1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. 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

3. 3Introduction  Background on cephalosporin antimicrobials  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

4. 4Cephalosporins  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)

5. 5Cephalosporins  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.

6. 6Cephalosporins  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  Lack of access of the drug to the penicillin binding protein target  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

7. 7Cephalosporins  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)

8. 8Cephalosporins  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

9. 9 Drug Approvals by Class

10. 10 Approvals of Beta-Lactams

11. 11 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.  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

12. 12 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.

13. 13 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

14. 14 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)

15. 15 Usage of Cephalosporins in Human Medicine  Inpatients setting most common diagnosis associated with billing for a cephalosporin is pneumonia 1  Individual drug usage from January 2000 to December 2005: 2  Cefazolin (1 st generation) with approximately 37 million projected discharges  Ceftriaxone (3 rd generation) with approximately 16 million projected discharges  Cefepime (4 th generation) in approximately 2 million projected discharges 2 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

16. 16 Usage of Cephalosporins in Human Medicine  3 rd and 4 th 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

17. 17 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

18. 18 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

19. 19 Importance of Antimicrobials in Human Medicine  Criteria 1) antimicrobial used to treat enteric pathogens that cause food borne disease 2) 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

20. 20 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

21. 21 Importance of Antimicrobials in Human Medicine  Ranking of 4 th 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

22. 22 Importance of Antimicrobials in Human Medicine  Ranking of 3 rd 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 4 th generation cephalosporins may confer resistance to all other cephalosporins including 3 rd generation drugs and may confer resistance to penicillins

23. 23 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

24. 24 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 3 rd and 4 th generation cephalosporins ranked as critically important in WHO ranking document

25. 25Conclusions  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 4 th generation cephalosporins as highly important and 3 rd 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

26. 26Thanks  Rosemary Johann-Liang  Vicky Borders-Hemphill  Laura Governale  Carol Pamer  In the Office of Surveillance and Epidemiology, FDA