Cephalosporins

GENERAL PRINCIPLES

• Cephalosporins exert their bactericidal effect by interfering with cell wall synthesis by the same mechanism as PCNs.

• These agents are clinically useful because of their broad spectrum of activity and low toxicity profile.

TREATMENT

• First-generation cephalosporins have activity against MSSA, streptococci, Escherichia coli, and many Klebsiella and Proteus species. These agents have limited activity against other enteric gram­negative bacilli and anaerobes. Cefazolin (1-2 g IV/IM q8h) is the most commonly used parenteral preparation, and cephalexin (250-500 mg PO q6h) and cefadroxil (500 mg-1 g PO q12h) are oral preparations. These agents are commonly used for treating skin/soft tissue infections, UTIs, MSSA infections, and for surgical prophylaxis (cefazolin IV).

• Second-generation cephalosporins have expanded coverage against enteric gram-negative rods and can be divided into above-the-diaphragm and below-the-diaphragm agents.

î Cefuroxime (1.5 g IV/IM q8h) is useful for treatment of infections above the diaphragm. This agent has reasonable MSSA and streptococcal activity in addition to an extended spectrum against gram­negative aerobes and can be used for skin/soft tissue infections, complicated UTIs (cUTIs), and some community-acquired respiratory tract infections. It does not cover Bacteroides fragilis.

^o Cefuroxime axetil (250-500 mg PO q12h), cefprozil (250-500 mg PO q12h), and cefaclor (250­500 mg PO q12h) are oral second-generation cephalosporins typically used for bronchitis, sinusitis, otitis media, UTIs, local soft tissue infections, and oral step-down therapy for pneumonia or cellulitis responsive to parenteral cephalosporins.

î Cefoxitin (1-2 g IV q4-8h) and cefotetan (1-2 g IV q12h) are useful for treatment of infections below the diaphragm. These agents, also known as cephamycins, have activity against gram negatives and anaerobes, including B. fragilis, and are commonly used for intra-abdominal or gynecologic surgical prophylaxis and infections, including diverticulitis and pelvic inflammatory disease.

• Third-generation cephalosporins cover aerobic gram-negative bacilli and retain significant activity against streptococci and MSSA (except ceftazidime). Ceftazidime is the only third-generation cephalosporin that is useful for treating serious Pseudomonas aeruginosa infections. Some of these agents (ceftriaxone, ceftazidime) have substantial central nervous system (CNS) penetration and are useful in treating meningitis when given at high doses (see Chapter 14, Treatment of Infectious Diseases). Third-generation cephalosporins are not reliable for the treatment of serious infections caused by organisms producing AmpC β-lactamases regardless of the results of susceptibility testing. These resistant pathogens should generally be treated empirically with carbapenems or cefepime.

î Ceftriaxone (1-2 g IV/IM q12-24h) can be used as empiric therapy for pyelonephritis, urosepsis, pneumonia, intra-abdominal infections (combined with metronidazole), gonorrhea, and meningitis. It can also be used for osteomyelitis, septic arthritis, endocarditis, and skin/soft tissue infections caused by susceptible organisms. Ceftriaxone 2 g IV q12h in combination with ampicillin IV is appropriate for treatment of ampicillin-susceptible Enterococcus faecalis endocarditis, especially when aminoglycosides need to be avoided.

î Cefpodoxime proxetil (100-400 mg PO q12h), cefdinir (300 mg PO q12h), ceftibuten (400 mg PO q24h), and cefditoren pivoxil (200-400 mg PO q12h) are oral third-generation cephalosporins useful for the treatment of bronchitis and complicated sinusitis, otitis media, and UTIs. These agents can also be used as step-down therapy for CAP.

î Ceftazidime (1-2 g IV/IM q8h) may be used for treatment of infections caused by susceptible strains of P. aeruginosa and other susceptible gram-negative bacilli, but lacks clinically significant activity against MSSA.

