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

Penicillins
Cephalosporins

Cephalosporins are a group of natural and numerous semisynthetic beta-lactam Antibiotics that are bicyclic compounds consisting of a ß-lactam ring and a dihydrothiazine ring fused to form 7-aminocephalosporanic acid, the common core Structure of all cephalosporin molecules. The first cephalosporins emerged over 40 years ago. Today, they hold a leading position in both clinical and outpatient practice, including the Treatment of the most severe infectious processes.

Out of more than 60 original cephalosporins currently existing worldwide, the preparations marked with an asterisk in Table 14 are registered in Ukraine. If trade names are also taken into account, there are approximately 50 different generations of cephalosporins available in our country (Table 15).

Class="center">Table 14. Classification of cephalosporins (S.V. Yakovlev, 1999; with modifications)

Table 15. Original cephalosporin preparations and their analogs registered and approved for medical use in Ukraine

Cephalosporins of different generations differ significantly in their antimicrobial spectrum (Table 16).

Thus, first-generation cephalosporins are characterized by high activity primarily against Gram-positive Bacteria (staphylococci, streptococci, including hospital strains). Their activity against Gram-negative bacteria is limited (only E. coli, Salmonella spp., Shigella spp., and P. mirabilis are sufficiently sensitive) due to the fact that these agents are easily hydrolyzed by the beta-lactamases of these pathogens.

Table 16. Antimicrobial spectrum of cephalosporins (S.V. Yakovlev, 1999, 2001)

Compared to first-generation cephalosporins, second-generation preparations exhibit greater efficacy against Gram-negative bacteria (primarily H. influenzae) and anaerobes, along with a somewhat weaker effect on staphylococci and streptococci. Their activity is insufficient against A number of Gram-negative microorganisms responsible for nosocomial infections: Enterobacter spp., Citrobacter spp., Serratia spp., Klebsiella spp., P. vulgaris, and P. rettgeri. Furthermore, Pseudomonas spp. and Acinetobacter spp. exhibit natural resistance to second-generation cephalosporins.

Third-generation cephalosporins possess high activity against the majority of Gram-negative microorganisms, including strains resistant to Other Antibiotics and nosocomial strains (Pseudomonas spp., Proteus spp., Bacteroides spp.); certain third-generation cephalosporins demonstrate anti-pseudomonal activity. In terms of their potency against P. aeruginosa, third-generation cephalosporins can be ranked in the following order: ceftazidime > cefoperazone > ceftriaxone > cefotaxime. Third-generation cephalosporins have insufficient efficacy against staphylococci, non-pyogenic streptococci, and enterococci (these drugs should not be prescribed for Infections caused by these microorganisms).

Fourth-generation cephalosporins combine the third-generation activity against Gram-negative microorganisms (Enterobacteriaceae family, Neisseriaceae, H. influenzae, M. catarrhalis, Pseudomonas spp., Acinetobacter spp.) with the specific efficacy of first- and second-generation cephalosporins against Gram-positive microorganisms (methicillin-susceptible staphylococci, streptococci) and certain Gram-positive anaerobes, while lacking activity against Bacteroides spp. Their potency against Gram-negative bacteria is comparable to the most effective third-generation cephalosporins, fluoroquinolones, and carbapenems. Despite The activity of fourth-generation cephalosporins against certain anaerobes, they are ineffective against the most common pathogens of intra-abdominal and wound anaerobic infections; therefore, in such cases, they must be combined with anti-anaerobic agents (Lincosamides, metronidazole).

They are resistant to ß-lactamases, including extended-spectrum beta-lactamases, which makes fourth-generation cephalosporins active against strains resistant to third-generation cephalosporins.

Cephalosporins with significant anti-anaerobic activity (cephamycins) include cefoxitin, cefotetan, and cefmetazole. The most active cephalosporins against P. aeruginosa and other non-fermenting microorganisms are ceftazidime, cefoperazone, cefepime, and sulperazone.

