Cephalosporin Antibiotics

1
Cephalosporin Antibiotics

• First discovered in 1945 from a Cephalosporium
  fungi
• Commercial drugs derived semi-synthetically
• From 7-aminocephalosporanic acid - produced by
  fermentation
• Similar to penicillins 4 Generations
• Derivatives acylated at the 7-amino group
• Reasons for synthetic modification include
• Increased acid stability
• Improved pharmacokinetics (oral absorption)
• Broaden antimicrobial spectrum
• Increased activity (decreased resistance due to
  destruction)
• Improved penetration
• Increased receptor affinity
• Decreased allergenicity
• Increased tolerance due to parenteral
  administration

2
Cephalosporin Antibiotics

• Transition from first generation to third
  generation agents reflects
• Broadening of the Gram (-) organism spectrum
• Loss of efficacy against Gram () organisms
• Greater efficacy against resistant organisms (but
  increased cost)
• MOA Inhibit cell wall synthesis ? osmotically
  induced cell lysis
• Usually bactericidal a function of dosage,
  organism susceptibility, tissue concentrations,
  and growth rate
• Cross allergenicity with penicillins is 5-16
• Drug interactions
• Alcohol use may produced a disulfiram like
  reaction - NMTT
• Aminoglycoside nephrotoxicity can be increased
• Anticoagulant effects can be potentiated - NMTT
• Antacids can decrease plasma concentrations of
  oral agents
• Loop diuretic nephrotoxicity can be increased
• Monitor renal function since all are renally
  excreted
• Cefoperazone the exception

3
Cephalosporin Antibiotics

• Classified by Generations - explosive advances
• First Generation
• Epitomized by cefazolin
• Good activity against Gram()
• Modest Gram(-) activity
• Second Generation
• Increased Gram(-) activity
• Some active against baccillus fragilis (highly
  resistant anaerobe)
• Third Generation - cost vs. efficacy
• Broad spectrum with high penicillinase
  resistance
• Greater Gram (-) spectrum
• Less active than G1 against most Gram()
• More active than G1 against enterobacter
• Fourth Generation - Cefepime
• Extended range of activity compared to G3 More
  Gram ()
• Increased stability against b-lactamases
• VERY useful for Gram(-) strains resistant to G3

4
Cephalosporin Antibiotics
5
Cephalosporin Antibiotics

• G1
• PO Cephalexin, Cephradine, Cephadroxil
• Parenteral Cefapirin, Cefazolin
• G2
• PO Cefaclor, Loracarbef, Cefprozil, Cefuroxime
• Parenteral Cefmetazole, Cefotetan, Cefonacid,
  Cefamandol, Cefoxitin
• G3
• PO Cefpodoxime, Cefixime, Cefdinir, Ceftitbuten
• Parenteral Cefotaxime, Ceftizoxime, Ceftriaxone,
  Ceftazidime, Cefaperazone
• G4 - Cefepime

