsillitis in children
• Prevention of endocarditis during dental procedures
• Scarlet fever
• Infections of the mouth and gums

Oxacillin

Features of antimicrobial activity

Active mainly against gram-positive cocci (Staphylococcus spp., S. pyogenes, S. pneumoniae, S. viridans, S. agalactiae); has no effect on enterococci. In terms of natural activity against gram-positive cocci, it is inferior to natural penicillins. Does not show activity against gram-negative bacteria (except Neisseria spp.), anaerobes. Stable to staphylococcal b-lactamases.

Acquired resistance

The resistance rate of community-acquired S. aureus strains is less than 5%; the frequency of oxacillin-resistant strains in hospitals varies between departments and can reach 50% or higher in intensive care units.

Main indications

Currently, the use of oxacillin is advisable exclusively for staphylococcal infections (mainly community-acquired).

• Staphylococcal infections of various localizations (drug of choice)
• Infections of suspected staphylococcal etiology:
• uncomplicated infections of the skin and soft tissues (furuncle, carbuncle, pyoderma, etc.) mastitis
• infective endocarditis in intravenous drug users (drug of choice)
• acute purulent arthritis (drug of choice)
• catheter-associated angiogenic infection

Dosing

Intravenously, intramuscularly and orally; daily dose 4-12 g (with an interval of 4-6 hours). The drug is preferably administered parenterally, since the bioavailability when taken orally is not very high. For oral use, cloxacillin is preferable. For severe infections, the daily dose is 8-12 g (4-6 injections).

Cloxacillin

Features of antimicrobial activity

The spectrum of antimicrobial activity is close to oxacillin (see). Stable to staphylococcal b-lactamases.

Acquired resistance - see Oxacillin

Main indications

• Staphylococcal infections of various localizations, mild and moderate severity
• Infections of suspected staphylococcal etiology: uncomplicated infections of the skin and soft tissues (furuncle, carbuncle, pyoderma, etc.)
• acute mastitis

Dosing

Orally 500 mg 4 times a day

Amoxicillin

Broad-spectrum semisynthetic penicillin for oral use.

Features of antimicrobial activity

Has a wide spectrum of antimicrobial action. Most active against gram-positive cocci (S. pyogenes, S. viridans, S. pneumoniae, penicillin-sensitive staphylococci), gram-negative cocci (N. gonorrhoeae, N. meningitidis), listeria, H. influenzae, gram-positive anaerobes, to a lesser extent - enterococci, H. pylori, some enterobacteria (E. coli, P. mirabilis, Shigella spp., Salmonella spp.).

Acquired resistance

Not stable to staphylococcal penicillinases, so most strains of S. aureus are resistant. The resistance of pneumococci and Haemophilus influenzae to amoxicillin in the Russian Federation is insignificant, the resistance of E. faecalis is 10-15%. The resistance of community-acquired strains of Enterobacteriaceae is moderate (10-30%), hospital-acquired strains are usually resistant.

Main indications

Currently considered as a treatment of choice for uncomplicated community-acquired respiratory infections in adults and children in outpatient practice; in these diseases it is not inferior in effectiveness to inhibitor-protected aminopenicillins. Included in the main regimens of eradication therapy for gastric and duodenal ulcers.

• Non-severe community-acquired infections of the upper and lower respiratory tract: pneumonia (drug of choice)
• exacerbation of chronic bronchitis
• acute otitis media (drug of choice)
• acute sinusitis (drug of choice)
• streptococcal tonsillitis - sore throat (drug of choice)

Prescription for infections of the urinary tract (E. coli resistance), skin and soft tissue infections (S. aureus resistance) is not recommended.

Dosing

It is used orally (for children in the form of a suspension). Frequency of application - 3 times a day. The recommended daily dose for adults is 1.5 g. Prevention of endocarditis - 3 g once.

Features of the dosage form: the dispersed dosage form of the antibiotic (solutab) is characterized by more complete absorption in the gastrointestinal tract compared to conventional dosage forms in the form of tablets and capsules, which is accompanied by the creation of higher serum concentrations in the blood, as well as a lesser effect of the drug on the intestinal microflora.