It is known that secondary resistance to cephalosporins develops slowly. This statement does not apply to third-generation cephalosporins, which tend to induce beta-lactamase production and, according to existing projections, were expected to become largely ineffective by the first decade of the 21st century, particularly in the treatment of nosocomial infections. For instance, in the 1980s, the majority of hospital microbial strains exhibited high susceptibility to third-generation cephalosporins. Over the past decade, however, an increase in the resistance of Gram-negative microorganisms to third-generation cephalosporins has been observed. The Emergence of pathogen strains producing extended-spectrum beta-lactamases plays a crucial role in these processes. Specifically, during the treatment of patients with severe hospital-acquired Pneumonia or Sepsis caused by Enterobacter spp. and Serratia marcescens using third-generation cephalosporins, strains that are hyperproducers of chromosomal beta-lactamases may emerge within just 3–5 days. This phenomenon is driven by Mutations in the regulatory Regions of the genome, leading to the depression of enzyme synthesis. Such strains of Enterobacter spp., which are insensitive to third-generation cephalosporins, are currently found in 30–60% of cases in European clinics. Another mechanism of resistance to all third-generation cephalosporins is The production of plasmid-mediated extended-spectrum beta-lactamases, most frequently registered in Klebsiella spp. (in 30% of cases).

Pharmacokinetics. The absorption of orally administered cephalosporins varies considerably—ranging from 40 to 95%—and generally does not depend on food intake (Table 17).

Plasma protein binding varies significantly, from 15 to 90%. For example, cefotaxime and ceftriaxone, both third-generation cephalosporins, exhibit 20–40% and 80–95% binding, respectively. Their wide distribution throughout the body enables the treatment of patients with infections localized in various Tissues, including bones and soft tissues. Third-generation cephalosporins cross the Blood-Brain barrier better than fourth-generation agents and, in particular, second- and first-generation drugs, making them suitable for use in Meningitis caused by N. meningitidis, H. influenzae, and penicillin-resistant S. pneumoniae.

Cephalosporins also differ in the duration of maintaining therapeutic concentrations in Blood Plasma, which dictates varying dosing frequencies. Thus, the duration of therapeutic concentration for first-generation cephalosporins is 3–4 hours (administered 6 times a day); for second-generation preparations, it is 6–8 hours (administered 3 times a day); for the third generation, 12–24 hours (administered 1–2 times a day); and for the fourth generation, 8–12 hours (administered 2–3 times a day).

Only two drugs—cephalothin and cefotaxime—are deacetylated in The Liver and Kidneys. The resulting metabolites retain partial activity. The remaining cephalosporins are excreted unchanged via the kidneys. Excretion of first-generation drugs occurs via tubular secretion, making them potentially nephrotoxic. Second- and fourth-generation drugs are eliminated primarily through Glomerular Filtration. The liver also plays a partial role in the elimination of fourth-generation cephalosporins. Elimination of third-generation cephalosporins is carried out by both the kidneys and the liver. Consequently, dosage adjustments for third-generation cephalosporins are unnecessary in renal impairment, and are required only in severe forms (creatinine clearance < 30 ml/min) for fourth-generation cephalosporins. Table 17 outlines the pharmacokinetic properties of major cephalosporins.

Table 17. Pharmacokinetics of cephalosporins (The Sanford Guide to Antimicrobial Therapy, 2001; with modifications)

Notes: N/A - data not available; C_m - maximum serum concentration; ¹ - maximum concentration in Bile divided by maximum concentration in serum × 100.

Indications for use. Cephalosporin antibiotics currently hold a leading position in the inpatient treatment of various infections. In most cases, they are preferred in initial empirical therapy regimens for infections of various localizations. This is due to their broad spectrum of antibacterial activity, optimal pharmacokinetic profile, and relatively good patient tolerability, even when administered at maximum doses. To broaden THE SPECTRUM OF antibacterial activity, they can be combined with other antibiotics, particularly in severe infectious processes caused by associations of multiresistant microorganisms. Fourth-generation cephalosporins are primarily indicated for the empirical therapy of severe hospital-acquired infections, given their broad antimicrobial spectrum and relatively low level of microbial resistance. Such infections include severe pneumonia (including ventilator-associated pneumonia), sepsis, intra-abdominal and gynecological infections (in combination with anti-anaerobic agents), intensive care unit infections, infections in oncological patients, and infections in patients with agranulocytosis (in combination with the aminoglycoside amikacin).

Fourth-generation cephalosporins become the drugs of choice for infections caused by Gram-negative microorganisms exhibiting high levels of resistance to third-generation cephalosporins, primarily Enterobacter spp., S. marcescens, and other Enterobacteriaceae.

