Analysis Of Five Generations Of Cephalosporins Antibiotics Essay

Cephalosporins Beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based upon a shared structural feature, the beta-lactam ring. Cephalosporins cover a broad range of organisms, are generally well-tolerated, and are easy to administer; thus, these agents are frequently used beta-lactam drugs.

Most of the available cephalosporins are semi-synthetic derivatives of cephalosporin C, a compound with antibacterial activity produced by the fungus Cephalosporium. The closely related cephamycin compounds (derived from Streptomyces spp) are regarded as members of the cephalosporin class. In clinical practice, these antibiotics are grouped into five “generations” based upon their spectrum of activity against aerobic and facultative gram-negative bacilli and gram-positive bacteria.

First generation — Cephalothin is the oldest of the first-generation cephalosporins and was previously used as the prototype of this group. Cephalothin was active against most gram-positive cocci (including penicillinase-producing staphylococci), but did not have clinically useful activity against enterococci, Listeria, methicillin-resistant staphylococci, or penicillin-resistant pneumococci. Cephalothin was active against most strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, but had little activity against indole-positive Proteus, Enterobacter, Serratia, and the non-enteric gram-negative bacilli such as Acinetobacter spp and Pseudomonas aeruginosa. Analysis Of Five Generations Of Cephalosporins Antibiotics Essay. Gram-negative cocci (such as the gonococcus and meningococcus) and H. influenzae were generally resistant. Cephalothin was active against most of the common anaerobic pathogens, with certain exceptions such as Bacteroides species, particularly B. fragilis. Analysis Of Five Generations Of Cephalosporins Antibiotics Essay.

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Cefazolin has a similar spectrum of activity to cephalothin, is available worldwide, and is now the only parenteral first-generation cephalosporin available in the United States. Cefazolin achieves substantially higher serum levels than cephalothin, and has a longer half-life of elimination. Cefazolin is less stable than cephalothin in vitro to the type A penicillinase of staphylococci; the relevance of this for clinical therapy, however, is not certain.

Second generation — Compared with first-generation agents, the second-generation cephalosporins are somewhat less active against staphylococci. In contrast, they have greater activity against certain gram-negative bacilli; specifically, one subgroup of second-generation cephalosporins has enhanced activity against H. influenzae and another, the cephamycins, has activity against Bacteroides.

Activity against Haemophilus influenzae — In the first subgroup, cefuroxime is available parenterally and orally, and is more active than cefazolin in vitro against strains of Enterobacter and indole-positive Proteus. However, this agent induces the AmpC chromosomal beta-lactamases of these organisms, leading to resistance and failures of clinical therapy.

Cefuroxime is also more active than cefazolin against H. influenzae, and cefuroxime is quite stable to the TEM beta-lactamase in ampicillin-resistant strains. Although cefuroxime is approved for the therapy of H. influenzae meningitis, delayed responses and treatment failures have occurred, and a third-generation cephalosporin is now preferred for therapy of meningitis due to ampicillin-resistant strains. Cefuroxime is also highly active against beta-lactamase producing Moraxella catarrhalis.

Cephamycin subgroup (active against Bacteroides) — The cephamycin subgroup of the second-generation cephalosporins includes cefoxitin and cefotetan.Analysis Of Five Generations Of Cephalosporins Antibiotics Essay.  This subgroup is active against most strains of E. coli, P. mirabilis, and Klebsiella, like the first-generation cephalosporins. The cephamycins are quite stable to many plasmid-mediated beta-lactamases, but the activity of this group against Enterobacter and indole-positive Proteus is limited by induction of chromosomal cephalosporinases of these species and selection of stably derepressed mutants. Unlike the first-generation cephalosporins, the cephamycins are active against many strains of Bacteroides. The combination of activity against common aerobic and facultative gram-negative bacilli plus Bacteroides has led to the use of the cephamycins in the prophylaxis and therapy of infections in the abdominal and pelvic cavities (where these organisms predominate). The cephamycins have no clear advantages over the first-generation cephalosporins for infections outside of the abdominal and pelvic areas. Analysis Of Five Generations Of Cephalosporins Antibiotics Essay.

