CEPHALOSPORINS

Teaching Basics
Dr.T.V.Rao MD

Dr.T.V.Rao MD

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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)
Dr.T.V.Rao MD 2

What are Cephalosporins
• The cephalosporins structurally related to the penicillin's consist of a –beta lactam ring attached to a dihydrothiazoline ring. Substitutions of
chemical groups result in varying pharmacologic properties and antimicrobial activitiesDr.T.V.Rao . MD

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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 β-lactamases but was not sufficiently potent for clinical use.
Dr.T.V.Rao MD 4

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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How Cephalosporins work
• Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins). Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. beta-lactam antibiotics mimic this site and competitively inhibit PBP crosslinking of peptidoglycan.
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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

– 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
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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

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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.

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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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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 toxicitiesDr.T.V.Rao MD 11

Important I st Generation Cephalosporins
• • • • • • • • • • • • • • • Cefacetrile (cephacetrile) Cefadroxil (cefadroxyl; Duricef) Cefalexin (cephalexin; Keflex) Cefaloglycin (cephaloglycin) Cefalonium (cephalonium) Cefaloridine (cephaloradine) Cefalotin (cephalothin; Keflin) Cefapirin (cephapirin; Cefadryl) Cefatrizine Cefazaflur Cefazedone Cefazolin (cephazolin; Ancef, Kefzol) Cefradine (cephradine; Velosef) Cefroxadine Ceftezole

Dr.T.V.Rao MD

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Classification of Cephalosporin
1. First generation Cephalosporins
Loracarbef Cephradine Cefprosil

Cefaclor

Cefazolin

Cephalexin Cefadroxil Cefoperazone
Cefuroxime Na Cefoxitin Na

Cefixime
Dr.T.V.Rao MD 13 Cefotetan Disodium

Advantages of I st generation Cephalosporins
• Very active against Gram + ve cocci Including penicillin senstive Pneumococci, Viridians streptococci Group A hemolytic streptococci Staphylococcus aureus Not useful against Enterococci, Methicillin resistant Staphylococcus Activity against H.influenzae, and Pencillin resistant Streptococci is poor Effective against gram – ve as E.coli,Klebsiella pneumonia, Proteus mirabilis But not effective
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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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Second Generation Cephalosporins
• The are heterogeneous group with Individual differences • Against Gram Negative organisms as like Ist generation Cephalosporins with extended spectrum of activity against Indole positive Proteus, Klebsiella, Moraxella catarrhalis Neisseria species
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Effective against Anaerobes
• Second generation cephalosporins with antianaerobial activity • Cefmetazole • Cefotetan • Cefoxitin
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Second generation Cephalosporins
• Cefuroxime useful in H influenza including Beta lactam producing strains • Lesser in activity against Serratia and B.fraglilis • Cefoxitin and Cefotetan active against B.fraglilis • Majority of 2nd generations are less active against Gram + ve organism than Ist generation compounds except cefuroxime • Not active against P aeruginosa

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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

(Ceclor, Distaclor, Keflor, Raniclor)

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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Third generation Cephalosporins

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

Ceftiolene Ceftizoxime (Cefizox) Ceftriaxone (Rocephin)

Dr.T.V.Rao MD

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Third Generation - Ceftriaxone
• Lower Respiratory Tract Infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenza, Haemophilus Parainluenza, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.

• 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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Third Generation - Ceftriaxone
• 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 Dr.T.V.Rao MD fragilis * or Peptostreptococcus species. 25

Preferred in cases of UTI
• Urinary Tract Infections (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.
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Third Generation – Ceftriaxone in Gonorrhoea's
• Uncomplicated Gonorrhoea (cervical/urethral and rectal) caused by Neisseria gonorrhoea, including both penicillinase- and nonpenicillinaseproducing strains, and pharyngeal gonorrhoea caused by nonpenicillinase-Dr.T.V.Rao MD

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Third Generation - Ceftriaxone
• Pelvic Inflammatory Disease caused by Neisseria gonorrhea. 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 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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In Bone and Joint Infections
• Bone and Joint Infections caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.
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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.

Cefozopran Cefpirome (Cefrom) Cefquinome

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

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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What are 5th generation Cephalosporins
• Fifth generation cephalosporins were developed in the lab to specifically target against resistant strains of bacteria. In particular, ceftobiprole is effective against methicillin-resistant Staphylococcus aureus (MRSA).
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Fifth Generation Cephalosporin
5. Fifth generation Cephalosporins

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.
Dr.T.V.Rao MD 38

FDA approves ceftaroline fosamil
• On October 29th, FDA has approved Ceftaroline Fosamil under the trade name Teflaro. Ceftaroline Fosamil (previously known by the research code TAK-599, the parent drug, Ceftaroline is also known as T-91,825) is an antibiotic indicated for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive and Gramnegative microorganisms, such as Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca, and also for the treatment of community-acquied bacterial pneumonia (CABP) caused by susceptible Grampositive and Gram-negative bacteria, such as Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilus influenzae , Klebsiella pneumoniae, Dr.T.V.Rao MD 39 Klebsiella oxytoca, and Escherichia coli.

Ceftaroline is modified from cefozopran
• Ceftaroline was developed by modifying the structure of the fourth-generation cephalosporin cefozopran The prodrug, ceftaroline fosamil, which contains a phosphono group to increase water solubility, is rapidly converted in plasma into the bioactive agent, ceftaroline The 1,3-thiazole ring attached to the 3-position of the cephalosporin nucleus and the oxime group in the C7 acyl moiety are responsible for the enhanced anti-MRSA activity observed with ceftaroline.
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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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Fifth generation Ceftobiprole
• 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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CLSI puts on the list of unnamed class
• Currently, ceftaroline and ceftobiprole are on an unnamed subclass of cephalosporins by the Clinical and Laboratory Standards Institute (CLSI).Dr.T.V.Rao MD

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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 • doctortvrao@gmail.com
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