Cephalosporins

By SherAlam Khan Mohmand student of Ayub Medical college,AbbottAbad,Pakistan.

Email Sheralamkhan97@yahoo.comCephalosporins are bactericidal agents. Cephalosporin was isolated from fungus called CEPHALOSPORIUM ACREMONIUM by BROTZU in from sewer water in Sardinia in 1948 in Willium Dunn School of Pathology. The first use agent was Cephalothin cephalosporin-C used clinically in 1964.Cephalosporins are structurally related to Penicillins consists of a Beta lactum ring attached to Dihydrothiazoilne ring.

The Cephalosporin nucleus, 7-Aminocephalosporanic acid (7-ACA) was derived from Cephalosporin-C and proved to be analogous to the penicillin nucleus, 6-Aminopenicillanic acid.

Modification of 7-ACA side chains resulted in development of useful antibiotic agents, and the first agent Cephalothin was launched by Eli Lilly in 1964.

These Agents are Active against

1)Gram Positive Bacteria

2)Gram Negative Bacteria

3)Some anaerobic bacteria

Mechanism of action:

Cephalosporins disrupt the Peptidoglycan layer of bacterial cell wall.

The Peptidoglycan is an important bacterial cell wall integrity.The final transpeptidation step ithe synthesis of peptidoglycan is facilitated by transpeptidases known as Penicillin Binding Protiens(PBP). These PBPs bind to

D-Ala-D-Ala at the end of muropeptides 9Peptidoglycan precursors) to crosslink the peptidoglycan. So the Beta Lactum agents competitivel inhibit PBP crosslinking of peptidoglycan.

Classification of Cephalosporins.

Cephalosporins fall in FIVE classes or Generations. Each subsequent generation of these drugs demonstrates greater efficacy against Gram negative bacteria.

Generalization that with increasing “generation” activity in vitro against Gram Positive Organisms decreases while activity against Gram Negative Organisms increases.

Note: Many drugs in the same generation are not chemically related and having different spectrum of activity. Division in generation is just for your convenience.

3rd and 4th genrstion cephalosporins are used in hospital setting in seriously ill patients for serious and life threatening diseases.Many of these diseases are due to organisms residing in gastro-intestinal tract. Drugs of last resort for serious infections due to food borne pathogens Salmonella and Shigella.

1st Generation Cephalosporins.

1) Cefacetrile2) Cefadroxil3) Cefalexin4) Cefaloglycin5) Cefalonium6) Cefaloridine7) Cefapirin8) Cefalothin9) Cefatrizine10) Cefazedone11) Cefrozadine12) Cefazolin13) Ceftezole14) Cefazaflur15) Cephradine

Activity of 1st generation cephalosporins.

1) Gram Positive Cocci

a)Pneumococci

b) Viridans Streptococci

c) Group-A hemolytic streptococci

d) Staphylococcus aureus

e) Streptococcus Pyogenese

f)Streptococcus Pneumoniae

2) Gram Negative Bacteriaa) E.Colib) Klebsiella Pneumoniac) Proteus Mirabilisd) Corynebacterium Diptheriaee) Salmonellaf) Neisseria

Indications of 1st generation Cephalosporins.

1) Nose infection2) Throat infection3) Chest infection4) Ear infection5) Urinary tract infection

6) Gynae infection7) Skin infectiom8) Gum infection 9) Bronchitis

Contra-indications of 1st generation cephalosporins.Avoid use in allergic persons.

Adverse effects of 1st Generation Cephalosporins.

Usually seen Adverse effects are: diarrhea that is watery or bloody. fever, chills, body aches, flu symptoms. tightness in your chest. unusual bleeding. seizure (convulsions). pale or yellowed skin, dark colored urine, fever, confusion or weakness. jaundice (yellowing of the skin or eyes). skin rash, bruising, severe tingling, numbness, pain, muscle weakness. Sore throat, and headache with a severe blistering, peeling, and red skin rash. Increased thirst, loss of appetite, swelling, weight gain, feeling short of breath, urinating less than usual

or not at all.

Less serious side effects of cephradine may include:

nausea, vomiting, stomach pain, mild diarrhea; stiff or tight muscles; joint pain; dizziness; feeling restless or hyperactive; unusual or unpleasant taste in your mouth; mild itching or skin rash; or vaginal itching or discharge.

