Why Cephalosporins

1
Why Cephalosporins?

• Broad spectrum of activity
• Stability to ?-lactamase
• Oral and parenteral preparations
• Widely accepted
• Treats day to day as well asserious
  infections
• High safety profile

2
Cephalosporins -Limitations

• Emerging resistance patterns
• III IV generation cephalosporins were available
  only as parenteral formulations
• Pharmacoeconomics

3
Cephalosporins Classification

• I Generation Predominantly active against gram
  positive pathogens
• II Generation Moderate activity against gram
  positive gram negative pathogens
• III Generation Predominantly active against gram
  negative pathogens

4
New Classification of Cephalosporins

• Group 1 Group 2 Group 3 Group 4
• Cephazolin Cefaclor Cefuroxime Cefotaxime
• Cephaloridine Cefadroxil Cefoxitin Ceftriaxone
• Cephalothin Cephalexin Cefotetan Ceftizoxime
• Lambert OGrady, 1997

5
New Classification of Cephalosporins

• Group 5 Group 6 Group 7
• Cefpodoxime Ceftazidime Cefpirome
• Cefixime Cefoperazone Cefepime
• Ceftibuten
• Cefprozil
• Lambert OGrady, 1997

6
MICs90 of Oral Cephalosporins against Common
Pathogens

• Cephalosporin H. influenzaea M.catarrhalisa E.coli
  S.pneumoniae S.aureusb Group A streptococci
  
• Cephalexin 16 16 16 4 4 1
• Cefadroxil 16 4 16 8 8 0.5
• Cefaclor 4 2 4 2 16 0.25
• Cefuroxime 2 2 4 0.12 2 0.25 axetil
• Cefixime 0.25 0.25 0.5 1 gt 16 0.25
• Cefpodoxime 0.12 0.5 1 0.03 2 lt 0.06
• Ceftibuten 0.12 2 0.5 4 gt 16 1
• a Includes b-lactamase and non-b-lactamase
  strains
• b Methcillin-sensitive, penicillin-resistant
  strains
• Infectious Diseases in Clinical practice, 1994,
  Vol.3, No.1

7
Cefpodoxime proxetil
Isopropyl oxoethyl oxocarbonyl
side chain confers increased rate
of absorption after oral administration
Aminothiazole moiety broadens
CH
3
antimicrobial spectrum and
increases antibacterial activity
COOCHOCOOCH(CH
)
3
2
S
O
N
H
N
2
CH
OCH
2
3
CONH
C
N
H
H
S
OCH
N
3
Methoxymethylgroup improves
Methoxyminogroup
the antibacterial activity against
protects against
gram positive bacteria, and
hydrolysis by
increases the stability of the molecule
beta lactamases
in the gastrointestinal tract
8
Goals of anti-microbial therapy

• The duration of time that serum conc. exceed the
  MIC is an important parameter.
• Studies in animals suggest that serum levels of
  ?-lactams need to exceed the MIC for about half
  of the dosing interval to obtain maximum
  antimicrobial efficacy.
• Diagn. Microbiol. Infect. Dis. 1996 25 213-217

9
How Effective is an Antibiotic

• Concentration
• Dependent Killing
• Efficacy determined by magnitude of serum
  concentration above MIC
• e.g. Aminoglycosides, quinolones, azalides

• Time Dependent Killing
• Efficacy determined by duration of time that
  serum concentrations exceed MIC
• e.g. b-lactams, macrolides, cotrimoxazole

10
The pharmacodynamics of b-lactams andmost
macrolide antibiotics
11
Plasma concentration-time curves (mean SD) for
cefpodoxime in 15 young (n) and 9 elderly (l)
patients with respiratory tract infections, after
the last morning dose of a 6- to 10-day regimen
of cefpodoxime proxetil (200 mg cefpodoxime
equivalent) twice daily. MIC90
4
M. catarrhalis
(MIC900.5 mg/L)
3
H. influenzae
(MIC900.05 mg/L)
S. pneumoniae
Cefpodoxime concentration (mg/L)
(MIC900.06 mg/L)
2
S. pyogenes
(MIC900.015 mg/L)
1
0
6
8
3
12
2
4
0
1
Time (hours)
Drugs 1991 42 (suppl 3) 160
12
Serum Bactericidal Activity Against H.influenzae

• Median Reciprocal SBT at Various Times (hrs)
• H.influenzae 1 2 3 4 6 8 12
• b-Lactamase negative
• Cefaclor 2 2 2 NA NA NA NA
• Loracarbef 8 8 4 2 2 2 2
• Cefprozil 4 4 2 2 2 2 2
• Cefpodoxime 8 16 16 16 16 16 8
• Cefuroxime 8 16 8 4 2 2 2
• b-Lactamase positive
• Cefaclor NA NA NA NA NA NA NA
• Loracarbef 4 4 2 NA NA NA NA
• Cefprozil 2 2 2 2 NA NA NA
• Cefpodoxime 8 16 16 16 8 8 4
• Cefuroxime 8 8 8 4 2 NA NA
• SBT serum bactericidal titer NA no serum
  bactericidal activity or less than 2
• Pharmacotherapy 1997 17 235-41

13
Time gt MIC

• S. H. Drug Regimen pneumoniae influenzae
• Cefaclor 500 mg 60 20 q 8h
• Cefuroxime 500 mg 75 35 q 12h
• Cefpodoxime 200 mg 83 100 q 12h
• Cefixime 400 mg 59 100 q 24 h
• Diagn. Microbiol. Infect. Dis. 1996 25 213-217

