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U.S. Department of Health and Human Services

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Use and Importance of Cephalosporins in Human Medicine

Use and Importance of Cephalosporins in Human Medicine

John H. Powers, MD
Lead Medical Officer
Antimicrobial Drug Development and Resistance Initiatives
Office of Drug Medical Policy
Center for Drug Evaluation and Research
U.S Food and Drug Administration

Use and Importance of Cephalosporins in Human Medicine - slide 1
 

Slide 2

Introduction

  • Background on cephalosporins anticmicrobials
  • Uses of cephalosporins in human medicine
  • Background on ranking process of ranking of drug according to
    important in human medicine for Guidance 152
  • Ranking process applied to cephalosporins

 

Use and Importance of Cephalosporins in Human Medicine - slide 2
 

Slide 3

Cephalosporins

  • Cephalosporin discovery credited to Brotzu in 1945 in sewer water off coast of Sardinina
  • Several compounds isolated from mold Acremonium chrysogenum with cephalosporin C as basic nucleus for future drugs
  • First introduced into clinical use in 1964 (cephalothin)

Use and Importance of Cephalosporins in Human Medicine - slide 3

Slide 4

Cephalosporins

  • Bicyclic ring structure
    • beta-lactam ring (in common with penicillins)
    • 6 membered sulfur containing dihidrothiaizine ring
  • Changes in side chain R groups gives changes in spectrum of activity, pharmacokinetics, etc.

Use and Importance of Cephalosporins in Human Medicine - slide 4

Slide 5

Cephalosporins

  • Mechanism of action: binds to penicillin binding proteins and inhibition of formation of cell wall
  • Mechanisms of resistance:
    • Changes in drug target of penicillin binding proteins  - methicillin-resistant Staphyloccocus aureus
      • Efflux pumps – MexAB-OprM efflux pump in Pseudomonas aeruginosa
      • Decreased permeability of cell wall – less common for cephalosporins
    • Alteration of drug itself by hydrolysis by beta-lactamases
      • Numbers and types of beta-lactamases increasing
      • Can be chromosomally or extra-chromosomally (more easily transmitted to other organisms) mediated
  • Resistance to one cephalosporin can result in resistance others depending on mechanism
  • Resistance to cephalosporins can confer resistance to other beta-lactam drugs like penicillins as well
Use and Importance of Cephalosporins in Human Medicine - slide 5
 

Slide 6

Cephalosporins

  • Divided into “generations” for convenience but many drugs in same “generation” not chemically related and different spectrum of activity
  • Currently four generations of cephalosporins but which generation a particular drug belongs often a matter of debate
  • Generalization that with increasing “generation” activity in vitro against Gram positive organisms decreases while activity against Gram negatives increases (but an oversimplification)
     
Use and Importance of Cephalosporins in Human Medicine - slide 6
 

Slide 7

Cephalosporins

  • First generation
    • Oral and intravenous forumlations
    • Activity against E. coli, Klebsiella, Proteus
    • In general, FDA approved for skin and soft tissue infections, urinary tract infections, respiratory tract infections
  • Second generation
    • Oral and intravenous - cefuroxime axetil
    • Anti-anaerobic activity (cephamycins) - cefoxitin
  • Third generation
    • Non-anti-pseudomonal – ceftriaxone, cefotaxime
    • Anti-pseudomonal – ceftazidime
  • Fourth generation – cefepime
Use and Importance of Cephalosporins in Human Medicine - slide 7
 

Slide 8

Drug Approvals by Class


Use and Importance of Cephalosporins in Human Medicine - slide 8

Slide 9

Approvals of Beta-Lactams


Use and Importance of Cephalosporins in Human Medicine - slide 9

Slide 10

Fourth Generation - Cefepime FDA approved indications

  • Pneumonia (moderate to severe) caused by Streptococcus pneumoniae , including cases associated with concurrent bacteremia, Pseudomonas aeruginosa , Klebsiella pneumoniae , or Enterobacter species.
  • Empiric Therapy for Febrile Neutropenic Patients.
  • Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae , when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae , or Proteus mirabilis , when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.
  • Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.   
  • Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by Escherichia coli , viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis
 