2nd Generation Cephalosporins.1)Cefotetan2)Cefmetazole3) Cefoxitin4)Cefaclor5) Cefonicid6)Cefprozil7)Cefuroxime8)Cefuzonam9)Cefamandole

Activity of 2nd generation cephalosporins against bacteria.1) Staphylococci2) Streptococcus pneumonia3) Moraxella catarrhalis4) H.influenzae5) E.Coli 6) Proteus Mirabilis7) Klebseilla8) Neisseria9) Citrobacter

Mechanism of action of 2nd generation cephalosporins.

Mechanism of action:

Cephalosporins disrupt the Peptidoglycan layer of bacterial cell wall.

The Peptidoglycan is an important bacterial cell wall integrity.The final transpeptidation step ithe synthesis of peptidoglycan is facilitated by transpeptidases known as Penicillin Binding Protiens(PBP). These PBPs bind to

D-Ala-D-Ala at the end of muropeptides 9Peptidoglycan precursors) to crosslink the peptidoglycan. So the Beta Lactum agents competitivel inhibit PBP crosslinking of peptidoglycan.

Indications of 2nd generation cephalosporins.1) Nose infection2) Throat infection3) Ear infection4) U.T.I5) Chest infection6) Skin infection7) Gonorrhea8) Diverticulitis9) Peritonitis10) Cefoxitin and Cefotetan are used as Prophylaxis in Colorectal

surgeries, vaginal or abdominal histerectomies and appendicitis because of activity against Bacteriod Fragilis.

Contra-indications of 2nd generation cephalosporins.

1) Use carefully in Pregnant and breast feeding women.2) Use carefully in patients with renal failure.3) Do not prescribe for sensitive pesrons.

Adverse Effects of 2nd generation cephalosporins.

1) Damage kidneys and liver.2) Sleep time decrease.3) Nausea,vomiting,diarrhea.4) Confusion.5) Pain in joints.6) Temporarily decrease in White Blood Cells.7) Generalized weakness.8) Lightheadedness.9) Giddiness.10) Prothrombin time gets increased.11) Fungus infection(Candidiasis)12) Indigestion.13) Sensitivity Reactions.

3rd generation cephalosporins.

1) Cefixime2) Cefdinir3) Cefpodoxime4) Cefteram5) Ceftibuten6) Cefminoxime7) Ceftizoxime8) Cefriaxone9) Cefotaxime10) Ceftazidime11) Cefopirazone

Mechanism of Action of 3rd generation.

Mechanism of action:

Cephalosporins disrupt the Peptidoglycan layer of bacterial cell wall.

The Peptidoglycan is an important bacterial cell wall integrity.The final transpeptidation step ithe synthesis of peptidoglycan is facilitated by transpeptidases known as Penicillin Binding Protiens(PBP). These PBPs bind to

D-Ala-D-Ala at the end of muropeptides 9Peptidoglycan precursors) to crosslink the peptidoglycan. So the Beta Lactum agents competitivel inhibit PBP crosslinking of peptidoglycan.

Activity of 3rd generation cephalosporin against Bacteria.1) Enterobacteriaceae 2) Pseudomonas aeruginosa3) Hemophilus influenza4) Neisseria5) Nonenterococcal streptococci 6) Anaerobic gram-positive cocci.7) Staphylococcus aureus8) Staphylococcus epidermidis9) Streptococcus pyogenese10)Streptococcus pneumoniae11)Streptococcus Group-B12)Streptococcus viridans

13) Moraxella catrrhalis14) Neisseria gonorrheae15) Neisseria meningitides16) Citrobacter 17) Enterobacter18) E.Coli19) Proteus20) Salmonella21) Shigella22) Vibrio 23) Pastuerella24) Yersinia25) Serratia

Indication of 3rd generation cephalosporins.1) Sinusitis2) Bronchitis3) Phyrangitis4) Tonsillitis5) Pneumonia6) Meningitis7) Otitis media8) Innfections caused by Staphylococcus aureus.9) Gonorrhea10) Skin infection.11) Pelvic inflammatory disease.12) Gynae infection.13) Nose infection.14) Throat infection.15) Kidneys infection.16) Bones and joints infection.17) Peritonitis18) Septicemia19) Infection after surgery20) Gall bladder infection

Adverse effects of 3rd generation cephalosporins.

1) Allergic reactions2) Nausea,vomiting,diarrhea.3) Flatulence4) Anemia5) Leukopenia

6) Pseudomembranous colitis7) Flushing8) Headache9)10) Giddiness11) Elivation of liver SGOT and SGPT12) Vaginitis13) Bronchospasm14) Allergic Pneumonitis15) Flatulence16) Dyspepsia17) Jaundice18) Hematuria19) Seizure 20) Serum sickness

4th generation cephalosporons

1) Cefepime2) Cefozopran3) Cefpirome4) Cefquinome5) Cefoselis6) CefluPrenam7) Cefclidine

Mechanism of Action of 4th generation.

