Drugs

Cephalosporins (CEPH)

Cephalosporins

Introduction

  • Cephalosporins are β-lactam antibiotics that are closely related both structurally and functionally to the penicillins.
  • Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.
  • Cephalosporins have the same mode of action as penicillins, and they are affected by the same resistance mechanisms. However, they tend to be more resistant than the penicillins to certain β-lactamases.

Classification

Cephalosporins have been classified as first, second, third, fourth, and advanced generation, based largely on their bacterial susceptibility patterns and resistance to β-lactamases.

  • Oral (O), Parenteral (P)
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Individual cephalosporins differ in their:

  • Antibacterial spectrum and relative patency against specific organisms.
  • Susceptibility to β-lactamases elaborated by different organisms.
  • Pharmacokinetic properties-many have to be injected, some are oral; majority are not metabolized, and are excreted rapidly by the kidney; have short t1/2s, probenecid inhibits their tubular secretion.
  • Local irritancy on i.m. injection; few cannot be injected i.m.

Mechanism of action 

  • Cephalosporins cause inhibition of bacterial cell wall synthesis. i.e. they have the same mechanism of action as penicillin. However, they bind to different proteins than those which bind penicillins.

Antibacterial spectrum 

Commercially available cephalosporins are ineffective against MRSA, L. monocytogenes, C. difficile, and the enterococci.

  • First generation : The first-generation cephalosporins act as penicillin G substitutes. They are resistant to the staphylococcal penicillinase (that is, they cover MSSA) and also have activity against Proteus mirabilis, E. coli, and K. pneumoniae.
  • Second generation : The second-generation cephalosporins display greater activity against three additional gram-negative organisms: H. influenzae, Enterobacter aerogenes, and some Neisseria species, whereas activity against gram-positive organisms is weaker. Antimicrobial coverage of the cephamycins (cefotetan and cefoxitin) also includes anaerobes (for example, Bacteroides fragilis). They are the only cephalosporins commercially available with appreciable activity against gram-negative anaerobic bacteria. However, neither drug is first line because of the increasing prevalence of resistance among B. fragilis to both agents.
  • Third generation : These cephalosporins have assumed an important role in the treatment of infectious diseases. Although they are less potent than first-generation cephalosporins against MSSA, the third-generation cephalosporins have enhanced activity against gram-negative bacilli, including those mentioned above, as well as most other enteric organisms plus Serratia marcescens.
    Ceftriaxone and cefotaxime have become agents of choice in the treatment of meningitis.
    Ceftazidime has activity against P. aeruginosa; however, resistance is increasing and use should be evaluated on a case-by-case basis.
    Third-generation cephalosporins must be used with caution, as they are associated with significant “collateral damage,” essentially meaning the induction and spread of antimicrobial resistance.
  • Fourth generation : Cefepime is classified as a fourth-generation cephalosporin and must be administered parenterally.
    Cefepime has a wide antibacterial spectrum, with activity against streptococci and staphylococci (but only those that are methicillin susceptible). Cefepime is also effective against aerobic gram-negative organisms, such as Enterobacter species, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa. When selecting an antibiotic that is active against P. aeruginosa, clinicians should refer to their local antibiograms (laboratory testing for the sensitivity of an isolated bacterial strain to different antibiotics) for direction.
  • Advanced generation : Ceftaroline is a broadspectrum, advanced-generation cephalosporin that is administered IV as a prodrug, ceftaroline fosamil. It is the only commercially available β-lactam in the United States with activity against MRSA and is indicated for the treatment of complicated skin and skin structure infections and community-acquired pneumonia. The unique structure allows ceftaroline to bind to PBP2a found with MRSA and PBP2x found with Streptococcus pneumoniae. In addition to its broad gram-positive activity, it also has similar gram negative activity to the third-generation cephalosporin ceftriaxone.
    Important gaps in coverage include P. aeruginosa, extendedspectrum β-lactamase (ESBL)-producing Enterobacteriaceae, and Acinetobacter baumannii. The twice-daily dosing regimen also limits use outside of an institutional setting.

Therapeutic uses 

Cephalosporins are now extensively used antibiotics. Their indications are:

  • As alternatives to PnG; particularly in allergic patients (but not who had anaphylactic reaction); one of the first generation compounds may be used.
  • Respiratory, urinary and soft tissue infections caused by gram-negative organisms, especially Klebsiella, Proteus, Enterobacter, Serratia. Cephalosporins preferred for these infections are cefuroxime, cefotaxime, ceftriaxone.
  • Penicillinase producing staphylococcal infections.
  • Septicaemias caused by gram-negative organisms: an aminoglycoside may be combined with a cephalosporin.
  • Surgical prophylaxis: the first generation cephalosporins are popular drugs. Cefazolin (i.m. or i.v.) is employed for most types of surgeries including those with surgical prosthesis such as artificial heart valves, artificial joints, etc.
  • Meningitis: Optimal therapy of pyogenic meningitis requires bactericidal activity in the CSF, preferably with antibiotic concentrations several times higher than the MBC for the infecting organism. For empirical therapy before bacterial diagnosis, i.v. cefotaxime/ ceftriaxone is generally combined with ampicillin or vancomycin.
    Ceftazidime + gentamicin is the most effective therapy for Pseudomonas meningitis.
  • Gonorrhoea caused by penicillinase producing organisms: ceftriaxone is a first choice drug for single dose therapy of gonorrhoea if the penicillinase producing status of the organism is not known. Cefuroxime and cefotaxime have also been used for this purpose. For chancroid also, a single dose is as effective as erythromycin given for 7 days.
  • Typhoid: Currently, ceftriaxone and cefoperazone injected i.v. are the fastest acting and most reliable drugs for enteric fever. They are an alternative to fluoroquinolones (especially in children) for empirical therapy, since many S. typhi strains are resistant to chloramphenicol, ampicillin and cotrimoxazole.
  • Mixed aerobic-anaerobic infections in cancer patients, those undergoing colorectal surgery, obstetric complications: cefuroxime, cefaclor or one of the third generation compounds is used.
  • Hospital acquired infections resistant to commonly used antibiotics: cefotaxime, ceftizoxime or a fourth generation drug may work.
  • Prophylaxis and treatment of infections in neutropenic patients: ceftazidime or another third generation compound, alone or in combination with an aminoglycoside.

Resistance

Acquired resistance to cephalosporins could have the same basis as for penicillins, i.e.:

  • alteration in target proteins (PBPs) reducing affinity for the antibiotic.
  • impermeability to the antibiotic or its efflux so that it does not reach its site of action.
  • elaboration of β-lactamases which destroy specific cephalosporins (cephalosporinases).
    Though the incidence is low, resistance has been developed by some organisms, even against the third generation compounds.

Side effects 

  • Like the penicillins, the cephalosporins are generally well tolerated. However, allergic reactions are a concern. Patients who have had an anaphylactic response, Stevens-Johnson syndrome, or toxic epidermal necrolysis to penicillins should not receive cephalosporins.
  • Cephalosporins should be avoided or used with caution in individuals with penicillin allergy. Current data suggest that the cross-reactivity between penicillin and cephalosporins is around 3% to 5% and is determined by the similarity in the side chain, not the β-lactam structure.The highest rate of allergic cross-sensitivity is between penicillin and first-generation cephalosporins.

Drug Interactions 

Contraindications 

For detailed query or in case of uncertainty, Always consult your doctor or pharmacist.

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