6
Cephalosporin Deactivation
Deactivated Cephalosporin
7
1st Generation Cephalosporins
Indications Respiratory tract infections,
Otitis media, skin and skin structure infections,
Bone infections, Gram (-) UTI. Used for staph or
strep infection in patients with mild
hypersensitivity to penicillins! Gram() aerobic
bacteria - limited Gram(-) Oral use only, 10
protein bound, gt90 excreted renally
unchanged One of the Top 200 Indications Oral
- Respiratory tract infections, Otitis media,
skin and skin structure infections, Bone
infections, GU infections, UTI Parenteral
Septicemia pre-, post- or intraoperative
prophylaxis Oral or IV/IM use, 17 protein bound,
gt90 excreted renally unchanged
Partial hydrogenation
Generally all are inactivated by b-lactamases
8
1st Generation Cephalosporins
Indications UTI, pharyngitis and tonsillitis
due to group A b-hemolytic Streptococcus, skin
and skin structure infections. Oral use only,
20 protein bound, gt90 excreted renally
unchanged Prolonged half-life allows once-a-day
dosing Indications Respiratory tract
infections, skin and skin structure infections,
Osteomyelitis, UTI, Septicemia, pre-, post- or
intraoperative prophylaxis IV/IM use only, 50
protein bound, 70 excreted renally
unchanged Methicillin substitute. Comparatively
resistant to Staph. penicillinase
Generally all are inactivated by b-lactamases
9
1st Generation Cephalosporins
Indications Respiratory tract infections, GU
infections, skin and skin structure infections,
Biliary tract infections, bone and joint
infections, Septicemia, endocarditits pre-,
post- or intraoperative prophylaxis. Used for
staph or strep infection in patients with mild
hypersensitivity to penicillins! NOT for
meningitis (cant cross BBB). IM/IV use only,
adjust dose as a function of creatinine clearance
with 80 excreted renally unchanged, 86 protein
bound Longer half-life than Cephapirin, less
irritating on injection, heat/light unstable
Generally all are inactivated by b-lactamases
10
2nd Generation Cephalosporins
Indications Respiratory tract infections, Otitis
media, skin and skin structure infections,
UTI Extended release tabs acute bacterial
exacerbations of chronic bronchitis, secondary
infections as a result of acute bronchitis,
pharyngitis and tonsillitis Oral use only, 25
protein bound, 85 excreted unchanged renally
Refrigerate suspension MOST susceptible to
b-lactamases in its class! Carbon Isostere of
cefaclor Indications Secondary bacterial
infection of acute bronchitits, pneumonia Otitis
media, acute maxillary sinusitis, pharyngitis,
tonsillitis, skin and skin structure infection,
UTI such as cystitis and pyelonephritis Oral use
only, 25 protein bound, gt90 excreted unchanged
in the urine Store suspension at room temperature
Variable resistance to b-lactamase, more Gram (-)
activity
11
2nd Generation Cephalosporins
Amoxicillin like group
Trans form here imparts Gram(-) activity
Indications pharyngitis, tonsillitis, otitis
media, acute sinusitis, acute and chronic
bronchitis, uncomplicated skin and skin structure
infections Oral use only, 36 protein bound, 60
renal excretion unchanged - dosage adjustment
necessary in renal failure - creatinine clearance
lt30 use 50 the usual dosage Similar to Cefaclor
with improved potency Top 200 drug
Variable resistance to b-lactamase, more Gram (-)
activity
12
2nd Generation Cephalosporins
Indications Lower respiratory tract infections,
UTI, intra-abdominal infections, GU infections,
skin and skin structure infections, bone and
joint infections, Septicemia, pre-, post- or
intraoperative prophylaxis Do NOT mix in the same
IV as aminoglycosides, stability of reconstituted
solution is a function of the diluent used, IV
use only, 73 protein bound, 85 excreted
unchanged in the urine Indications ORAL
Respiratory tract infections, UTI, early Lyme
disease, uncomplicated gonorrhea, skin and skin
structure infections PARENTERAL As above plus
septicemia, meningitis, bone and joint
infections, mixed infections. Community acquired
pneumonia Oral or IV/IM use, 50 protein bound,
up to 100 excreted in the urine unchanged -
reduce dosage in renal impairment based on
creatinine clearance, may be taken with food, Do
NOT mix in the same IV as aminoglycosides or use
sodium bicarbonate injection as diluent, do NOT
chew tablets due to very bad tasteswallow
whole Top 200 drug
Cephamycin Anaerobic activity
Can cross the BBB meningitis Not used as
ceftriaxone cefotaxime preferred
Variable resistance to b-lactamase, more Gram (-)
activity
13
2nd Generation Cephalosporins
Indications UTI, lower respiratory infections,
skin and skin structure infections,
intra-abdominal infections, pre-operative
prophylaxis IM/IV use only, 65 protein bound,
85 recovered unchanged in the urine Do NOT mix
in the same IV with aminoglycosides
Indications UTI, lower respiratory infections,
skin and skin structure infections,
intra-abdominal infections, peri-operative
prophylaxis, GU infections, bone and joint
infections Watch for nephrotoxicity when use with
aminoglycosides - be sure to adjust dosage in
renal failure based on creatinine clearance and
do NOT mix in the same IV IM/IV only, 90
protein bound, 81 recovered unchanged from the
urine
These agents cefoxitin have reasonable
anaerobic activity Peritonitis diverticulitis
Variable resistance to b-lactamase, more Gram (-)
activity
14
2nd Generation Cephalosporins
Indications Lower respiratory infection, UTI,
skin and skin structures, septicemia, bone and
joint infections, pre-operative prophylaxis IV/IM
use only, 90 protein bound, 99 excreted
unchanged in the urine----dosage adjustment
necessary in renal failure Admix incompatibility
with aminoglycosides Longer half-life than other
G2, lower Gram() potency Indications Lower
respiratory infection, UTI, peritonitis, skin and
skin structures, septicemia, bone and joint
infections pre-, intra- and post-operative
prophylaxis Admix incompatibility with
aminoglycosides IV/IM use only, dosage reduction
necessary based on renal function NMTT bleeding
and disulfuram problems
NMTT
Variable resistance to b-lactamase, more Gram (-)
activity
15
3rd Generation Cephalosporins
Diester prodrug!!-extended spectrum
agent Indications acute community-acquired
pneumonia, chronic bronchitis, acute otitis
media, pharyngitis, tonsilllitis, acute
uretheral, cervical or rectal gonorrhea but NOT
pharyngeal disease skin and skin structure
infections, UTI Useful in cirrhosis patientsno
dosage adjustment needed, renal failure
necessitates dosage adjustment Oral use only, 29
protein bound, 33 excreted unchanged in the
urine Indications UTI, otitis media,
pharyngitis, tonsillitis, acute and acute chronic
bronchitis, cervical or urethral gonorrhea Oral
use only, 65 protein bound, 50 excreted
unchanged in the urine DOC gonorrhea single
400mg dose
16
3rd Generation Cephalosporins

