# Presentation: 915893

##  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***

## Introduction

**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**

## 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)**

## 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.**

## 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***
**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**

## 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)**

## 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**

## Drug Approvals by Class

## Approvals of Beta-Lactams

## 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***

## 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*****. **

## 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**

## 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)**

## 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 AdvisorTM, Years 2000 - 2005, Extracted 9-13-06, Premier Powers 2006-41  9-13-06 cephalosporins ICD-9.xls**
**2. Premier RxMarket AdvisorTM, Years 2000 - 2005, Extracted 9-13-06, Premier Powers 2006-41  9-13-06 class product discharges.xls**
**3. Premier RxMarket AdvisorTM, Years 2000 - 2005, Extracted 9-13-06, Premier Powers 2006-41 9-13-06 cefepime ICD-9.xls**

## 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**

## 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**

## 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**

## 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***** ***

## 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**

## 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**

## 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**

## 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**

## 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**

## 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 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**

## Thanks

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