CEPHALOSPORINS

CEPHALOSPORINS

Introduction

History

Discovery

                The first chemical compounds of the cephalosporin group were isolated from Cephalosporium acremonium, a cephalosporin-producing fungus first discovered by Giuseppe Brotzu in 1948 from a sewage outfall off the Sardinian coast. From crude filtrates of the Cephalosporium acremonium culture scientists got new antibacterial activity. It was noted that the crude filtrate could inhibit the growth of Staphylococcus aureus.

                Further investigations by Abraham and Newton were made in England and isolation of culture fluids from the Sardinian fungus yielded cephalosporin P, N and C. These natural compounds were not found to be potent enough to use as antimicrobial agents but with chemical methods and removal of the natural side chain it was possible to produce 7-aminocephalosporanic acid (7-ACA) which could be further fit with unnatural side chains. 7-ACA is analogous to 6-aminopenicillanic acid (6-APA), a starting block for making several derivatives of penicillins.

                In 1959 Abraham reported that his N-phenylacetyl derivative of cephalosporin C was much more potent against Staphylococcus aureus strains than the parent compound. This derivative was later named Cephaloram, a cephalosporin analogue of benzylpenicillin.

                Eli Lilly developed a method for producing 7-ACA based on cleaving the α-aminoadipoyl side chain of cephalosporin C. Further work by Robert Morin led to semisynthesis of 3-deacetoxy-7-ACA (7-ADCA) from penicillins which is convenient because penicillins can be fermented with more ease than cephalosporins. For example 7-ADCA can be semisynthesized in seven chemical reaction steps from phenoxymethylpenicillin.

The cephalosporins are β-Lactam antibiotics that are closely related both structurally and functionally to the penicillins. Mechanism of action, mechanism of resistance and some other properties of cephalosporins are identical to penicillins. Cephalosporins are one of the most widely used antibiotics and are equal in importance to penicillin. The cephalosporins are isolated from: - Cephalosprium species; - Prepared semisynthetically.

In 1945 Giuseppe Brotzu`s discovered that cultures of Cephalosporium acremonium inhibited the growth of a wide variety of Gram-positive and Gram-negative bacteria. In 1948 Abraham and his colleagues have been supplied cultures of the fungus and was isolated three principal antibiotic components:

- Cephalosporin P, (a steroid antibiotic that resembles fusidic acid) with minimal antibacterial activity.

- Cephalosporin N, later discovered to be identical with synnematin N (a penicillin derivative now called penicillin N)

- Cephalosporin C.
Penicillin N (Cephalosporin N) 
 

*Most of the antibiotics introduced since 1965 have been semisynthetic cephalosporins.

Cephalosporin C can be hydrolyzed by acid to 7-aminocephalosporanic acid.  

 *Compounds containing 7-aminocephalosporanic acid are:

               - Relatively stable in dilute acid.

               - Highly resistant to penicillinase, regardless of the nature

                 of their side chains and their affinity for the enzyme.

Basic structure of cephalosporins

Cephalosporin C

                The core of the basic cephalosporin molecule consists of a two ring system which includes a β-lactam ring condensed with dihydrothiazine ring.

                The core itself can also be referred to as 7-aminocephalosporanic acid which can be derived by hydrolysis from the natural compound cephalosporin C.

                Chemical compounds containing this core are relatively stable to acid hydrolysis and tolerance to β-lactamases.

                Cephalosporin C contains a side-chain which is derived from D-aminoadipic acid. Modification of side chains on the relevant positions has been used to create a whole new class of cephalosporin antibiotics.

                Modification of side-chains in position 7 of the lactam ring seems to affect the antibacterial activity while position 3 of the dihydrothiazine ring alters pharmacokinetic properties and receptor binding affinity.

This compound has been modified by the addition of different side chains to create a whole family of cephalosporin antibiotics.

 

 

General Properties

The physical and chemical properties of the cephalosporins are similar to those of the penicillins, although the cephalosporins are somewhat more stable to pH and temperature changes.

                Cephalosporins are weak acids derived from 7-aminocephalosporanic acid. They are used either as the free base form for PO administration (if acid stable) or as sodium salts in aqueous solution for parenteral delivery (sodium salt of cephalothin contains 2.4 mEq sodium/g).

                Cephalosporins also contain a β-lactam nucleus that is susceptible to β-lactamase (cephalosporinase) hydrolysis. These β-lactamases may or may not also attack penicillins.