Cefazolin (zolfin, ifisol, kefzol, reflin, totacef, cezolin, cefazolin-KMP, cefazolin-TEVA, cephamezin, cefazolin "Biochemi") is a first-generation broad-spectrum cephalosporin. It is active against oxacillin-susceptible staphylococci, streptococci (excluding S. faecalis), and a range of gram-negative microorganisms (E. coli, P. mirabilis and P. vulgaris, Klebsiella spp., H. influenzae, Enterobacter aerogenes). It is inactive against oxacillin-resistant staphylococci, penicillin-resistant pneumococci, enterococci, H. influenzae, other gram-negative enterobacteria, bacteroides, resistant indole-positive Proteus strains (P. rettgeri, P. morganii), P. aeruginosa, rickettsiae, Viruses, Protozoa, and Fungi. It exerts a bactericidal effect by inhibiting Introduction/37.html">Bacterial Cell wall synthesis and is degraded by beta-lactamases of gram-negative bacteria.

Pharmacokinetics. Following intramuscular administration of cefazolin, the maximum plasma concentration is reached within 1 hour; effective plasma concentrations are maintained for 8–12 hours after both intramuscular and intravenous administration. It is eliminated from the body via the kidneys through glomerular filtration and tubular secretion. It penetrates well into Organs and tissues, easily crossing the placental barrier.

Indications for use. Cefazolin is indicated for infections caused by susceptible microorganisms: community-acquired Skin and soft tissue infections, acute mastitis, mild postoperative wound infections (in combination with Aminoglycosides), acute Osteomyelitis, for preoperative surgical prophylaxis, and for Staphylococcal infections caused by oxacillin-susceptible strains.

The drug is administered at a dose of 0.25–0.5 g every 8 hours intramuscularly or intravenously (by bolus or infusion) for infections caused by gram-positive microorganisms, and 0.5–1.0 g every 6–8 hours for diseases caused by gram-negative susceptible microflora. For respiratory tract infections caused by pneumococci and genitourinary infections (including Gonorrhea), the drug is prescribed at 0.5–1.0 g every 12 hours.

Cefazolin is contraindicated in hypersensitivity to beta-lactam antibiotics; it should be used with caution in patients with renal impairment and intestinal diseases.

Interactions. Co-administration with drugs that block tubular secretion increases the risk of toxic reactions, while concurrent use with indirect anticoagulants enhances their anticoagulant effect.

Cephalexin (lexin-125, lexin-250, lexin-500, oracef, ospexin, sporidex, cephabene, cephaclen, cephalexin-250, cephalexin-TEVA, kepexin, piasan, palitrex) is a first-generation broad-spectrum cephalosporin antibiotic.

Spectrum of antibacterial activity: gram-positive cocci — S. pyogenes, S. viridans, S. agalactiae, S. pneumoniae (penicillin-susceptible strains), S. aureus, Staphylococcus spp. (oxacillin-susceptible strains), streptococci (excluding enterococci), and Corynebacterium diphtheriae. It is active against certain gram-negative microorganisms: meningococci, gonococci, shigellae, salmonellae, and Escherichia coli (currently, the majority of hospital-acquired E. coli strains are resistant to cephalexin). It is inactive against Pseudomonas aeruginosa, indole-positive Proteus strains, and anaerobic microorganisms. The bactericidal mechanism of the drug is due to the disruption of the bacterial cell membrane during the Replication phase.

Pharmacokinetics. Cephalexin is acid-stable. When taken orally on an empty Stomach, it is rapidly (in 1.5–2 hours) and almost completely (95%) absorbed. Effective concentrations of cephalexin are maintained in the blood for 4–6 hours. Approximately 80% of the drug is excreted unchanged via the kidneys.

Indications for cephalexin use: ENT infections (otitis media, sinusitis, streptococcal tonsillitis, pharyngitis), acute Pyelonephritis, cystitis, prostatitis, mild community-acquired infections of the skin, soft tissues, bones, and joints, as well as other conditions caused by susceptible microorganisms.

The drug is administered orally (in capsules or as an oral suspension) at 0.25–0.5 g 4 times a day, regardless of meals. The suspension, prepared from powder supplied in vials, can be stored in a refrigerator for up to one week.

Cephalexin is not recommended for pregnant women, during Lactation, or in infants under 6 months of age. It should be used with caution in patients with impaired renal function and a history of pseudomembranous colitis.

Cefuroxime axetil (zinacef, zinnat, yokel, cefuroxime "Biochemi") is a second-generation oral cephalosporin with bactericidal activity.