β-lactamase inhibitors[edit | edit code]

Source: Clinical Pharmacology by Goodman and Gilman Volume 3
.
Editor
: Professor A.G.
Gilman Ed.
: Practice, 2006.

These drugs are able to bind and inactivate beta-lactamases, thereby preventing the hydrolysis of beta-lactam antibiotics. β-lactamase inhibitors are most active against β-lactamases encoded by plasmid genes (including extended-spectrum enzymes that destroy ceftazidime and cefotaxime). However, in therapeutic doses, these drugs do not act on type I β-lactamases encoded by chromosomal genes, produced by gram-negative rods (Enterobacter spp., Acinetobacter spp. and Citrobacter spp.). As already mentioned, the production of type I beta-lactamases encoded by chromosomal genes begins in response to treatment with second and third generation cephalosporins.

Clavulanic acid

produced by Streptomyces clavuligerus.
Its structural formula is as follows: Structural formula of clavulanic acid
Clavulanic acid does not have high antimicrobial activity, but has the ability to irreversibly bind β-lactamases of many gram-positive and gram-negative bacteria (Neu and Fu, 1978). The drug is well absorbed when taken orally, but it can also be administered parenterally. Clavulanic acid is part of the combination drugs amoxicillin/clavulanate for oral administration and ticarcillin/clavulanate for intravenous administration.

Amoxicillin/clavulanate is active, in vitro and in vivo, against β-lacgamase-producing staphylococci, as well as Haemophilus influenzae, gonococci and Escherichia coli (Ball et al., 1980; Yogev et al., 1981). Good results were obtained when oral amoxicillin/clavulanate was administered in combination with ciprofloxacin to patients who experienced fever and neutropenia during chemotherapy (Freifeld et al., 1999; Kern et al., 1999). Amoxicillin/clavulanate also helps with acute otitis media in children, sinusitis, bite wounds, cellulitis and diabetic foot. The addition of clavulanic acid broadens the antimicrobial spectrum of ticarcillin, making it similar to imipenem/cilastatin. Ticarcillin/clavulanate acts against aerobic gram-negative bacilli, Staphylococcus aureus and Bacteroides spp. However, the activity of ticarcillin/clavulanate against Pseudomonas spp. no higher than ticarcillin alone (Bansal et al., 1985). In case of renal failure, the dose is reduced. Ticarcillin/clavulanate is especially useful for mixed hospital infections. It is often combined with one of the aminoglycosides.

Sulbactam

similar in structure to clavulanic acid. It can be taken orally or administered parenterally along with β-lactam antibiotics. Sulbactam is produced as a combination drug with ampicillin for intravenous and intramuscular administration. For patients with impaired renal function, the dose is reduced. Ampicillin/sulbactam is highly active against gram-positive cocci (including β-lactamase-producing strains of Staphylococcus aureus), gram-negative aerobes (except Pseudomonas spp.) and anaerobes. The drug is successfully used to treat mixed infections of the abdominal and pelvic organs (Reinhardt et al., 1986).

Tazobactam

is a sulfonepenicillanic acid. Like other β-lactamase inhibitors, it has little activity against inducible β-lactamases of enterobacteria encoded by chromosomal genes, but inhibits many β-lactamases encoded by plasmid genes, including some of the extended-spectrum enzymes. A piperaillin/tazobactam combination drug is available for IV administration (Bryson and Brogden, 1994).

The addition of tazobactam does not increase the activity of piperacillin against Pseudomonas aeruginosa, since their resistance is due either to β-lactamases encoded by chromosomal genes or to the fact that the antibiotic has difficulty penetrating the periplasmic space. Piperacillin/tazobactam is usually prescribed at a dose of 3 g piperacillin and 375 mg tazobactam IV 3-6 times a day, that is, 9-18 g piperacillin per day. Piperacillin alone (without tazobactam) for monotherapy of severe infections is used in a higher dose, 3-4 g IM or IV 4-6 times a day, that is, 12-24 g of piperacillin per day. Therefore, there have been concerns that piperacillin/tazo-bactam may be less effective than piperacillin for Pseudomonas aeruginosa infections. The antimicrobial spectrum of piperacillin/tazobactam is similar to that of ticarcillin/clavulanate.

Ampicillin

Broad-spectrum semisynthetic penicillin for parenteral and oral use.