Mechanism of action:

Cephalosporins disrupt the Peptidoglycan layer of bacterial cell wall.

The Peptidoglycan is an important bacterial cell wall integrity.The final transpeptidation step ithe synthesis of peptidoglycan is facilitated by transpeptidases known as Penicillin Binding Protiens(PBP). These PBPs bind to

D-Ala-D-Ala at the end of muropeptides 9Peptidoglycan precursors) to crosslink the peptidoglycan. So the Beta Lactum agents competitivel inhibit PBP crosslinking of peptidoglycan.

Activity of 4th generation cephalosporins against bacteria.

1) Pseudomonas auregenosa2) Klebseilla pneumonia3) E.Coli4) Prteus mirabilis5) Enterobacter Species6) Bacteroids Fragilis7) Staphylococcus aureus.8) Streptococcus pyogenese9) Salmonella10) Citro bacter11) Shigella12) H.influenzae13) Streptococcus viridans

Indications of 4th generation cephalosporins.

1) Otitis media2) Sinusitis3) Phyrangitis4) Tonsillitis5) Bronchitis6) U.T infections7) Gonorrhea

8) Gynae infection9) Infection after delivery10) Skin infections11) Intra abdominal infection (use with metronidazole)12) Typhoid fever13)

Contra indications:

1) Use carefully in Pregnant Women2) Do not use in allergic Patients

Adverse effects of 4th generation Cephalosporins.1) Diarhea (bloody or watery)2) Confusion3) Hallucinations4) Seizures5) Fever,Chills, body aches.6) Weakness7) Easily bruising or bleeding.8) Sore throat9) Severe headache10) Abdominal pain11) Flatulence

INDICATIONSMAXIPIME is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms (see alsoPRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION):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. Cefepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.

Uncomplicated and Complicated Urinary Tract Infections (includingpyelonephritis) 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.

DOSAGE AND ADMINISTRATION

SITE AND TYPE OF INFECTION DOSE FREQUENCYDURATION

(DAYS)

Adults

Moderate to Severe Pneumonia due to S. pneumoniae*, P. 1 to 2 g IV

Every 12 hours 10

aeruginosa, K. pneumoniae, or Enterobacter species

Empiric therapy for febrile neutropenic patients (See INDICATIONS AND USAGEand Clinical Studies.) 2 g IV

Every 8 hours 7**

Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli, K.pneumoniae, or P. mirabilis*

0.5 to 1 g IV/IM***

Every 12 hours 7 to 10

Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli or K. pneumoniae* 2 g IV

Every 12 hours 10

Moderate to Severe Uncomplicated Skin and Skin Structure Infections due to S. aureus or S. pyogenes 2 g IV

Every 12 hours 10

Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by E. coli, viridans group streptococci, P. aeruginosa, K. pneumoniae, Enterobacter species, or B. fragilis. (See Clinical Studies.) 2 g IV

Every 12 hours 7 to 10

Pediatric Patients (2 months up to 16 years) The maximum dose for pediatric patients should not exceed the recommended adult dose. The usual recommended dosage in pediatric patients up to 40 kg in weight for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia is 50 mg per kg per dose, administered every 12 hours (50 mg per kg per dose, every 8 hours for febrile neutropenic patients), for durations as given above. *including cases associated with concurrent bacteremia **or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently.***Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to E. coli when the intramuscular route is considered to be a more appropriate route of drug administration.

5th Generation Cephalosporons

These agents were developed in laboratory to specifically target against resistant strains of bacteria. In particular CEFTOBIPROLE is effective against Methicillin Resistant Staphylococcus Aureus(MRSA).

Ceftobiprole is the only available agent of 5th generation. It has powerful antiPseudomonal activity.

Mechanism of Action of 5th generation cephalosporins.

Same as other generations.

Activity of 5th generation cephalosporins.

1) MRSA

2) Streptococcus Pneumoniae3) Pseudomonas Aeruginosa4) EnteroCocci5) E.Coli6) Methicillin resistant Staphylococcus Epidemidis

Indication of 5th generation cephalosporins.

1) Hospital acquired pneumonia2) Community acquired Pneumonia3) Bacteremia4) Chemotherapy induced Neutropenia and fever.

Adverse effects of 5th generation.1)Nausea,vomiting,diarrhea2)Flushing of skin3) Weakness4) Liver,kidneys damage5) Indigestion