Cephalosporins

Pharmacology L3
PHCL-L3-AntiMicrobials

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 Learning Objectives
 Describe the structural differences between penicillins and cephalosporins
 Explain the mechanism of action of cephalosporins
 Describe the four generations of cephalosporins with specific examples and the
differences in their antimicrobial spectrum and pharmacokinetic properties
 List the clinical uses of respective generations of cephalosporin
 List the advantages of each of cephalosporins over penicillin
 Describe the adverse effects due to cephalosporins

 Referring to the therapeutic use of cephalosporin for the management of the following
conditions: otitis media, sinusitis, meningitis, pyelonephritis and septicemia,
► choose a drug (generic name) that could be recommended for the management of the respective
disease conditions
► As applicable,
• Cite a commercial name of the drug
• List various dosage forms as available
• Provide essential pharmacokinetic elements of the drug
• Describe the mechanism of action of the drug
• List the adverse effects of the drug
• List drug interaction facts of the drug
• List the contra-indications of the drug
• Describe a potential mechanism of resistance

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Inhibition of cell wall synthesis
Beta-lactam Antibiotics
►Penicillins (Derived from Penicillium)
►Cephalosporins (from Cephalosporium)
►Carbapenems (Synthetic)
►Monobactams
►New and experimental agents
Others..
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Figure 12.7
Classification of Cephalosporins

• Divided into 4 major groups called

“Generations”
• Are divided into Generations based
on
► Antimicrobialactivity
► Resistance to -lactamase

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 Classification
Céphalosporines de première génération Céphalosporines de troisième génération
Céfaclor Alfatil® Céfépime Axépim® Céfadroxil
Oracéfal® Céfixime Oroken®
Céfalexine Kéforal® + ... Céfopérazone Céfobis®
Céfalotine Céfalotine® Céfotaxime Claforan®
Céfapirine Céfaloject® Céfotétan Apacef®
Céfatrizine Céfapéros® Céfotiam Takétiam®,
Céfazoline Céfacidal® Cefpirome Céfrom®
Céfradine Céfirex® + ... Cefpodoxime Orelox®
CefsulodinePyocéfal®
Ceftazidime Fortum®
CeftizoximeCefizox®
Ceftriazone Rocéphine®
Céphalosporines de deuxième génération
Céfamandole Kéfandol®
Céfoxitime Mefoxin®
Céfuroxime Zinnat®
 First Generation Cephalosporins
Cefazolin (IV), Cephalexin (PO) CEFACLOR®

• Cephalothin, the prototype first-generation

• Best activity against gram-positive aerobes,
with limited activity against a few gram-
negative aerobes
• Good for staph and strep skin and soft tissue
infections
Gram-positive Gram-negative
meth-susc S. aureus E. coli
pen-susc S. pneumoniae K. pneumoniae
Group streptococci P. mirabilis
viridans streptococci

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 Second Generation
Cephalosporins
• In general, slightly less active against
gram-positive aerobes, but more active
against gram-negative aerobes
• Several second generation agents have
activity against anaerobes
• Good for treating respiratory tract
infections, intra-abdominal infections,
pelvic inflammatory disease, diabetic
foot ulcers
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Second Generation Cephalosporins
Spectrum of Activity
The cephamycins: cefoxitin
(Oracefal®), and cefmetazole are the
only 2nd generation cephalosporins
that have activity against anaerobes
Anaerobes
Bacteroides fragilis
Bacteroides fragilis group

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Second Generation Cephalosporins
Cefuroxime (IV and PO) (ZINNAT)

Gram-positive Gram-negative
meth-susc S. aureus E. coli
pen-susc S. pneumoniae K. pneumoniae
Group streptococci P. mirabilis
viridans streptococci H. influenzae
M. catarrhalis
Neisseria sp.