Features of antimicrobial activity

The spectrum of natural activity is similar to amoxicillin. Acquired resistance - see Amoxicillin

Main indications

• E. faecalis infections (drug of choice)
• Meningitis caused by Listeria and Haemophilus influenzae (in combination with aminoglycosides)
• Lower respiratory tract infections: moderately severe community-acquired pneumonia (drug of choice)
• exacerbation of chronic bronchitis

Prescription for infections of the urinary tract (E. coli resistance), skin and soft tissue infections (S. aureus resistance), and for the eradication of H. pylori is not recommended.

Dosing

It is used parenterally and orally. The drug is characterized by low bioavailability when taken orally, so it is advisable to use amoxicillin for oral use, with the exception of intestinal infections.

The daily dose for intramuscular and intravenous administration is 4-12 g (with an interval of 4-6 hours): for respiratory infections - 4 g / day, for infections of the central nervous system and endocarditis - 8-12 g / day; orally (only for intestinal infections) - 0.5-1 g 4 times a day.

Preparations with beta-lactam rings

28.02.2018

The group of drugs with beta-lactam rings includes penicillins, cephalosporins, monobactams and other antibiotics, the molecules of which contain a common fragment in their structure - the beta-lactam ring. These are drugs with fairly high antimicrobial activity, but resistance to them quickly develops.

Penicillin is a waste product of various fungi of the genus Penicillium. It disrupts the synthesis of bacterial cell walls and causes the dissolution of microorganisms. Effective against gram-positive bacteria, spirochetes and some actinomycetes. The number of antibiotics in this group is quite large. One of the most commonly prescribed penicillins is ampicillin. This is a broad-spectrum antibiotic, as it acts on both gram-positive and gram-negative microorganisms. It is excreted mainly by the kidneys , partially excreted in bile, and in nursing mothers - in milk.

Ampicillin is a drug indicated for pneumonia , bronchopneumonia (inflammation of the bronchi and lungs ), tonsillitis , peritonitis stomach or intestinal contents enter it , for example, when an ulcer or the appendix ruptures), cholecystitis (inflammation of the gallbladder ), sepsis ( blood contamination by microbes from the focus of purulent inflammation), intestinal infections, abscesses (purulent inflammations) of the lungs , postoperative soft tissue infections and other infections caused by microorganisms sensitive to the drug.

Ampicillin is very effective for urinary tract infections caused by E. coli, Proteus, enterococci or mixed infections, since it is excreted unchanged and in high concentrations in the urine , that is, it passes along the genitourinary system, exerting its therapeutic effect. In addition, the drug is very effective against gonorrhea.

The average dosage for adult patients is 0.25 g of ampicillin 4 times a day an hour before meals. To treat infectious diseases of the digestive system, take 1/2 g 4 times a day. For not too severe infectious diseases, adult patients should be administered intramuscularly from 250 to 500 mg of ampicillin once every 6 hours.

Ampicillin is contraindicated in case of individual intolerance to drugs of the penicillin group, carbapenems, cephalosporins, severe liver , lymphocytic leukemia, mononucleosis, severe diseases of the digestive system, during lactation, for children in the first month of life.

When taking ampicillin, side effects are possible: skin rashes, inflammation of the mucous membranes of the eyes , swelling of the larynx, disturbance of the intestinal , the appearance of ulcers on the oral , discomfort in the oral cavity , in the epigastric area, diarrhea, migraine-like pain, trembling of the limbs, spontaneous contractions of the muscles of the limbs (only during treatment with large quantities of the drug).

When treating with ampicillin, the dose should not be exceeded. In case of overdose, diarrhea and vomiting may occur. With long-term treatment with ampicillin in a weakened body, the development of superinfection is possible (a severe, rapidly developing form of an infectious disease caused by drug-resistant microorganisms that were previously in the body, but did not manifest themselves).

Other beta-lactam antibacterial drugs include cephalosporins.

Their chemical structure is largely similar to penicillins, but they have a wider spectrum of action against gram-negative bacteria. There are currently four generations of defalosporins.

First generation drugs (cefazolin, cephalexin) work well in the fight against staphylococci.