It possesses a broad spectrum of antimicrobial activity, acting against many beta-lactamase-producing microorganisms that are resistant to ampicillin and amoxicillin. It is most active against gram-positive cocci, including staphylococci such as S. aureus and Staphylococcus spp. (excluding oxacillin-resistant strains); S. pneumoniae (penicillin-susceptible strains) and other beta-hemolytic streptococci, and group B streptococci; certain gram-negative bacteria (H. influenzae, M. catarrhalis, E. coli, Klebsiella spp., P. mirabilis, P. rettgeri, Providencia spp.); and anaerobes (Peptococcus spp., Peptostreptococcus spp., Clostridium spp., Bacteroides spp., Fusobacterium spp.).

Pharmacokinetics. Following oral administration, the drug is rapidly hydrolyzed in the intestinal mucosa and enters the systemic Circulation as cefuroxime, reaching peak plasma concentrations within 2–3 hours. It is excreted unchanged via the kidneys.

Cefuroxime axetil is used for community-acquired infections, including Bronchitis, pneumonia (serving as a drug of choice in empirical therapy for community-acquired pneumonia), otitis media, sinusitis, tonsillitis, pharyngitis, cystitis, urethritis, pyelonephritis, and skin and soft tissue infections.

The drug is prescribed orally after meals at a dose of 0.5 g twice daily (in severe infections, the dose may be increased to 1.0 g twice daily).

Cefuroxime is also available as a parenteral preparation (zinacef, ketocef) for intramuscular or intravenous administration, which shares the same antimicrobial spectrum as cefuroxime axetil. In addition to the indications listed above, zinacef can be used for acute osteomyelitis, septic Arthritis, community-acquired intra-abdominal infections (in combination with lincosamides or metronidazole), and for surgical prophylaxis.

Interactions. Pharmaceutical incompatibility exists between the injectable form of cefuroxime and aminoglycosides or sodium bicarbonate solution (they must not be administered in the same syringe). Concurrent use with loop Diuretics reduces the renal clearance of cefuroxime.

It must be prescribed with caution in patients with renal impairment, during Pregnancy, and during lactation.

Cefotaxime (claforan, spirozin, talcef, tarcefoxim R, facocef, cefantral, cefotaxime-KMP, cefotam, cefotaxime-MILI) is a third-generation broad-spectrum cephalosporin.

Spectrum of activity. It is most active against gram-negative microflora: N. gonorrhoeae, N. meningitidis, H. influenzae, M. catarrhalis, and Enterobacteriaceae (E. coli, Proteus spp., Shigella spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Citrobacter spp., Serratia spp.). It exerts a bactericidal effect on certain gram-positive microorganisms, including staphylococci (S. aureus, including penicillinase-producing strains, S. epidermidis), streptococci (S. pneumoniae, S. pyogenes, S. agalactiae), and B. subtilis. It is also active against anaerobic microorganisms such as bacteroides, C. perfringens, peptococci, and peptostreptococci.

Pharmacokinetics. Following intramuscular administration of cefotaxime, peak plasma concentrations are observed within 30 minutes, and effective concentrations are maintained for over 12 hours. The drug penetrates well into organs and tissues, achieving bactericidal levels in peritoneal, synovial, and pleural fluids. It is excreted by The Kidneys in unchanged form (30–50%) and as active metabolites.

Cefotaxime is used for severe community-acquired pneumonia, complicated Urinary Tract infections, community-acquired intra-abdominal infections (in combination with lincosamides or metronidazole), mild-to-moderate hospital-acquired intra-abdominal infections, Purulent meningitis, acute gonorrhea, postoperative skin and soft tissue infections, and generalized salmonellosis.

The drug is administered intramuscularly or intravenously (slow bolus or infusion) at a dose of 1.0 g twice daily (in severe cases, the dose can be increased to 2.0 g 3–4 times daily, up to a maximum daily dose of 12.0 g). In patients with renal impairment, the dosage of cefotaxime (as with other cephalosporins) should be adjusted according to creatinine clearance.

Interactions. Pharmaceutical incompatibility is observed with aminoglycosides and other antibiotics (they should not be administered in the same syringe or infusion set). When combined with nonsteroidal anti-inflammatory drugs and antiplatelet agents, the risk of bleeding increases; drugs that block tubular secretion inhibit The excretion of cefotaxime.