• The fourth-generation cephalosporin cefepime (500 mg-2 g IV/IM q8-12h) has excellent aerobic gram-negative coverage, including P. aeruginosa and other bacteria producing AmpC β-lactamases. Its gram-positive activity is similar to that of ceftriaxone. Cefepime is routinely used for empiric therapy in febrile neutropenic patients. It also has a prominent role in treating infections caused by antibiotic­resistant gram-negative bacteria and some infections involving both gram-negative and gram-positive aerobes in most sites. Anaerobic coverage should be added where anaerobes are suspected.

• Ceftaroline (600 mg IV q12-8h) is a cephalosporin with anti-MRSA activity. Ceftaroline's unique MRSA activity stems from its affinity for PBP2a, the same cell wall component that renders MRSA resistant to all other β-lactams. Ceftaroline has similar activity to ceftriaxone against gram-negative pathogens, with virtually no activity against Pseudomonas, Acinetobacter, and other organisms producing AmpC β-lactamase, extended-spectrum β-lactamase (ESBL), or Klebsiella pneumoniae - carbapenemase (KPC).

• Novel cephalosporins and combination agents include ceftolozane-tazobactam and ceftazidime- avibactam, as well as the novel siderophore cephalosporin cefiderocol. A summary of activity of new gram-negative beta-lactams is provided in Table 15-1.

î Ceftolozane-tazobactam (1.5-3 g tazobactam IV q8h) combines ceftolozane, a novel cephalosporin, and the β-lactamase inhibitor tazobactam in a 2:1 ratio. This agent is approved by the U.S. Food and Drug Administration (FDA) for treatment of complicated intra-abdominal infections (in combination with metronidazole), cUTIs, including pyelonephritis, and hospital- acquired/ventilator-associated bacterial pneumonia (HABP/VABP).

TABLE 15-1

CRAB, carbapenem-resistant Acinetobacter baumannii; CRPA, carbapenem-resistant Pseudomonas aeruginosa; ESBL, extended-spectrum β-lactamase; KPC, Klebsiella pneumoniae carbapenemase; MBL, metallo-β-lactamases; OXA-48, oxacillinase-48.

î Ceftazidime-avibactam (2.5 g IV q8h) contains ceftazidime in combination with the novel β- lactamase inhibitor avibactam. This agent is FDA-approved for treatment of cUTIs, complicated intra-abdominal infections (in combination with metronidazole), and HABP/VABP.

î Cefiderocol (2g IV q8h) is a novel siderophore cephalosporin with broad coverage of gram­negative bacilli, including CRE, Stenotrophomonas, Acinetobacter, and Pseudomonas species resistant to other β-lactam antibiotics. This agent chelates free iron to enter cells via iron active transport channels, resulting in high concentrations in the periplasmic space, where cefiderocol binds to PBPs to disrupt cell wall synthesis. Cefiderocol is FDA-approved for the treatment of cUTI, including pyelonephritis, and HABP/VABP. Cefiderocol is stable to hydrolysis by most β- lactamases, including AmpC, ESBL, KPC, OXA-48, and MBLs; however, cefiderocol does not possess reliable activity against gram-positive pathogens and anaerobes.

SPECIAL CONSIDERATIONS

Adverse events: All cephalosporins have been rarely associated with anaphylaxis, interstitial nephritis, elevated LFTs, anemia, thrombocytopenia, and leukopenia. PCN-allergic patients may have a cross­hypersensitivity reaction to cephalosporins. These agents should not be used in a patient with a reported severe PCN allergy (i.e., anaphylaxis, hives) without prior skin testing or desensitization, or both. Prolonged therapy (>2 wk) is typically monitored with a weekly serum creatinine and CBC. Because of its biliary elimination, ceftriaxone may cause biliary sludging. Cefepime has been associated with CNS side effects, including delirium and seizures, especially when given at high doses in individuals with renal impairment.