The second generation (cefuroxime) has a list of merits in the fight against Escherichia coli (for example, E. coli, which can cause cystitis, fulminant diarrhea and other diseases), Klebsiella and Proteus (cause pneumonia , conjunctivitis, meningitis, sepsis, acute intestinal and urogenital infections, in including in newborns, weakened and elderly persons).

Third generation drugs (cefotaxime, ceftriaxone) are characterized by a wider spectrum of action, especially against gram-negative bacteria.

The highlight of fourth-generation drugs (cefepime) is their high effectiveness against anaerobic bacteria.

Cephalosporins taken orally are well absorbed from the gastrointestinal tract. They are also very effective when administered intramuscularly. Drugs, especially the third generation, as well as cefepime, which belongs to the fourth generation, are able to penetrate the brain and create therapeutic concentrations in the cerebrospinal fluid, which is important in the fight against bacterial inflammation of the brain .

Most cephalosporins are practically not destroyed in the body. They are excreted primarily by the kidneys , and very high concentrations of drugs are created in the urine , which makes it possible to use them for the treatment of urogenital infections. Almost all drugs are quickly eliminated from the body, so you will have to take such tablets often, but some (ceftributen, ceftriaxone), on the contrary, are eliminated slowly (3 and 8 hours, respectively), so they need to be taken only once a day, which, of course, is significant convenient.

Allergic reactions to cephalosporins occur less frequently than to penicillins.

These drugs are usually not prescribed to pregnant women, since the question of whether these drugs affect the development of the fetus has not been sufficiently studied.

Adverse reactions when taking cephalosporins: urticaria , rash, erythema multiforme, fever, eosinophilia, serum sickness, bronchospasm, Quincke's edema , anaphylactic shock , convulsions (when using high doses in patients with impaired renal ), increased transaminase activity (more often when using cefoperazone ), in rare cases, eosinophilia, leukopenia, neutropenia, hemolytic anemia. Cefo-perazone can cause hypoprothrombinemia with a tendency to bleeding. Ceftriaxone in high doses - cholestasis and pseudocholelithiasis, abdominal , nausea , vomiting, diarrhea , pseudomembranous colitis. If pseudomembranous colitis is suspected (the appearance of loose stool mixed with blood ), it is necessary to discontinue the drug and conduct a sigmoidoscopy examination. Local reactions: pain and infiltration with intramuscular administration, phlebitis with intravenous administration.

Carbapenems are a small group of drugs used to treat the following serious infections in children and adults caused by one or more drug-sensitive pathogens: pneumonia, abdominal infections, septicemia, meningitis , gynecological infections (endometritis and pelvic inflammatory disease), urinary infections - excretory system, skin and soft tissues. Medicines can be prescribed alone or in combination with antiviral or antifungal drugs, aminoglycosides, cephalosporins or semisynthetic penicillins.

As a rule, doctors do not immediately prescribe carbapenems, but keep them “in reserve” if other antibiotics do not help, but in some especially dangerous, life-threatening infections they are prescribed first. Drugs in this group are administered exclusively by injection.

Consider the combination drug imipenem + cilastatin. It is administered intravenously: adults 0.5-1.0 g every 6-8 hours (but not more than 4.0 g per day), over 3 months with a body weight less than 40 kg - 15-25 mg/kg every 6 hours, more than 40 kg - as in adults (but not more than 2.0 g per day); intramuscularly for adults 0.5–0.75 g every 12 hours.

Carbapenems are well distributed in the body, and in case of inflammation of the meninges, they are able to penetrate into the brain . They are excreted unchanged by the kidneys Therefore, in case of renal failure, drugs are prescribed carefully and dosages are carefully monitored.

Among the side effects, it is necessary to note allergic reactions , which are cross reactions within the group and in 50% of cases with penicillins. This means that if you are allergic to penicillins, you are more likely to have an allergy to carbapenems.

Published in Medicines Premium Clinic

Carbenicillin

Broad-spectrum anti-pseudomonal penicillin.

Features of antimicrobial activity

Shows activity against gram-positive and gram-negative microbes, including streptococci, pneumococci, neisseria, listeria, gram-positive anaerobes (clostridia, peptostreptococci), to a lesser extent - some types of enterobacteria, Haemophilus influenzae, Pseudomonas aeruginosa (in terms of antipseudomonal activity it is inferior to other antipseudomonal penicillins).