Third generation — The third-generation cephalosporin class is marked by stability to the common beta-lactamases of gram-negative bacilli, and these compounds are highly active against Enterobacteriaceae (E. coli, Proteus mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter), Neisseria, and H. influenzae. They are the therapy of choice for gram-negative meningitis due to susceptible Enterobacteriaceae. Third-generation cephalosporins may also be useful alternatives to the aminoglycosides in treating gram-negative infections resistant to other beta-lactams, particularly in the patient with renal dysfunction. However, mutants of Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal beta-lactamase, are resistant to these antibiotics. Even if these organisms (Enterobacter, indole-positive Proteus, Serratia, and Citrobacter) test susceptible to cephalosporins, use of a third-generation cephalosporin as a single agent for treatment of serious infections due to these bacteria can lead to the emergence of resistance during therapy. Analysis Of Five Generations Of Cephalosporins Antibiotics Essay.

The third-generation cephalosporins are less active against most gram-positive organisms than the first-generation cephalosporins and are inactive against enterococci, Listeria, methicillin-resistant staphylococci, and Acinetobacter. Cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third-generation cephalosporins as well. Treatment with third-generation cephalosporins may be complicated by superinfection (particularly with enterococci or Candida) or by the emergence of resistance on therapy (particularly when used as single agents for Enterobacter, indole-positive Proteus, or P. aeruginosa infections). Third-generation cephalosporins are not currently recommended for prophylactic use in surgery.

Poor activity against Pseudomonas — One subgroup of the third-generation cephalosporins, cefotaxime and ceftriaxone, has poor activity against P. aeruginosa. Within this subgroup, cefotaxime has the shortest serum half-life (1 hour) because of partial metabolism in the liver to desacetyl-cefotaxime. However, this metabolite also has antibacterial activity and a longer half-life in serum (1. 7 hours), allowing dosing every six hours.

Ceftriaxone has the longest serum half-life of this group (6. 4 hours) and can be administered once or twice a day. Ceftriaxone has been particularly recommended for the therapy of penicillin-resistant gonorrhea, Lyme disease involving the central nervous system or joints, meningitis due to ampicillin-resistant H. influenzae, and meningitis in children. One of the complications of ceftriaxone therapy, however, has been the formation in the biliary tract of “sludge” composed of ceftriaxone crystals, causing the syndrome of biliary pseudolithiasis.

Activity against Pseudomonas — the other of the third-generation cephalosporins, ceftazidime, has activity against P. aeruginosa. Ceftazidime is quite stable to the common plasmid-mediated beta-lactamases and is highly active against Enterobacteriaceae, Neisseria, and H. influenzae. Analysis Of Five Generations Of Cephalosporins Antibiotics Essay. Ceftazidime is also particularly active against P. aeruginosa and is an effective therapy for serious infections due to P. aeruginosa when the organism is resistant to the anti-pseudomonal penicillins or the patient is penicillin allergic. In addition, it is effective therapy for meningitis caused by P. aeruginosa. As with the anti-pseudomonal penicillins, however, ceftazidime should generally be given at least initially in combination with an aminoglycoside for treatment of serious P. aeruginosa infection, when susceptibilities are unknown. Ceftazidime has poor activity against gram-positive organisms and should be reserved for use in infections proven or highly suspected to be due to P. aeruginosa.

Fourth generation — Cefepime is the fourth-generation cephalosporin currently available. It has a positively charged quaternary ammonium attached to the dihydrothiazone ring, which results in better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third generation cephalosporins for certain chromosomal beta-lactamases of gram-negative bacilli.