Use and Importance of Cephalosporins in Human Medicine - slide 10
 

Slide 11

Third Generation - Ceftriaxone

  • Lower Respiratory Tract Infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.
  • Acute Bacterial Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains).
  • Skin and Skin Structure Infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii*, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis * or Peptostreptococcus species.
  • Urinary Tract Infections (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.
  • Uncomplicated Gonorrhea (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae.   
Use and Importance of Cephalosporins in Human Medicine - slide 11
 

Slide 12

Third Generation - Ceftriaxone

  • Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae. Rocephin, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.
  • Bacterial Septicemia caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae.
  • Bone and Joint Infections caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.
  • Intra-Abdominal Infections caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of C. difficile are resistant) or Peptostreptococcus species.
  • Meningitis caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae. Rocephin has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis* and Escherichia coli.*
     * Efficacy for this organism in this organ system was studied in fewer than ten infections.
  • Surgical Prophylaxis
Use and Importance of Cephalosporins in Human Medicine - slide 12
 

Slide 13

Usage of Cephalosporins in Human Medicine

  • Beta-lactam antibiotics make up 40% of total prescriptions of antibiotics in the outpatient setting (amoxicillin most commonly prescribed drug)
  • Cephalosporins make up 14% of total outpatient antibiotic prescriptions accounting for over 50 million prescriptions per year
  • Cephalosporin most commonly used to treat outpatient indications of pneumonia, skin and soft tissue infections, sinusitis, urinary tract infections, otitis
    • Data from Verispan, LLC Vector One National (VONA)
       
Use and Importance of Cephalosporins in Human Medicine - slide 13
 

Slide 14

Usage of Cephalosporins in Human Medicine

  • Inpatients setting most common diagnosis associated with billing for a cephalosporin is pneumonia1
  • Individual drug usage from January 2000 to December 2005:2
    • Cefazolin (1st generation) with approximately 37 million projected discharges
    • Ceftriaxone (3rd generation) with approximately 16 million projected discharges
    • Cefepime (4th generation) in approximately 2 million projected discharges2 with pneumonia as most common usage for drug (approx. 157,000)3

      1. Premier RxMarket Advisor™, Years 2000 - 2005, Extracted 9-13-06, Premier Powers 2006-41  9-13-06 cephalosporins ICD-9.xls
      2. Premier RxMarket Advisor™, Years 2000 - 2005, Extracted 9-13-06, Premier Powers 2006-41  9-13-06 class product discharges.xls
      3. Premier RxMarket Advisor™, Years 2000 - 2005, Extracted 9-13-06, Premier Powers 2006-41 9-13-06 cefepime ICD-9.xls
Use and Importance of Cephalosporins in Human Medicine - slide 14
 

Slide 15 

Usage of Cephalosporins in Human Medicine

  • 3rd and 4th generation cephalosporins used in hospital setting in seriously ill patients for serious and life-threatening diseases
  • Many of these diseases due to organisms that reside in the gastrointestinal tract
  • Drugs of last resort for serious infections due to food-borne pathogens Salmonella and Shigella
    • These organisms may be resistant to other drugs.
    • Quinolones may be effective but avoid in children due to potential for toxicities
Use and Importance of Cephalosporins in Human Medicine - slide 15
 

Slide 16

Importance of Antimicrobials in Human Medicine

  • Desire to preserve usefulness of antimicrobials of greatest importance in treatment of human disease
  • Guidance 152 includes categorization of drugs based on relative importance in human  medicine
    • drugs ranked as critically important, highly important or important in human medicine based on several factors
    • considered in hazard identification and consequence assessments
  • Joint CVM-CDER team developed criteria for categorization of drugs
Use and Importance of Cephalosporins in Human Medicine - slide 16
 

Slide 17

Importance of Antimicrobials in Human Medicine

  • Developing criteria important to ensure fair approach and lack of bias
  • Criteria presented at open public meeting in October 2002 and Anti-Infective Drugs Advisory Committee meeting in January 2003
  • Criteria refined based on AIDAC advice with input from public comments including animal health industry
  • Utilized related to a specific drug at VMAC meeting in 2004
Use and Importance of Cephalosporins in Human Medicine - slide 17
 