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Third Generation Cephalosporins
• Cefotaxime, ceftriaxzone, cefoperazone,
cefpodoxime
• In general, are even less active against gram-
positive aerobes, but have greater activity
against gram-negative aerobes
• Ceftriaxone(Rocephine®) and cefotaxime
(Claforan®) have the best activity against
gram-positive aerobes, including pen-resistant
S. pneumoniae
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Third Generation Cephalosporins
Spectrum of Activity

 Broad spectrum G- killers and Drugs of choice for

serious infections

 Spectrum
► Gram-negative aerobes
• E. coli, K. pneumoniae, P. mirabilis , H. influenzae, M. catarrhalis, N.
gonorrhoeae (including beta-lactamase producing); N. meningitidis

• Citrobacter sp., Enterobacter sp., Acinetobacter sp. Morganella morganii,

Serratia marcescens, Providencia

• Pseudomonas aeruginosa : ceftazidime (Fortum®) and cefoperazone

• No effect against Listeria and beta-lactamase producing pneumococci

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Fourth Generation Cephalosporins
• Only cefepime is currently available

• 4th generation cephalosporins have 3

advantages over 3rd generation
► Extended spectrum of activity
 Gram-positives: similar to ceftriaxone
 Gram-negatives: similar to ceftazidime, including
Pseudomonas aeruginosa; also covers beta-lactamase
producing Enterobacter sp.
► Better stability against -lactamases;
► poor inducer of extended-spectrum -lactamases
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 Cephalosporin
Pharmacology
• Absorption
• First generation
• Cefazolin given parentally, others orally

• Distribution
► parenteral 3rd and 4th generation cephs, and aztreonam
penetrate the CSF
• Elimination
• Excreted by kidneys unmetabolized
• Except : ceftriaxone, and cefoperazone are eliminated
primarily by the liver;
► ALL -lactams have short elimination half-lives (< 2º),
except for a few cephalosporins (ceftriaxone)

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Route of Administration

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 Cephalosporins
Clinical Uses
 First Generation  Second Generation
 Skin and soft tissue  Sinusitis,
infections,
 septic arthritis,
 otitis media,
 osteomyelitis,  upper and lower
 endocarditis, respiratory tract infections
 surgical prophylaxis,  Intraabdominal infections
 urinary tract infections, - cefoxitin,
 bacteremias

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 Cephalosporins
Clinical Uses
 Third Generation  Fourth Generation
 Bacteremia,
 pneumonia,
 Pneumonia,
 complicated urinary tract  bacteremia,
infections,  urinary tract infections,
 peritonitis,
skin and soft tissue
 intraabdominal infections,
 skin and soft tissue
infections,
infections,  intraabdominal infections,
 bone and joint infections,  febrile neutropenia
 meningitis
 Uncomplicated gonorrhea;

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 Cephalosporins
Adverse Effects

 Hypersensitivity reactions (uncommon) essentially

same as for penicillins
► Cross-reaction between 2 classes

 Hypersensitivity – 3 to 10 %
► Mild to severe allergic reactions – rash to anaphylaxis and
death
 Cephalosporin-specific:
► N-methylthiotetrazole side chain (MTT side chain) -
cefamandole, cefotetan, cefmetazole, cefoperazone,
moxalactam
• Hypoprothrombinemia - due to reduction in vitamin K-producing
bacteria in GI tract
• Ethanol intolerance

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 Cephalosporins-summary
 Structure and function similar to penicillins

 Broader spectrum of activity

 Poor oral absorption for many cephalosporins

 More toxic than penicillins-- particularly renal

 Some cross-reactivity with penicillin-sensitive

patients

 More expensive than penicillins

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Gen. Anaerobes
Gm (+) Gm (-)

I
+++ + -
II
++ ++ +
III
++ ++ ++

IV
++ +++ +++
Cephalosporins Pen V/G: covers
G+ (strep), oral anarobes, T. Pallidum
(Lacks efficacy vs BL’ase,
Develop agent vs BL’ase B. fragilis, G-, atypicals)
producing staph (MSSA) and Add activity vs B. Fragilis,
“easy to kill” non-BL’ase G- and “easy to kill” G-

1st gen Cephs

Eg: cephalexin, Cefoxitin
cefazolin
Add resistance to “easy to kill”
BL’ase G- & B. Frag, loss of some
G+ coverage

2nd gen Cephs None are effective against enterococcus, L.

Eg: cefuroxime, monocytogenes, MRSA
cefaclor
Add activity vs “hard to kill” G-, reduce
staph coverage, retain strep coverage,
loss of B. Frag coverage
3rd gen Cephs
Eg: cefotaxime,
ceftriaxone, cefixime,
ceftazidime
Add activity vs
3rd/4th gen Cephs
pseudomonas
Eg: Ceftazidime,
Cefepime