Cephalosporins Teaching Basics
Cephalosporins Teaching Basics
Cephalosporins Teaching Basics
Teaching Basics
Dr.T.V.Rao MD
Dr.T.V.Rao MD
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)
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History of Cephalosporins
Cephalosporin compounds were first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu. He noticed that these cultures produced substances that were effective against Salmonella typhi, Researchers at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C, which had resistance to -lactamases but was not sufficiently potent for clinical use.
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Resembles Penicillin
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 the 7-ACA side-chains resulted in the development of useful antibiotic agents, and the first agent cephalothin (cefalotin) was launched by Eli Lilly in 1964.
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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 Staphylococcus 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
Cephalosporins
Cephalosporins
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 Dr.T.V.Rao MD
Generation of Cephalosporins
Cephalosporin drugs fall into five classes or generations. Each subsequent generation of these drugs demonstrates greater efficacy against gramDr.T.V.Rao MD negative bacteria.
Cephalosporins
Divided into generations for convenience but many drugs in same generation not chemically related and different spectrum of activity Currently five 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)
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Classification of Cephalosporin
1. First generation Cephalosporins
Loracarbef Cephradine Cefprosil
Cefaclor
Cefazolin
Cefixime
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Clinical uses
Orally useful in Urinary tract infection. Intravenous preparations are useful in surgical prophylaxis in clean cases But 2nd and 3rd generation drugs are more useful in colorectal surgeries and Hysterectomy cases Ist Generation drugs are not useful in Meningitis.
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Classification of Cephalosporin
Second generation Cephalosporins
> have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. They are also more resistant to beta-lactamase.
Cefaclor
Cefonicid (Monocid) Cefprozil (cefproxil; Cefzil) Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroks Cefuzonam
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2nd generation cephalosporins are more useful in Beta lactamases producing H influenza, Moraxella catarrhalis Apart from Aerobic infections Cefoxitin, Cefmetazole, and Cefotetan can be used to treat mixed anaerobic infections, including peritonitis, and diverticulitis However it is proved that in life threating infections better to choose alternative antibiotics Cefoxitin and Cefotenan are useful as prophylaxis in colorectal surgeries,vaginal or abdominal hysterectomies and appendicitis , because of activity against B.fraglilis. Dr.T.V.Rao MD 20
Clinical Uses
Antipseudomonal activity
Cephalosporins with Antipseudomonal activity Cefoperazone (Cefobid) Ceftazidime (Fortum, Fortaz)
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Classification of Cephalosporin
Third-generation cephalosporins have a broad spectrum of activity and further increased activity against Gram-negative organisms. They may be particularly useful in treating hospital-acquired infections, although increasing levels of extended-spectrum beta-lactamases are reducing the clinical utility of this class of antibiotics. They are also able to penetrate the CNS, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillinresistant N. gonorrhoeae.
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Classification of Cephalosporin
Third generation Cephalosporins
Cefcapene Cefdaloxime Cefdinir (Omnicef, Cefdiel) Cefditoren Cefetamet
Cefpodoxime (Vantin,) Cefteram Ceftibuten (Cedax) Ceftiofur Cefixime (Suprax) Cefmenoxime Cefodizime Cefotaxime (Claforan) Cefpimizole
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Acute Bacterial Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenza (including betalactamase producing strains) or Moraxella catarrhalis (including betalactamase producing strains).
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C. trachomatis is one of the suspected pathogens, appropriate anti chlamydial coverage should be added.
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In Bacterial Septicaemia
Bacterial Septicaemia caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenza or Klebsiella pneumoniae. Dr.T.V.Rao MD
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Intra-Abdominal Infections
Intra-Abdominal Infections caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of C. difficle are resistant) or Peptostreptococcus Dr.T.V.Rao MD species.
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In Meningitis
Meningitis caused by Haemophilus influenza, 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. Dr.T.V.Rao MD Surgical Prophylaxis
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Classification of Cephalosporin
4. Fourth generation Cephalosporins
Fourth-generation cephalosporins are extended-spectrum agents with similar activity against Grampositive organisms as firstgeneration cephalosporins. They also have a greater resistance to beta-lactamases than the third-generation cephalosporins.
Cefclidine Cefepime (Maxipime) They are also used against Cefluprenam Pseudomonas aeruginosa. Cefoselis Dr.T.V.Rao MD
Many can cross the blood-brain barrier and are effective in meningitis.
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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 Neutropenia 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. Dr.T.V.Rao MD 34
Fourth Generation Cefepime FDA approved indications 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 Dr.T.V.Rao MD fragilis 35 species, or Bacteroides
Classification of Cephalosporin
Ceftobiprole has been described as "fifth 5. Fifth though generation Cephalosporins generation" acceptance for this terminology is not universal. Ceftobiprole (and the soluble prodrug medocaril) are on the FDA fast-track. Ceftobiprole has powerful Antipseudomonal characteristics and appears to be less susceptible to development of resistance.
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Ceftobiprole has been described as "fifth generation" though acceptance for this terminology is not universal. Ceftobiprole (and the soluble prodrug medocaril) are on the FDA fast-track. Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance.
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Advantage of Ceftaroline
Ceftaroline is an injectable cephalosporin active against MRSA & MSSA [ & RTI pathogens] It is approved for use in cSSSI & CABP Its use may be extended when combined with NXL 104 to include ESBL +ve GNB strains
It is inactive against Non fermenters GNB & Carbapenemases producers.
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Ceftobiprole (and the soluble prodrug medocaril) are on the FDA fast-track. Ceftobiprole has powerful Antipseudomonal characteristics and appears to be less susceptible to development of resistance.
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5th generation cephalosporins are not ultimate solutions for antibiotic resistance Antimicrobial stewardship programmes can be implemented to reduce inappropriate use of antimicrobials, thereby controlling the development of resistance. These programmes are also useful in limiting toxicity and overgrowth of pathogenic organisms such as C. difficile. Typical stewardship programmes target antimicrobials that pose a risk of development of resistance, are associated with significant toxicity, require therapeutic drug monitoring, have the potential to select for pathogenic or have a 44 Dr.T.V.Raoorganisms MD high cost.
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
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Programme Created by Dr.T.V.Rao MD for Medical and Paramedical Students in the Developing World Email [email protected]
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