Ceftriaxone (ificef, lendacin, oframax, rocephin, ceftriaxone-KMP, meghion, tercef, ceftriaxone-MILI, teftriaxone) is a 3rd-generation cephalosporin. It possesses a broad spectrum of activity and is most active against Gram-negative microorganisms: N. gonorrhoeae, N. meningitidis, H. influenzae, M. catarrhalis, Enterobacteriaceae (E. coli, Proteus spp., Shigella spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Citrobacter spp., Serratia spp., Providencia spp., M. morganii). It is active against streptococci, including penicillinase-resistant S. pneumoniae. It is ineffective against oxacillin-resistant staphylococci, enterococci, P. aeruginosa, and Bacteroides spp.

Pharmacokinetics. Following intramuscular administration, an effective plasma concentration is achieved within 1–1.5 hours and is maintained for 24 hours. The drug readily penetrates all body tissues and fluids, including across the blood-brain barrier (permeability increases in the presence of meningeal inflammation).

It is excreted from the body unchanged via the kidneys (60%), and partially through the bile.

Ceftriaxone is indicated for infections caused by susceptible microorganisms, in the same clinical scenarios as cefotaxime.

The drug is administered intramuscularly at a dose of 1–2 g once daily for moderate infections, and up to 4 g daily for severe conditions. For the prophylaxis of postoperative complications, it is administered preoperatively at a dose of 1–2 g, and postoperatively at 0.25 g. For uncomplicated gonorrhea, a single intramuscular dose of 0.25–0.5 g of ceftriaxone is sufficient.

The drug is not recommended during pregnancy and lactation, in newborns under 7 days of age (especially premature infants), in neonatal Hyperbilirubinemia, and in patients with a history of antibiotic-associated intestinal disorders. Dosage adjustment is required in renal and hepatic impairment.

Cefepime (maxipime) is a broad-spectrum 4th-generation cephalosporin antibiotic. It exhibits high activity against Gram-negative microorganisms — N. gonorrhoeae, N. meningitidis, H. influenzae, M. catarrhalis, Enterobacteriaceae (E. coli, Proteus spp., Shigella spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Citrobacter spp., Serratia spp., Providencia spp., M. morganii) — as well as Gram-positive cocci, including streptococci, pneumococci (including penicillin-resistant strains), and S. aureus. Cefepime shows moderate activity against coagulase-negative staphylococci, Gram-positive anaerobes, P. aeruginosa, and Acinetobacter spp. It is inactive against oxacillin-resistant staphylococci and bacteroides.

Pharmacokinetics. Following intravenous administration, T_1/2 is approximately 2 hours. About 20% of the drug is bound to Plasma Proteins. Cefepime crosses the blood-brain barrier in meningitis. 75–90% of the drug is excreted unchanged in the urine.

Cefepime is used to treat nosocomial infections: pneumonia (including in mechanically ventilated patients), urinary tract infections, intra-abdominal and gynecological infections (in combination with anti-anaerobic agents), postoperative wound infections, sepsis, infections in neutropenic patients, Pseudomonas aeruginosa infections, and infections caused by Enterobacteriaceae resistant to 3rd-generation cephalosporins.

The drug is administered intravenously in a daily dose of 1–2 g (divided into two injections), and in cases of neutropenia, 2 g (divided into three injections).

The drug should be used with caution during pregnancy and lactation, in newborns (especially premature infants), in neonatal hyperbilirubinemia, and in patients with a history of colitis.

Cefpirome (cefrom, caiten) is a broad-spectrum 4th-generation cephalosporin antibiotic. It is highly active against Gram-positive and Gram-negative microorganisms (both aerobic and anaerobic). To a greater extent than 3rd-generation cephalosporins, it is stable against beta-lactamases produced by Gram-negative bacteria. It has no effect on methicillin-resistant staphylococci. It is active against all Proteus species, Serratia strains, E. coli, Bacteroides, and Klebsiella. It is active against pneumococci, including strains with reduced susceptibility to benzylpenicillin. It is effective against microorganisms resistant to Penicillins, erythromycin, Tetracyclines, chloramphenicol, and aminoglycosides.

Pharmacokinetics. Upon intravenous administration, the therapeutic concentration of the drug in the blood is maintained for 12 hours. It is excreted via the kidneys and partially through the bile.

Cefpirome is used for the empirical therapy of nosocomial infections (severe pneumonia, intra-abdominal and gynecological infections), infections in intensive care units, febrile episodes in agranulocytic patients, and infections caused by Gram-negative pathogens exhibiting high resistance to 3rd-generation cephalosporins.