Indications Community acquired pneumonia, acute
exacerbation of chronic bronchitits, acute
maxillary sinusitis, pharnygitis, tonsillitis,
skin and skin structure infections, acute otitis
media Oral use only, 70 protein bound, 17
excreted unchanged in the urine but dosage still
needs reduced in renal failure Indications
acute bacterial exacerbations of chronic
bronchitis, acute bacterial otitis media caused
by H. influenza, pharyngitis and tonsillitits
caused by S. pyogenes Oral use only, 65 protein
bound, 56 excreted unchanged in the urine -
dosage adjustment as a function of creatinine
clearance
Ceftibuten
17
3rd Generation Cephalosporins
Indications Lower respiratory infection, UTI,
gynecological infection, bacteremia/septicemia,
skin and skin structure infections,
intra-abdominal infections, bone or joint
infections, meningitis or other CNS infections,
perioperative prophylaxis CDC recommended
treatment for gonorrhea IM/IV, 40 protein bound,
60 renal excreted unchanged adjust with renal
fx
18
3rd Generation Cephalosporins
Indications Lower respiratory infection, UTI,
gonorrhea and PID, septicemia, skin and skin
structure infections, intra-abdominal infections,
bone or joint infections, meningitis IM/IV use
only, 30 protein bound, 80 excreted unchanged
in the urine---dosage reduction necessary in
renal failure Indications Lower respiratory
infection, UTI, gonorrhea and PID, septicemia,
skin and skin structure infections,
intra-abdominal infections, bone or joint
infections, meningitis, surgical prophylaxis,
effective in treating Lyme disease infection
causing neurological complications, arthritis and
carditits refractory to PenG DOC Gonorrhea
single injection IM/IV use only, 95 protein
bound, 67 excreted unchanged in the urine
19
3rd Generation Cephalosporins
Indications Lower respiratory infections, skin
and skin structure infections, UTI, bacterial
septicemia, bone and joint infections,
gynecological infections, intra-abdominal
infections, CNS infections, concomitant
antibiotic therapy in immunocompromised
patients Renal excretion---adjust dosage as a
function of GFR90 unchanged Sodium bicarbonate
solution is NOT recommended as a diluent, do NOT
mix with aminoglycosides IM/IV use only, lt10
protein bound Indications Respiratory tract
infections, peritonitits and other
intra-abdominal infections, bacterial septicemia,
skin and skin structure infections, PID,
endometritis, UTI IM/IV only, 93 protein
bound, 30 excretion unchanged
in the urine Extensively excreted in the
bilemonitor serum concentrations in high doses
in the case of hepatic disease or biliary
obstruction Renal failure-no dose adjustment
except in high doses
20
4th Generation Cephalosporins
Indications UTI, skin and skin structure
infections, pneumonia (moderate to severe),
complicated intra-abdominal infections, empirical
therapy for febrile neutropenic patients,
pediatric patients 2 months to 16 years of age
as above plus pyelonephritis IM/IV only,
20protein bound, 85 excreted unchanged in the
urinedosage adjustment needed in renal
failure Admixture stability can vary based on
diluent
21
Cephalosporin Summary

• Generation
• Cefazolin Cephalexin
• Staph or Strep infections
• Surgical prophylaxus
• Many differences within this group watch for
  Superinfection
• Cefotetan Cefoxitin
• B. fragilis intraperotoneal and pelvic
  infection (surgery)
• Cefuroxime Cefaclor
• H. influenza
• BIG guns reserved for SERIOUS infections
• Cross BBB (blood-brain barrier)
• Exceptions Ceftriaxone (IV) Cefixime (PO) DOC
  ? gonorrhea
• Ceftriaxone injection 10d of amoxicillin
  (otitis media)
• Cefipime clinically like G3
• Good Gram () and (-) activity

22
b-Lactam Bottom Line Gram()

• Bacteria DOC 2nd Line

Streptococcus Penicillin (G or
VK) Cephalosporin G1 Amoxicillin Ceftriaxone
Ampicillin Cefotaxime Staphylococcus Nafci
llin Cephalosporin G1 Oxacillin Vancom
ycin Enterococcus Penicillin (G or
VK) Vancomycin Amoxicillin Gentamicin Amp
icillin
CNS
23
b-Lactam Bottom Line Gram(-)

• GENERALLY(some exceptions)
• First Choice Aminopenicillin inhibitor
• Amoxicillin clavulanate (Augmentin)
• Ampicillin sulbactam (Unasyn)
• Next Option Cephalosporin G2 or G3