14
Percentage of Dosing Interval Time gt MIC
100
80
60
Time Above MIC
40
20
0
CFP
CFU
CFZ
LCF
b-lactamase negative isolate b-lactamase positive
isolate
Pharmacotherapy 1997 17(2) 235-241
15
Tobramycin, ciprofloxacin and ticarcillin killing
curves
Diagn. Microbiol. Infect. Dis. 1997 27 29-33
16
Relationship Between Time Above MIC and Mortality
For Beta-lactam Antibiotics in Animal Infection
Models
Diagn. Microbiol. Infect. Dis. 1996 24
17
Bacteriological Cure Versus Time Above MIC in
Otitis Media
Diagn. Microbiol. Infect. Dis. 1996 24
18
Switch Therapy

• It is a practice of early transition from
  parenteral to oral therapy with the objective
  of reducing the duration of hospital stay and
  overall cost of treatment, without compromising
  clinical outcome.

19
The Natural History of a Serious Infection
The Three Stages on the Recovery of Infections
20
Switch Therapy Approach to Treatment
The Annals of Pharmacotherapy 1998 32 S22-26.
21
Application of Switch Therapy

• Hospital-acquired pneumonia
• Pneumonia caused by Gram-negative bacilli
• Sepsis of unknown origin
• Sepsis caused by Gram-negative bacilli
• Pyelonephritis
• Arthritis caused by Gram-negative bacilli
• J of Antimicrobial Chemotherapy199433169-171

22
Similarity
Therapeutic Drugs, 2nd ed 1 C113135
23
In vitro antibacterial activity

• Mean Mean
• MIC90 MIC90
• Gram-negative Gram-positive
• H. influenzae lt0.24 S. pyogenes lt0.02
• M. catarrhalis 0.63 S. pneumoniae lt0.05
• N. gonorrhoeae lt0.06 S. aureus 2.5
• K. pneumoniae 0.9
• E. coli 1
• P. mirabilis lt0.46

Drug 1992 44 (5) 889917
24
Similarity (Contd.)

• Organisms Cefpodoxime Ceftriaxone
• S.pneumoniae lt0.06 0.5
• H.influenzae 0.06 0.01
• E.coli 0.5 0.25
• K.pneumoniae 0.12 0.25
• P.mirabilis 0.06 0.25

Mandel 1995 1 247263
25
Similarity (Contd.)

• Both compounds can be administered in a
  convenient once or twice daily dosing schedules
• Ceftriaxone susceptibility results can be used to
  predict cefpodoxime susceptibility
• The Annals of Pharmacotherapy 199529566-565

26
PneumoniaClinical efficacy of cefpodoxime 200 mg
as compared to ceftriaxone 1 g injection
Clinical efficacy
Drugs 1992 44(5) 889 - 917
27
I.V. ceftriaxone to cefpodoxime

• 20 patients were converted from IV ceftriaxone to
  oral cefpodoxime.
• Another 20 patients served as control group
• Results Average time for receiving IV and oral
  antibiotic were 9.1 days while in the control
  group it was 11.9 days
• The Annals of Pharmacotherapy 199529561-565

28
Efficacy confirmed in an Indian Study

• 40 patients given cefpodoxime100 mg bid 10 days.

Cefpodoxime
Clinical efficacy
29
Skin and soft tissue infectionsClinical response
after 100 mg of Cefpodoxime
n number of patients
95n55
83n41
79n76
93n41
Drug 1992 44(5) 889-917
30
Nausea
Other therapies Cefpodoxime
Vomiting
Abdominal pains
Soft stools
Diarrhoea
Pruritus
Skin eruption
Mycosis
Asthenia
Headache
0
1
2
3
4
5
Incidence ()
Drugs 1991 42 (suppl 3) 166
31
Dosage and Administration

• Adults (Age 13 years older)
• Upper respiratory tract infections 100 mg bid
  for 5-10 days
• Acute exacerbation of chronic bronchitis 200 mg
  bid for 10 days
• Acute community acquired pneumonia 200 mg bid
  for 14 days
• Uncomplicated gonorrhoea 200 mg single dose
• Uncomplicated urinary tract infections100 mg bid
  for 7 days

32
Dosage and Administration

• Adults (Age 13 years older)
• Skin skin structure infections 400 mg bid for
  7-14 days
• Children (Age 5 months to 12 years)
• Acute otitis media 10 mg/kg (max 100 mg/dose)
  OD or 5mg/kg (max 200 mg/dose) bid for 10 days
• Pharyngitis and /or tonsillitis 5 mg/kg/dose
  (max100 mg/dose) bid for 5-10 days

33
Highlights of the Molecule

• Potent orally active 3rd generation
  cephalosporin.
• Wide antibacterial spectrum against gram-positive
  and gram-negative bacterias with enhanced
  anti-staphylococcal activity and stability in the
  presence of several?-lactamases.
• Serum concentration above MIC90 of commonly
  encountered pathogens for at least 90 of the
  dosing interval.

34
Highlights of the Molecule (Contd.)

• Comparable or better efficacy to that of standard
  ?-lactams in various respiratory tract, skin and
  soft tissue and urinary tract infections.
• Cefpodoxime provides antimicrobial power
  equivalent to injectable ceftriaxone.
• Convenient oral alternative for injectable
  therapy in elderly patients and patients with
  serious underlying disorder.
• Safe and well-tolerated in adults and children.