The drug is administered intravenously (as a bolus or infusion) or intramuscularly at a dose of 2.0 g twice daily; in renal impairment, the dose is adjusted to 0.5–1.0 g twice daily.

The Use of the drug is discouraged during pregnancy and lactation, in newborns under 7 days of age (especially premature infants), in neonatal hyperbilirubinemia, and in patients with a history of antibiotic-associated intestinal disorders.

Adverse effects of cephalosporins. The most significant adverse effects of cephalosporins include: allergic reactions, hematological reactions, hepatic dysfunction, nephrotoxicity, dysbiocenosis and superinfection, local reactions (resulting from irritant effects), and Central Nervous system effects.

Allergic reactions to cephalosporins occur in 2–18% of patients. Based on the risk of adverse reactions, the drugs can be ranked in the following order: ceftriaxone > cefoperazone > cefoxitin > ceftazidime > cefotaxime > cefuroxime. Maculopapular or scarlatiniform skin rashes and fever develop most frequently. Urticaria, serum sickness-like reactions (especially with cefaclor), anaphylactic Shock, immune cytopenias, and acute interstitial nephritis are less common. Compared to 1st-generation (cephalothin, cefazolin, cephalexin, cephadroxil) and 2nd-generation (cefamandole, cefuroxime) agents, the likelihood of generalized IgE-mediated systemic reactions with 3rd-generation agents is lower. When treating with any cephalosporin, the potential for cross-allergy with penicillins should be considered; this occurs in 5–18% of cases and is due to the shared chemical structure (presence of the beta-lactam ring) of these two antibiotic groups. Cross-allergy with penicillins is most frequently observed with 1st-generation cephalosporins and is minimal for 3rd- and 4th-generation agents. Nevertheless, cephalosporins are contraindicated in patients with a history of IgE-mediated allergic reactions to penicillins (anaphylactic shock, angioedema, urticaria, etc.). The possibility of cross-reactivity between cephalosporins and other beta-lactam drugs cannot be ruled out, including carbapenems (tienam, meropenem), Monobactams (aztreonam), carbacephems (loracarbef), clavulanic acid and its derivatives such as amoxicillin/clavulanate (augmentin, etc.).

Cephalosporins, particularly 1st- and 2nd-generation agents, can cause hemorrhages resulting from the inhibition of platelet function and the slowing of Blood Coagulation. 3rd-generation cephalosporins (especially cefotaxime, cefoperazone, latamoxef), as well as cefotetan, cefamandole (2nd generation), and cephalothin (1st generation), may act similarly to indirect anticoagulants by inhibiting hepatic epoxide reductase in the vitamin K cycle, which is accompanied by The Development of hemorrhagic diathesis. Such hemorrhages must be managed by administering vitamin K. The Pathogenesis of increased bleeding tendency induced by cephalosporins (most commonly during treatment with cefazolin and cefamandole) also involves The formation of Antibodies against clotting factors V and VIII, and the inhibition of The conversion of fibrinogen to fibrin. Decreased blood coagulation is more likely to develop when cephalosporins are administered to malnourished patients or those with liver disease, who exhibit low vitamin K levels and hypoprothrombinemia.

Blood dyscrasias (leukopenia, neutropenia, thrombocytopenia) occur relatively rarely during cephalosporin therapy, more often with the use of cephalothin, cephalexin, or high doses of cephalosporins. A decrease in neutrophil count can occur abruptly after 9–28 days of therapy, most commonly after 3 weeks. Following discontinuation of the drugs, the blood neutrophil count recovers.

During treatment with cephalothin, cefamandole, cefotaxime, or ceftazidime, positive Coombs test results are frequently observed. However, autoimmune hemolytic anemia does not develop in the majority of patients; therefore, this is referred to as a "false-positive Coombs reaction." Cases of acute intravascular hemolysis have been described during treatment with cephalexin, cefuroxime, cefoperazone, and ceftibuten.

Oral administration of cephalosporins (most frequently cephalexin) causes irritation of the gastrointestinal mucosa, leading to nausea, occasionally vomiting, dysgeusia, and diarrhea. The latter may resolve spontaneously even if treatment is continued.