Acquired resistance

A high level is typical for staphylococci, enterobacteria, and Pseudomonas aeruginosa, and therefore use is limited to cases of infections with documented sensitivity of pathogens to the antibiotic.

Main indications

Infections caused by carbenicillin-sensitive strains of P. aeruginosa (in combination with aminoglycosides or fluoroquinolones).

Currently, indications for the use of carbenicillin are limited due to the high level of microbial resistance to the drug.

Dosing

It is used as an intravenous infusion in large doses (5 g 5-6 times a day).

Prescribe with caution when:

• renal dysfunction
• history of bleeding
• cardiovascular failure
• arterial hypertension

In cardiovascular or renal failure, the use of carbenicillin can cause hypernatremia and hypokalemia.

This group includes piperacillin, azlocillin, mezlocillin, but only azlocillin remains important in medical practice.

Azlocillin

Features of antimicrobial activity

The spectrum of antimicrobial activity includes gram-positive and gram-negative microbes, as well as anaerobes. Against bacteria of the Enterobacteriaceae family, it is more active against E. coli, P. mirabilis, P. vulgaris. Highly active against H. influenzae and N. gonorrhoeae. It belongs to the antipseudomonal penicillins, and its activity is superior to carbenicillin.

Acquired resistance

Not stable to staphylococcal penicillinases, so most strains are resistant. Currently, many hospital strains of gram-negative bacteria exhibit resistance to azlocillin.

Main indications

Infections caused by carbenicillin-sensitive strains of P. aeruginosa (in combination with aminoglycosides or fluoroquinolones)

Currently, indications for the use of carbenicillin are limited due to the high level of microbial resistance to the drug.

Dosing

It is used intravenously (drip, bolus), intramuscularly. The standard dose for adults is 2 g 3 times a day. For severe infections: a single dose of 4-5 g (even 10 g).

Prescribed with caution: in the first trimester of pregnancy; when breastfeeding; with the simultaneous administration of hepatoxic drugs and anticoagulants.

One of the methods of combating microbial resistance associated with the production of b-lactamases is the use of special substances with a b-lactam structure that bind enzymes and thereby prevent their destructive effect on b-lactam antibiotics. These substances are called “b-lactamase inhibitors,” and their combinations with b-lactam antibiotics are called “inhibitor-protected b-lactams.”

Currently, 3 b-lactamase inhibitors are used:

• Clavulanic acid
• Sulbactam
• Tazobactam

B-lactamase inhibitors are not used alone, but are used only in combination with b-lactams.

Inhibitor-protected penicillins include: amoxicillin/clavulanate, ampicillin/sulbactam, amoxicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate.

These antibiotics are fixed combinations of semisynthetic penicillins (aminopenicillins, carboxypenicillins or ureidopenicillins) with b-lactamase inhibitors, which irreversibly bind various b-lactamases and thus protect penicillins from destruction by these enzymes. As a result, strains of microorganisms resistant to penicillins become sensitive to the combination of these drugs with inhibitors. The spectrum of natural activity of inhibitor-protected b-lactams corresponds to the penicillins contained in them; only the level of acquired resistance differs.

Inhibitor-protected penicillins are widely used in clinical practice, with amoxicillin/clavulanate, ampicillin/sulbactam and amoxicillin/sulbactam mainly for community-acquired infections, and ticarcillin/clavulanate and piperacillin/tazobactam for hospital-acquired infections.

What are Beta-lactamases?

Antibiotic resistance of bacteria is currently one of the most important and pressing problems in infectology. Almost all bacteria known to science that cause infectious diseases (with rare exceptions) exhibit resistance to one or another antibacterial drug to a greater or lesser extent.

