Cephalosporins are produced from 7-aminocephalosporanic acid by adding different side chains to the beta-lactam ring or the dihydrothiazine ring.
Cephamycins are similar to cephalosporins but have a methoxy group at position 7 of the beta-lactam ring.
Structure
- The nucleus is made of 7-aminocephalosporanic acid that consist of a beta-lactam ring and a dihydrothiazine ring fused together.
- Addition of different side chains at position 7 of the beta-lactam ring alters the antibacterial activity, while modifications at position 3 of the dihydrothiazine ring alter the pharmacokinetic properties.
Mechanism of Action
- All cephalosporins are bactericidal and inhibits the bacterial cell wall synthesis (similar to penicillin, but binds to different PBPs).
First Generation Cephalosporins
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Have good activity against gram-positive bacteria and relatively modest activity against gram-negative.
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Anaerobic cocci (eg. peptostreptococci, peptococci) are sensitive, but not the B. fragilis group.
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Includes :
- Cefazolin
- Cephalexin
- Cefadroxil
- Caphalothin
- Cephapirin
- Cephradine
Second Generation Cephalosporins
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Heterogenous group with differences in activity, pharmacokinetics and toxicity.
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Have broader spectrum than first-generation and are effective against Enterobacter, indole positive Proteus and Klebsiella.
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Weaker than first generation agents against gram positive bacteria, while are more active against gram-negative organisms.
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Includes :
- Cefaclor
- Cefuroxime
- Cefprozil
- Cefamandole
- Cefonicid
- Loracarbef
- Ceforanide
- Cefuroxime axetil
- Cephamycins : Cefoxitin, Cefotetan.
Third Generation Cephalosporins
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Generally less active against gram-positive cocci and anaerobes, but have expanded gram-negative coverage and highly augmented activity against Enterobacteriaceae, including beta-lactamase producing strains.
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All are resistant to beta-lactamases produced by gram-negative bacteria.
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Penetrates body fluids and tissues well, and can achieve sufficient levels in CSF to inhibit most susceptible pathogens when given IV.
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Includes :
- Cefotaxime
- Ceftazidime
- Ceftriaxone
- Cefixime
- Cefpodoxime proxetil
- Cefdinir
- Cefditoren pivoxil
- Ceftibuten
- Cefoperazone
- Ceftizoxime
- Moxalactam
- Ceftamet pivoxil
Fourth Generation Cephalosporins
- Have extended activity spectrum compared to third generation.
- Not susceptible to inducible chromosomal beta-lactamases produced by some resistant bacteria.
- Highly active against Enterobacteriaceae.
- Includes : Cefepime and Cefpirome.
Fifth Generation Cephalosporins
- Active against MRSA and some other resistant bacteria.
- Includes : Ceftaroline fosamil, Ceftobuprole medocaril.
Commonly Used Cephalosporins
Cephalexin
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Orally used first-generation cephalosporin (widely used in the United States).
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Excretion is mainly by glomerular filtration and tubular secretion into the urine. Hence, the dosage must be reduced in patients with renal impairment.
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Indications :
- Treatment of urinary tract infections
- Staphylococcal or streptococcal infections, including cellulitis or soft tissue abscess.
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Dosage : 250-500 mg qid (25-50 mg/kg/d in 4 doses).
Cefazolin
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Used parenterally.
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Indications :
- Surgical prophylaxis.
- Streptococcal and Staphylococcal infections requiring intravenous therapy.
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Dosage (IV) : 0.5-2 g every 8 hour (25-100mg/kg/d in 3 or 4 doses), can also be administered intramuscularly.
Cefuroxime
- Active against some Citrobacter and Enterobacter species, but lacks activity against B. fragilis.
- Resistant to gram-negative beta-lactamases and effective for treatment of meningitis caused by H. influenzae, N. meningitidis, S. pneumoniae.
- Concentration in CSF is around 10% of those in plasma.
- Has been superseded by third generation cephalosporins in the treatment of meningitis.
- Can be used for single dose IM therapy of gonorrhoea due to PPNG.
- Cefuroxime axetil : Ester of cefuroxime, 30-50% absorbed orally and then hydrolysed to cefuroxime.
Cefaclor
- Active against H. inluenzae and Moraxella catarrhalis.
- Retains significant activity by the oral route but highly susceptible to beta-lactamases.
- Dosage : 0.25-1.0 g every 8 hour.
- Loracarbef : similar in activity to cefaclor and more stable against beta-lactamases.
Cefprozil
- More active against penicillin-sensitive streptococci, E. coli, P. mirabilis, Klebsiella and Citrobacter species.
- Has good oral absorption (more than 90%).
- Indications : Bronchitis, ENT and skin infections.
- Dosage : 240-500mg BD (20mg/kg/day).
Cephamycins
- Includes Cefoxitin and Cefotetan.
- Active against anaerobes including B. fragilis strains.
- Can be used to treat mixed anaerobic infections such as peritonitis, diverticulitis, and pelvic inflammatory disease.
Cefotaxime
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Highly resistant to many beta-lactamases and has good activity against aerobic gram-negative and some gram-positive bacteria.