Intramuscular administration of cephalosporins is associated with pain and aseptic inflammation at the injection site due to the irritant effect. Intravenous administration may lead to phlebitis and thrombophlebitis (especially with cephalothin, cefotaxime, and cefepime). The frequency of this complication is reduced when buffered solutions are used and administered slowly intravenously (over 5–10 minutes) or, even better, as an infusion. 3rd- and 4th-generation agents cause this adverse effect less frequently.

Dysbiosis and superinfection are considered among the most dangerous complications of cephalosporin therapy and develop more frequently with oral administration (cephalexin, cefaclor, cefuroxime axetil, etc.), although parenteral administration does not completely exclude their occurrence. Cases of pseudomembranous colitis have been reported (among parenterally administered cephalosporins, most commonly caused by cefotaxime), which are associated with the intensive proliferation of enterotoxigenic clostridia (C. difficile) in the intestinal lumen. Vancomycin (or teicoplanin) or metronidazole is used to suppress them, and cholestyramine is used to bind their toxin.

Cephalosporins, particularly first-generation drugs eliminated primarily via renal tubular excretion, are known for their potential adverse effects on renal function. In such cases, the nephrotoxicity of agents such as cefaclor, cephalothin, and cefazolin is attributed to their accumulation within renal tubular epithelial Cells, where they inhibit mitochondrial Respiration. Cephaloridine is retained in the renal tubular epithelial cells, where it is metabolized by cytochrome P-450 into cytotoxic epoxides. The adverse renal impact of cephalosporins can manifest as acute interstitial nephritis or acute tubular necrosis, potentially leading to oliguria and uremia, which may be either reversible or irreversible. Cephalexin, 70–80% of which is excreted unchanged in the urine and which is frequently prescribed for urinary tract infections, may induce Hematuria and reversible non-oliguric renal failure.

Hepatotoxicity associated with cephalosporins (such as cefoperazone, ceftriaxone, ceftazidime, and cefuroxime) typically presents as elevated serum liver Enzymes (aminotransferases, Lactate dehydrogenase, alkaline phosphatase), anicteric hepatitis, and intrahepatic cholestasis. Ultrasonography may occasionally reveal pseudocholelithiasis (Gallbladder "shadows" that resolve upon discontinuation of the cephalosporin). However, in patients with a history of cholelithiasis, these drugs may precipitate acute exacerbations. Kernicterus has also been reported in infants under one year of age.

High-dose administration of cephalosporins (including cephaloridine and cephalexin) can induce encephalopathy within 12–72 hours of treatment initiation. Clinical manifestations include nystagmus, behavioral changes, hallucinations, hyperreflexia, myoclonic, focal, and generalized seizures, as well as coma. This complication arises from the antagonism between cephalosporins and GABA, which abolishes its inhibitory effect on central nervous system neurotransmission. Therefore, high-dose cephalosporin therapy necessitates the concurrent administration of diazepam or phenobarbital. Seizures may also occur when cefazolin is administered in the presence of renal impairment if appropriate dosage adjustments are not made.

A disulfiram-like or antabuse-like reaction (characterized by nausea, vomiting, diarrhea, facial flushing, tachycardia, and hypotension) may occur when alcohol is consumed during cephalosporin therapy, resulting from the inhibition of acetaldehyde dehydrogenase activity. Notably, moxalactam, cefoperazone, and cefmenoxime do not provoke this reaction.

The use of cephalosporins during pregnancy is not contraindicated. Nevertheless, the therapeutic benefits must always be carefully weighed against potential risks prior to initiating treatment. Most cephalosporins do not exert adverse effects on nursing infants when excreted into breast milk. However, caution should be exercised when cefoperazone, ceftriaxone, or cefuroxime are administered to nursing mothers. Due to a lack of clinical safety data regarding third-generation cephalosporins (such as pivoxil, cefetamet, ceftibuten, and cefixime), their use during lactation should be avoided.

Interactions with drugs from other pharmacological classes. First-generation cephalosporins should not be combined with polymyxins, amphotericin B, furosemide, ethacrynic acid, or indomethacin, as this significantly increases the risk of nephrotoxicity. Cephalosporins of other generations may be combined with aminoglycosides when necessary to broaden the antimicrobial spectrum and potentiate antibacterial efficacy; however, such combinations must be clinically justified and accompanied by rigorous renal function monitoring.

Cephalosporins must not be co-administered in the same syringe or intravenous infusion line with aminoglycosides (as chemical interaction leads to the formation of inactive metabolites) or with aminophylline (which results in precipitation).