Slide 18

Importance of Antimicrobials in Human Medicine

  • Criteria
    1. antimicrobial used to treat enteric pathogens that cause food borne disease
    2. Sole therapy or one of few alternatives to treat serious human disease or drug is essential component among many antimicrobials in treatment of human disease
    3. Antimicrobials used to treat enteric pathogens in non-food-borne disease
    4. No cross-resistance within drug class and absence of linked resistance with other drug classes
    5. No cross-resistance within drug class and absence of linked resistance with other drug classes
Use and Importance of Cephalosporins in Human Medicine - slide 18
 

Slide 19

Importance of Antimicrobials in Human Medicine

  • Drugs that meet criteria 1 AND 2 considered critically important
  • Drugs that meet criteria 1 OR 2 considered highly important
  • Drugs that meet any of criteria 3, 4 , or 5 considered important
Use and Importance of Cephalosporins in Human Medicine - slide 19
 

Slide 20

Importance of Antimicrobials in Human Medicine

  • Ranking of 4th generation cephalosporins
    • Criteria 2: One of sole therapies approved for empirical therapy of febrile neutropenic patients
    • Criteria 3: Used to treat disease due to enteric pathogens in non-food borne illnesses (e.g. pneumonia)
  • Ranked as highly important based upon meeting criteria 2 and 3
  • Not often specifically used to treat gastrointestinal diseases or food borne illness
Use and Importance of Cephalosporins in Human Medicine - slide 20
 

Slide 21

Importance of Antimicrobials in Human Medicine

  • Ranking of 3rd generation cephalosporins
    • Criteria 1: Treatment of typhoid fever and gastrointestinal disease due to Salmonella and Shigella (not FDA approved for this indication) – only therapy in children who cannot take quinolones
    • Criteria 2: Sole or limited therapy
      • to treat serious disease such as acute bacterial meningitis (few other altenative for Gram negative meningitis)
         
      • One of sole therapies to treat serious disease due to Salmonella or Shigella in children (avoid quinolones due to potential toxicities)
    • Criteria 3: Use to treat disease due to enteric pathogens in non-food-borne diseases such as Gram negative meningitis
  • Ranked as critically important based on meeting criteria 1 and 2
  • Resistance to 4th generation cephalosporins may confer resistance to all other cephalosporins including 3rd generation drugs and may confer resistance to penicillins
Use and Importance of Cephalosporins in Human Medicine - slide 21
 

Slide 22

Importance of Antimicrobials in Human Medicine

  • Following issuance of Guidance 152, World Health Organization convened meeting to rank drugs according to importance in human medicine on global basis
  • This effort use a different but related set of criteria:
    • 1a) Sole therapy or one of few alternatives to treat serious human disease (no direct linkage to food-borne disease needed)
    • 1b) Antibacterial used to treat diseases caused by organisms that may be transmitted via non-human sources or diseases causes by organisms that may acquire resistance genes from non-human sources
  • Meeting both criteria defined drug as critical, meeting one or the other defined drug as highly important
Use and Importance of Cephalosporins in Human Medicine - slide 22
 

Slide 23

Importance of Antimicrobials in Human Medicine

  • Disease due following organisms:
    • E. coli
    • Salmonella
    • Campylobacter
    • Pseudomonas
    • Enterococcus
    • BUT does not exclude other organisms
  • Based on these criteria, both 3rd and 4th generation cephalosporins ranked as critically important in WHO ranking document

Use and Importance of Cephalosporins in Human Medicine - slide 23

Slide 24

Conclusions

  • Cephalosporins one of most widely used drug classes in the US and worldwide
  • Mechanisms of resistance to cephalosporins may confer resistance to other beta-lactam agents
  • Ranking of 4th generation cephalosporins as highly important and 3rd generation agents as critically important in Guidance 152; both critically important in WHO criteria
  • Ranking of antimicrobials according to importance in human medicine one factor to consider in overall risk-management strategy for use of drugs in animals according to Guidance 152
Use and Importance of Cephalosporins in Human Medicine - slide 24
 

Slide 25

Thanks

  • Rosemary Johann-Liang
  • Vicky Borders-Hemphill
  • Laura Governale
  • Carol Pamer
  • In the Office of Surveillance and Epidemiology, FDA
Use and Importance of Cephalosporins in Human Medicine - slide 25