Cefepime has similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and methicillin-sensitive S. aureus. Like the earlier third generation agents, it is active against the Enterobacteriaceae, Neisseria, and H. influenzae but has greater activity against the gram-negative enterics that have a broad-spectrum, inducible, chromosomal AmpC beta-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and Serratia). Analysis Of Five Generations Of Cephalosporins Antibiotics Essay. The role of cefepime in therapy of infections due to stably-derepressed mutants of these organisms has not yet been fully defined, but some data suggest that it may be effective. In a study of 96 patients with infections due to laboratory-confirmed AmpC beta-lactamase producing organisms, 96 percent of the isolates were susceptible to cefepime. Among patients who received cefepime, the 30 day mortality rate and duration of hospitalization were similar to those observed in a matched subset of patients who received meropenem. Analysis Of Five Generations Of Cephalosporins Antibiotics Essay.

Cefepime is as active as ceftazidime for P. aeruginosa, and is active against some ceftazidime-resistant isolates. As with the anti-pseudomonal penicillins, cefepime should generally be given in combination with an aminoglycoside for treatment of serious P. aeruginosa infection when susceptibilities are unknown. There has not been enough clinical experience with cefepime in meningitis to recommend its routine use for this purpose. It is also not currently recommended for prophylactic use in surgery. Acinetobacter isolates are frequently resistant to cefepime.

Despite these potential advantages over third-generation cephalosporins, especially against organisms with inducible, chromosomal resistance, comparative trials of third- and fourth-generation cephalosporins have not yet been performed. A review by the United States Food and Drug Administration (FDA) of cefepime safety data was initiated in 2007 following findings of a meta-analysis that raised concern regarding increased all-cause mortality associated with cefepime use (risk ratio 1. 26, 95% CI 1. 08-1. 49). The FDA reviewed these study data, conducted additional analyses based on other data, and determined that the data do not indicate a higher rate of death in cefepime-treated patients. Cefepime remains an appropriate therapy for its approved indications.

Treatment with cefepime may be complicated by superinfection (particularly with enterococci or Candida). Cefepime use also carries a risk of seizures (specifically nonconvulsive status epilepticus), particularly in patients with renal failure for whom the dose is not appropriately adjusted downwards.

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Fifth generation — Ceftaroline is a fifth-generation cephalosporin whose active metabolite has a spectrum of in vitro activity similar to ceftriaxone but with improved gram-positive activity. In particular, ceftaroline has higher affinity for PBP2a in methicillin-resistant staphylococci, and has activity against MRSA, as well as vancomycin-intermediate Staphylococcus aureus (VISA) and hetero-VISA. In addition, ceftaroline has activity for Streptococcus pneumoniae that is intermediate or resistant to penicillin or ceftriaxone. Ceftaroline is not active for enterococci nor against AmpC-overproducing or ESBL-producing Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, or Bacteroides fragilis. Analysis Of Five Generations Of Cephalosporins Antibiotics Essay.  Two randomized, double-blind controlled clinical trials have suggested that ceftaroline is noninferior to vancomycin plus aztreonam for treatment of complicated skin and soft tissue infections including those due to MRSA, and to ceftriaxone for therapy of community-acquired pneumonia. The efficacy of this anti-MRSA cephalosporin is not yet known for hospital-acquired MRSA pneumonia or for bacteremia.

Ceftobiprole is a cephalosporin available in Canada and some European countries (but not the United States) that is also capable of binding to penicillin binding protein 2a, the protein conferring S. aureus resistance to beta-lactam antibiotics. It can also bind penicillin binding protein 2x in penicillin-resistant S. pneumoniae. It has in vitro activity similar to that of ceftazidime or cefepimeagainst Enterobacteriaceae; it also has activity against enterococci. In addition, ceftobiprole appears to have a low potential for selection of resistance.

Cefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria. In most cases, it is considered to be equivalent to ceftriaxone in terms of safety and efficacy.  Analysis Of Five Generations Of Cephalosporins Antibiotics Essay.