The main mechanism of bacterial resistance to beta-lactam antibiotics is the synthesis of various beta-lactamases (penicillinases, cephalosporinases, etc.). According to the definition of the Nomenclature Committee of the International Biochemical Society, beta-lactamases are classified as “enzymes that hydrolyze amides, amidines and other C–N bonds ... isolated on the basis of a substrate - ... cyclic amides.” The term "beta-lactamases" is therefore functional and combines various bacterial enzymes capable of cleaving beta-lactam antibiotics containing a cyclic amide bond in their structure. Most known beta-lactamases exhibit strong structural homology with penicillin-binding proteins (PBPs), indicating an evolutionary relationship between the enzymes of these groups. Like PSBs, beta-lactamases containing a serine residue in the active site interact with beta-lactam antibiotics to form an ester complex. However, in the case of beta-lactamases, this complex is rapidly cleaved, releasing the native enzyme and an inactivated substrate molecule. The lack of effect when using beta-lactam antibiotics in the treatment of patients in some cases is due to two reasons: 1. The presence of biological resistance associated with the destruction of beta-lactam antibiotics in blood serum and other biological fluids (pleural fluid, peritoneal fluid, etc.) under exposure to beta-lactamase activity caused by albumin and globulin fractions. 2. The presence of microbiological resistance caused by the destruction of antibiotics in biological fluids, associated with the active growth and reproduction of microorganisms producing beta-lactamases that destroy the beta-lactam ring, which is the basis of the structure of beta-lactam antibiotics (cerebrospinal fluid, sputum, urine, saliva, pleural fluid, peritoneal fluid, daily culture of infected material). The ability to produce beta-lactamases in various concentrations is detected in many bacteria, both gram (+) and gram (-). Almost all bacteria are capable of synthesizing these enzymes. Microorganisms may have a natural ability to produce beta-lactamases due to the presence of the corresponding genes in their chromosome, or they acquire this ability after successful transduction of DNA from another microorganism (usually as part of continuous R-plasmids). Currently, 4 main classes of beta-lactamases have been identified - A, B, C and D. The natural or acquired ability to produce beta-lactamases is the main mechanism of the ever-increasing resistance of bacteria to this class of antibacterial drugs, which leads to the clinical ineffectiveness of the use of antibiotics and associated this leads to the occurrence of complications, worsening the prognosis of diseases, prolongation of treatment and hospitalization of patients. It is generally accepted that the formation of new beta-lactamases with altered structure and mechanism of action is the most common mechanism of adaptation of microorganisms to the introduction of new beta-lactam drugs into clinical practice, i.e., in fact, the response of bacteria to the evolutionary pressure created by the use of appropriate treatment regimens, especially among gram (-) bacteria.

The BioLactam test system, developed by the educational institution Vitebsk State Order of Peoples' Friendship Medical University, is designed to determine and quantify the beta-lactamase activity of biological substrates, which is necessary to resolve the issue of the advisability of using beta-lactam antibiotics in the treatment of patients.

The functioning of the BioLactam test system is based on a technique based on the change in color of a synthetic cephalosporin antibiotic due to the breakdown of its beta-lactam bond. In this case, a bathochromic shift occurs in the chromophore system of the molecule, and the color of the reaction mixture changes from yellow to red-orange. The absorption maximum of the reaction product changes from 390 nm to 486 nm, which makes spectrophotometric detection possible. Beta-lactamase activity is estimated as the % breakdown of the standard amount of cephalosporin used added to the sample.

The blood serum of the studied patients is separated by centrifugation of freshly obtained whole blood, kept in a refrigerator at +4°C for 4-6 hours to form a fibrin clot, at 3000 rpm for 15 minutes.

Serum beta-lactamase activity depends on pH, temperature (it increases significantly when the temperature rises to 39-40°C) and the ionic strength of the solution (it decreases when the ionic strength increases above the level typical of blood plasma). As a rule, a group of people is identified with high (more than 68.2%) beta-lactamase activity of blood serum or peritoneal and pleural fluids, severe infectious diseases of a bacterial nature, a significant duration of antibacterial therapy, frequent changes of antibiotics and frequent prescription of reserve antibacterial drugs of all groups . Determination of beta-lactamase activity using the BioLactam test system is characterized by high sensitivity (70%), specificity (90%) and reproducibility.

Determining biological and microbiological resistance to beta-lactam antibiotics in the early stages of the disease allows for timely correction of treatment and reducing the frequency of unjustified prescription of beta-lactam antibiotics by 20-30%, which will lead to a reduction in the length of hospitalization of specialized patients and significant savings in money. The Ministry of Health of the Republic of Belarus recommends that healthcare organizations consider the need to determine the level of beta-lactamase activity before prescribing antibacterial therapy.