                Modifications of the 7-aminocephalosporanic acid nucleus and substitutions on the sidechains by semisynthetic means have produced differences among cephalosporins in antibacterial spectra, β-lactamase sensitivities, and pharmacokinetics.

Antibacterial Spectrum

Ø  First generation

Ø  Second generation

Ø  Third generation

Ø  Fourth generation

Ø  Increased generation number, increased gram negative bacterial susceptibility, increased b-lactamase resistance, decreased efficacy against gram +

Classification of cephalosporins

Cephalosporins have been classified as first, second, third and fourth generation largely on the basis of bacterial susceptibility patterns and resistance to β- lactamases:

First generation	Second generation	Third generation	Fourth generation
Cephalothin Cephapirin Cefazolin Cephalexin* Cephradine* Cefadroxil	Cefamandole Cefuroxime Cefonicid Ceforanide Cefaclor* Cefoxitin Cefotetan Cefprozil* Cepuroxime axetil* Cefmetazole	Cefotaxime Ceftizoxime Ceftriaxone Ceftazidime Cefoperazone Cefixime* Cefpodoxime proxetil* Ceftibuten* Cefdinir*	Cefepime Cefpirome Cefclidin

* Oral agents

First Generation

Ø  The first generation cephalosporins are generally effective against most gram-positive aerobic cocci and several of the gram-negative bacteria, including E coli and Proteus, Klebsiella, Salmonella, Shigella, and Enterobacter spp. Cefazolin is more effective against E coli compared to cephalexin. Cephalosporinase-producing organisms are not susceptible.

Ø  Gram + cocci, gram - bacilli, oral anaerobes Staphylococcus aureus, Proteus mirabilis, E. coli, Klebsiella pneumonia

Ø  Cefazolin, Cephalothin (parenteral)

Ø  Cephalexin, Cefadroxil, Cephradine (oral)

Second Generation                                     

Ø  The second-generation cephalosporins have greater activity against gram-negative organisms but are somewhat less active against gram-positive species. An exception is cefoxitin, which has excellent efficacy against gram-positive bacteria and potentially Pseudomonas spp.

Ø  Less active against G+, more G-

Ø  Haemophilus influenzae, Enterobacter aerogenes, Neisseria

Ø  Cefaclor, Cefuroxime axetil (Oral)

Ø  Cefamandole, Cefonicid, Cefuroxime, Cefotetan, Ceforanide (Parenteral)

Ø  Cefoxitin- Bacteroides fragilis

Ø  Used with aminoglycosides for G - bacilli

Third Generation

Ø  It is difficult to identify trends among third- and fourth-generation cephalosporins

Ø  More Gm – bacilli, Serratia marcescens

Ø  Cefixime (Oral)

Ø  Cefotaxime

Ø  Ceftizoxime

Ø  Ceftazidime

Ø  Cefoperazone

Ø  Ceftriaxone

Ø  Cefpodoxime

Fourth Generation

Ø  Similar spectrum to third generation

Ø  More resistance to b-lactamases

Ø  Cefepime hydrochloride

Cephalosporins Active Against Methicillin-Resistant Staphylococci

Ø  Ceftaroline fosamil

Ø  Ceftobiprole medocaril

Ø  Binding to penicillin-binding protein 2a

5th generation cephalosporins :

                A) Ceftaroline fosamil (prodrug) and

                B) Ceftobiprole medocaril (prodrug)

Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.

Cephalosporins (7α-H) and cephamycins (7α-OCH3): Most natural cephalosporin and cephamycin are not used clinically for side effects, but semi-synthetic products are used.

Mechanism of action

PBP are responsible for cross-linking in the bacterial cell wall. They make peptide bonds between lysine and alanine. Cephalosporins bind into the reaction site of PBP’s rendering the enzyme unable to cross-link the bacterial wall giving bactericidal activity.

The mechanism of resistance of Micro Organisms

Alteration of binding site.

Decrease permeability.

Production of β–lactamase enzymes (enzymatic inactivation).

CLASSIFICATION OF CEPHALOSPORINS

Grouped into "generations" based on their spectrum of antimicrobial activity.  Newer generation has significantly greater gram-negative antimicrobial properties. Successive generations have increased activity against gram-negative bacteria. Cephalosporins are derived from cephalosporin C which is an acid-stable molecule.