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Poor activity against anaerobes (particularly B. fragilis), S. aureus and Pseudomonas aeruginosa.
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Attains relatively high CSF levels.
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Indications :
- Meningitis caused by gram-negative bacilli.
- Life-threatening resistant/ hospital-acquired infections.
- Septicemias.
- Infections in immunocompromised patients.
- Alternative to Ceftriaxone for typhoid fever
- Single dose therapy (1g IM + 1g Probenecid oral) for PPNG urethritis.
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Dosage (IV) : 1-2g every 6-12 hour (50-200 mg/kg/d in 4-6 doses).
Ceftazidime
- Highly active against Pseudomonas aeruginosa.
- Indications : Febrile neutropenic patients with hematological malignancies, burn, etc.
- Dosage : 1-2g every 8-12 hourly IM or IV (75-150 mg/kg/d in 3 doses).
- Adverse Effects : Neutropenia, Thrombocytopenia, Rise in plasma transaminase and blood urea.
Ceftriaxone
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Have a half-life of around 8 hours, hence, longer duration of action and once or twice daily dose is effective.
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Have high efficacy against wide range of serious infections, eg. bacterial meningitis (esp. in children), multi-resistant typhoid fever, complicated urinary tract infections, abdominal sepsis and septicaemia.
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Indications :
- Skin, soft tissue or urinary infections : 1-2 g IV or IM per day.
- Meningitis : 4 g followed by 2 g IV (75-100mg/kg) once daily for 7-10 days.
- Gonorrhoea (incl. PPNG) and Chancroid : 1g IM single dose is curative.
- Typhoid : 4g IV daily x 2 days, followed by 2g/day (75mg/kg) till 2 days after fever subsides.
- Alternative drug for syphilis : 1g IM for 7 days (early syphilis) and for 15 days (late syphilis).
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Adverse Effects : Hypoprothrombinaemia and bleeding.
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Combination (to overcome resistance) :
- Ceftriaxone (250mg) + Sulbactam (125mg).
- Ceftriaxine (1g) + Tazobactam (125mg).
Cefixime
- Orally active third generation cephalosporin.
- Highly active against Enterobacteriaceae, H. influenzae, Streptococcus pyogens.
- Resistant to many beta-lactamases.
- Not active against S. aureus, most pneumococci and Pseudomonas.
- Half-life is around 3 hours.
- Indications : Respiratory, urinary and biliary infections.
- Dosage : 200mg twice daily or 400mg once daily.
- Adverse Effects : Stool changes and diarrhoea.
- *Due to increasing resistance, cefixime is no longer recommended for the treatment of uncomplicated gonococcal urethritis and cervicitis.
Cefipime
- Relatively resistant to chromosomally encoded and some extended spectrum beta-lactamases.
- Active against many Enterobacteriaceae that are resistant to other cephalosporins, but inactive against MRSA.
- Indication :Sserious infections like hospital-acquired pneumonia, febrile neutropenia, bacteraemia and septicaemia.
- Dosage : 0.5-2 g every 12 hour IV (75-120mg/kg/d in 2 or 3 divided doses).
Ceftaroline fosamil
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Pro-drug, that after IV infusion is rapidly converted to active metabolite, ceftaroline.
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Has increased affinity to PBP 2a, which mediates methicillin resistant in staphylococcus and PBP2b and PBP2x (in penicillin resistant Streptococcus pneumoniae).
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Not active against AmpC or extended spectrum beta-lactamase producing organisms.
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Indications :
- Complicated skin and soft tissue infections.
- Community-acquired pneumonia particularly those caused by MRSA and penicillin resistant Streptococcus pneumoniae.
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Dosage : 600mg IV every 12 hours.
Points to Note
- Several cephalosporins (eg. cefotaxime, ceftriaxone and cefepime) penetrate into CSF in sufficient concentration and hence, useful in the treatment of meningitis.
- Cephalosporins also cross the placenta and are found in high concentrations in synovial and pericardial fluids.
- Concentrations sufficient for treatment of ocular infections (caused by gram positive and certain gram negative bacterias) can be achieved by systemic administration of third generation cephalosporins.
- Second generation cephalosporins may exhibit in-vitro activity against Enterobacter species, but resistant mutants that express a chromosomal beta-lactamase that hydrolyses these compounds are readily selected. Hence, these drugs should not be used to treat Enterobacter infections.
References
- Essentials of Medical Pharmacology 8th Edition (K.D. Tripathi)-Jaypee Brothers Medical Publishers (P) Ltd.
- James Ritter, Rod Flower, Graeme Henderson, Yoon Kong Loke, David MacEwan, Humphrey Rang - Rang & Dale’s Pharmacology-Elsevier (2019).
- Laurence L. Brunton - Goodman & Gilman's Manual of Pharmacology and Therapeutics-McGraw-Hill Medical (2008).
- Basic and Clinical Pharmacology, 15th Edition, Bertram G. Katzung, Todd W. Vanderah, McGraw Hill.
*This article is an excerpt from the above mentioned books and Medical Sutras does not make any ownership or affiliation claims.