Antibiotics Review _ __________________________________________________________________________
First-Generation Cephalosporins The first-generation cephalosporins are most active against aerobic gram-positive cocci. These agents include cefazolin, cephalexin, and cefadroxil, and they are often used for skin infections caused by S. aureus and Streptococcus and for suscep- tible urinary tract infections. They have activity against E. coli and some activity against H. influenzae and Klebsiella species, but because of the limited gram-negative coverage, they are not first-line agents for infections that are likely to be caused by gram-negative bacteria. Second-Generation Cephalosporins The second-generation cephalosporins are more active against gram-negative organisms, such as Moraxella , Neisseria , Salmo- nella , and Shigella . Cefoxitin and cefotetan, which are included in this group under this classification system although they are technically cephamycins, also have more coverage against anaerobic bacteria. The true cephalosporins that are also part of this class are cefprozil, cefuroxime, cefaclor, cefoxitin, and cefotetan. These drugs are used primarily for respiratory tract infections because they are better against some strains of beta- lactamase producing H. influenzae . Third-Generation Cephalosporins The third-generation cephalosporins have enhanced activity and a broader spectrum against gram-negative organisms, including Neisseria species, M. catarrhalis , Klebsiella , and other Enterobacteriaceae . Of these agents, ceftriaxone has the best activity against gram-positive cocci, specifically S. pneumoniae and methicillin-sensitive S. aureus . Ceftazidime is active against P. aeruginosa . Other cephalosporins in this class include cef- dinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftibu- ten, and ceftriaxone. These drugs are useful for more severe community-acquired respiratory, intraabdominal, and urinary tract infections and for nosocomial infections (because of the high incidence of resistant organisms) [37]. Fourth-Generation Cephalosporins Cefepime is classed as a fourth-generation cephalosporin because it has good activity against both gram-positive and gram-negative bacteria, including P. aeruginosa and many Entero- bacteriaceae . The gram-negative and anaerobic coverage makes cefepime useful for intra-abdominal infections, respiratory tract infections, and skin infections. Fifth-Generation Cephalosporins Ceftaroline fosamil is a novel advanced-generation cephalo- sporin approved by the U.S. Food and Drug Administration (FDA) in 2010, for the treatment of community-acquired bacterial pneumonia and bacterial skin and soft-tissue infec- tions [6]. As with other beta-lactams, ceftaroline exerts its antimicrobial affect by binding to PCP and inhibiting cell wall synthesis. This agent is unique in that it also has a high
affinity for PBP2a, which is associated with resistance to methicillin. Consequently, ceftaroline is highly active against methicillin-sensitive and resistant strains of S. aureus and against multidrug-resistant S. pneumoniae [38]. It is ineffective for P. aeruginosa , and its activity against Enterobacteriaceae is vari- able. Beta-lactamase-producing Enterobacteriaceae and AmpC mutants are resistant. Prospective clinical trials have shown that the efficacy of ceftaroline is comparable to vancomycin plus aztreonam for the treatment of bacterial skin and soft-tissue infection (including methicillin-resistant S. aureus [MRSA]) and to ceftriaxone for the treatment of community-acquired bacterial pneumonia [39]. Among cases of pneumonia caused by S. pneumoniae , clinical cure rates were higher with ceftaroline (83.3%) than with ceftriaxone (70%) in a phase III clinical trial, and the agent was well tolerated [40]. Ceftobiprole is a fifth-generation cephalosporin with a broad spectrum of antimicrobial activity, including drug-resistant pneumococci, P. aeruginosa , and methicillin-resistant S. aureus (MRSA). The drug is approved for the treatment of commu- nity- and hospital-acquired pneumonia in Canada and parts of Europe, The results of a pivotal clinical trial of patients hos- pitalized with community-acquired pneumonia treated with ceftobiprole showed a high rate of clinical cure [41; 42; 43]. ABSORPTION/ELIMINATION The orally administered cephalosporins include cefaclor, cefadroxil, cephalexin, cefprozil, cefuroxime axetil, cefixime, cefpodoxime proxetil, ceftibuten, and cefdinir. In general, the orally administered cephalosporins are absorbed rapidly. Cephalexin, cefadroxil, cefaclor, cefixime, ceftibuten, and cefdinir are nonesterified and are absorbed from the GI tract by active transport in the small intestine. Other agents, such as cefuroxime axetil and cefpodoxime proxetil, are prodrug esters and are passively absorbed. Once absorbed into the cells lining the small intestine, these agents are hydrolyzed and then excreted into the blood stream as active cephalosporins [44]. The presence of food or antacids may increase or decrease the absorption, depending on the drug. Cefuroxime axetil and cefpodoxime proxetil have increased absorption when taken with food. Cefaclor, cefadroxil, and cephalexin have slowed absorption when food is in the stomach. Cefixime, cefpro- zil, and ceftibuten are not affected by the presence of food. Cefpodoxime is the only cephalosporin whose absorption is decreased by the presence of antacids or H2 antagonists [45]. There is extensive distribution of the cephalosporins into body tissues and fluids. They readily cross the placenta and are also found in synovial fluid. Concentrations in bile and urine are high. Most cephalosporins do not cross into the CSF in suf- ficient concentration to be recommended for the treatment of meningitis, but there are some exceptions. Cefuroxime, cefotaxime, ceftriaxone, cefepime, and ceftaroline all have good penetration into the CSF [38; 46].
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