Pharmaceutical Microbiology (Note 2)

MCB 525

500 Level

CEPHALOSPORINS

Cephalosporin	Dose	Route	Dosing Interval	Renal
1st
Cefazolin	1-2gm	IV/IM	8	yes
Cephalothin	1-2gm	IV/IM	4-6	yes
Cephapirin	0.5-1gm	IV/IM	4-6	yes
Cephalexin	250-500mg	PO	6	yes
Cefadroxil	500mg	PO	12	yes
Cephradine	250mg <500mg>	PO PO	6 12	yes
2nd
Cefamandole	1-2gm	IV/IM	4-6	yes
Cefuroxime	0.75-1.5gm 250-500mg	IV/IM PO	8 12	yes
Cefoxitin	1-2gm	IV/IM	4-6	yes
Cefotetan	1-2gm	IV/IM	12	yes
Cefmetazole	2gm	IV	6-12	yes
Cefaclor	250-500mg	PO	8	yes
Cefprozil	250-500mg	PO	12-24	yes
Cefpodoxime	200-400mg	PO	12	yes
Loracarbef	200-400mg	PO	12	yes
3rd
Cefotaxime	1-2gm	IV/IM	6-8	yes
Ceftriaxone	1-2gm	IV/IM	12-24
Ceftizoxime	1-2gm	IV/IM	8-12	yes
Ceftazidime	1-2gm	IV/IM	8	yes
Cefoperazone	1-2gm	IV/IM	12
Cefixime	400mg 200mg	PO PO	24 12	yes
4th
Cefipime				yes

I. BACKGROUND

Cephalosporins are beta-lactam compounds in which the beta-lactam ring is fused to a 6-membered dihydrothiazine ring, thus forming the cephem nucleus. Side chain modifications to the cephem nucleus confers (1) an improved spectrum of antibacterial activity,( 2) pharmacokinetic advantages, and (3) additional side effects. Cephalosporins can be broadly categorized into four generations.

II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES

1.     Prevents cell wall synthesis by binding to enzymes called penicillin binding proteins (PBPs). These enzymes are essential for the synthesis of the bacterial cell wall.

2.     Bactericidal.

3.     Concentration-independent bactericidal activity, with maximal killing at 4-5 times the MIC of the organism.

4.     Clinically significant post-antibiotic effect is not observed.

Given these pharmacodynamic properties (concentration-independent bactericidal activity and lack of a post-antibiotic effect, optimal dosing regimens should be designed to continuously maintain drug levels above the MIC of pathogens.

III. SPECTRUM OF ACTIVITY

In general, 1st generation cephalosporins have better activity against gram-positive bacteria and less gram-negative activity, while 3rd generation agents, with a few exceptions, have better gram-negative activity and less gram-positive activity. The only fourth generation agent has both gram-positive and gram-negative activity.

IV. MECHANISMS OF BACTERIAL RESISTANCE

It is not uncommon for several resistance mechanisms to be operating simultaneously.

1.     destruction of beta-lactam ring by beta-lactamases; an intact beta-lactam ring is essential for antibacterial activity

2.     altered affinity of cephalosporins for their target site, the penicillin binding proteins

3.     decreased penetration of antibiotic to the target site, the PBPs. This is only applicable to gram-negative bacteria because gram-positive bacteria lack an outer cell membrane, and therefore penetration to the target site is not a problem.

V. GENERAL INFORMATION FOR CEPHALOSPORINS

SPECTRUM OF ACTIVITY.

PHARMACOKINETICS: Generally distributes well into the lung; kidney; urine; synovial, pleural, and pericardial fluids. Penetration into the cerebral spinal fluid (CSF) of some 3rd generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) is adequate to effectively treat bacterial meningitis.
Elimination is primarily via the kidneys, though a few exceptions include cefoperazone and ceftriaxone which have significant biliary elimination.

GENERAL CLINICAL USES: Their broad spectrum of activity and safety profile make the cephalosporins one of the most widely prescribed class of antimicrobials. The earlier generation cephalosporins are commonly used for community-acquired infections, while the later generation agents, with their better spectrum of activity against gram-negative bacteria make them useful for hospital-acquired infections or complicated community-acquired infections.

GENERAL SIDE EFFECTS/PRECAUTIONS:

A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever (1-3%); interstitial nephritis. Given the structural similarity of cephalosporins and penicillins, an estimated 1-7% of patients with penicillin allergies will also be hypersensitive to cephalosporins. Cephalosporins should be avoided in patients with immediate allergic reactions to penicillins (eg: anaphylaxis, bronchospasm, hypotension, etc.). Cephalosporins may be tried with caution in patients with delayed or mild reactions to penicillin.

B. Thrombophlebitis (1-5%).