Laboratory Diagnostics Doctor, Central House of Writers

Novopolotsk city hospital

Vasilyeva S.G.

Amoxicillin/clavulanate

Features of antimicrobial activity

Clavulanic acid prevents the enzymatic inactivation of amoxicillin by the action of b-lactamases.

Active against gram-positive (streptococci, pneumococci, staphylococci, except oxacillin-resistant) and gram-negative (N. gonorrhoeae, N. meningitidis) cocci, listeria, H. influenzae, M. catarrhalis, anaerobes (including B. fragilis), less active against enterococci and some enterobacteria (E. coli, P. mirabilis, Klebsiella spp.).

Acquired resistance

Most community-acquired strains of S. aureus are susceptible. The resistance of S. pneumoniae and H. influenzae in the Russian Federation is insignificant. In recent years, there has been an increase in the resistance of community-acquired uropathogenic E. coli strains, currently amounting to about 30%. The resistance of gram-negative coliform bacteria varies—community-acquired strains are usually sensitive, while hospital-acquired strains are often resistant.

Main indications

It is the most well studied among inhibitor-protected aminopenicillins in controlled clinical trials and therefore has the widest indications.

• Community-acquired infections of the upper and lower respiratory tract: mild and moderate pneumonia
• pneumonia destructive and abscessive (drug of choice)
• exacerbation of chronic bronchitis (drug of choice)
• acute otitis media
• acute sinusitis
• exacerbation of chronic sinusitis (drug of choice)
• recurrent tonsillopharyngitis (drug of choice)
• epiglottitis (drug of choice)

Dosing

Orally 375-625 mg 3 times a day or 1 g 2 times a day, intravenously 1.2 g 3 times a day. Prevention in surgery: 1.2 g intravenously 30-60 minutes before surgery.

Features of the dosage form: the dispersed dosage form of the antibiotic (solutab) is characterized by more uniform absorption in the gastrointestinal tract compared to conventional dosage forms of the drug, which ensures more stable therapeutic concentrations of amoxicillin and clavulanic acid in the blood. As a result of increased bioavailability of clavulanic acid, the incidence of gastrointestinal side effects is reduced.

Mechanism of action of beta-lactamases

Beta-lactamase enzymes destroy the beta-lactam ring by two main mechanisms. The first mechanism inherent in lactamases of classes A, C and D (division into classes is carried out depending on the sequence of amino acids in the enzyme structure) is binding to the substrate due to the presence of a special flexible active site (Fig. 1). Irreversible binding to the carbonyl group of the beta-lactam ring occurs and its integrity is disrupted, which renders the antibiotic inactive and simultaneously ensures the regeneration of beta-lactamase. These classes of beta-lactamases are active against many penicillins, cephalosporins and monobactams. The second mechanism is inherent in a less common group of beta-lactamases, which belong to class B. Enzymes of this class are also called metallo-beta-lactamases because they contain a mobile divalent metal ion, most often a zinc ion, which is able to bind to the carbonyl group of most penicillins, cephalosporins and carbapenems, but not monobactams [1].

Ampicillin/sulbactam

Features of antimicrobial activity

Active against gram-positive (streptococci, staphylococci, except oxacillin-resistant) and gram-negative (N. gonorrhoeae, N. meningitidis) cocci, listeria, H. influenzae, M. catarrhalis, anaerobes (including B. fragilis), less active against enterococci and some enterobacteria (E. coli, P. mirabilis, Klebsiella spp.).

Acquired resistance - see Amoxicillin/clavulanate

Main indications

• Skin and soft tissue infections
• Community-acquired intra-abdominal infections
• Community-acquired gynecological infections
• Community-acquired destructive or abscess pneumonia
• Prevention in abdominal surgery and obstetrics-gynecology

For upper respiratory tract infections and pneumonia, it is more advisable to prescribe amoxicillin/clavulanate.

Dosing

Intravenously 1.5-3 g 4 times a day, orally 375-750 mg 2 times a day. Prevention in surgery: intravenously 3 g 30-60 minutes before surgery