FIRST GENERATION

Are moderate spectrum agents.

Effective for treating staphylococcal and streptococcal infections and for skin and soft-tissue infections, as well as for streptococcal pharyngitis.

Have activity against some Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis

FIRST GENERATION CEPHALOSPORINS

Cefadroxil.

Cephalexin.

Cephaloridine.

Cephalothin.

Cephapirin.

Cefazolin.

Cephradine.

SECOND GENERATION

Have a greater gram-negative spectrum.

More resistant to beta-lactamase.

Useful agents for treating upper and lower respiratory tract infections, sinusitis and otitis media.

Cefoxitin is a second generation cephalosporin with anaerobic activity.

SECOND GENERATION CEPHALOSPORINS

Cefaclor.

Cefoxitin.

Cefprozil.

Cefuroxime.

THIRD GENERATION

Have a broad spectrum of activity and increased activity against gram-negative organisms.

Have excellent activity against most strains of Streptococcus pneumoniae.

Have activity against Neisseria gonorrhoeae.

THIRD GENERATION CEPHALOSPORINS

Cefdinir.

Cefixime.

Cefpodoxime.

Ceftibuten.

Ceftriaxone.

Cefotaxime.

FOURTH GENERATION

                Have a greater resistance to beta-lactamases than the third generation cephalosporins.

                Can cross blood brain barrier and are effective in meningitis.

                Cefpirome is more active against pneumococci.                  

                Activity against nosocomial pathogens such as Enterobacter and Acinetobacte.

FOURTH GENERATION CEPHALOSPORINS

Cefepime.

Cefluprenam.

Cefozopran.

Cefpirome.

Cefquinome.

Pharmacokinetics

1- Administration:

All cephalosporins except cefadroxil, cephalexin, cephradine, cefaclor, cefuroxime axetil, cefdinir, cefixime and ceftibuten must be administered intravenously because of their poor oral  absorption. Only a few cephalosporins are acid stable and thus effective when administered PO (eg, cephalexin, cephradine, cefadroxil, cefpodoxime, and cefachlor). They are usually well absorbed, and bioavailability values are 75–90%. The others are administered either IV or IM, with plasma concentrations peaking ∼30 min after injection. Ceftiofur is available in a sustained-release form; its duration of action is extended by administration at the base of the ear in food animals.

2- Distribution:

Cephalosporins are distributed into most body fluids and tissues, including kidneys, lungs, joints, bone, soft tissues, and the biliary tract, but in general, the volume of distribution is <0.3 L/kg. However, poor penetration into the CSF, even in inflammation, is a notable feature of the standard cephalosporins.

Cephalosporins are substrates for p-glycoprotein efflux from the CNS. The third-generation cephalosporins (eg, moxalactam) may achieve good penetration into the CSF.

The degree of plasma-protein binding is variable (eg, 20% for cefadroxil and 80% for cefazolin). The high degree of protein binding of cefovecin (90% dogs, 99% cats) contributes to its long elimination half-life (5.5 days in dogs, 6.9 days in cats). However, drug concentrations in transudate remain above the MIC₉₀ of both Staphyloccocus intermedius and E coli for up to 14 days.

All of cephalosporins distribute very well into body fluids. 

However, several cephalosporins penetrate into CSF in  sufficient  concentration to be useful for the treatment of meningitis. These include: Cefuroxime (2^nd gen.), ceftriaxone,          cefotaxime and ceftizoxime (3^rd gen.).

3. Biotransformation:

Several cephalosporins (such as cephalothin, cephapirin, ceftiofur, cephacetrile, and cefotaxime) are actively deacetylated, primarily in the liver but also in other tissues. The deacetylated derivatives are much less active with the exception of ceftiofur. Ceftiofur is metabolized to several active metabolites that can contribute significantly to efficacy. Few of the other cephalosporins are metabolized to any appreciable extent.

4- Fate:  

Elimination occurs through tubular secretion and/or glomerular filtration. Cefoperazone are excreted through the bile and are frequently used in patients with renal insufficiency.

Generally, these β-lactam antibiotics maintain effective blood concentrations for only 6–8 hr. Exceptions include ceftiofur, cefpodoxime, and cefovecin.

Elimination, Distribution, and Clearance of Cephalosporins
Cephalosporin	Species	Elimination Half-life (min)	Volume of Distribution (mL/kg)	Clearance (mL/kg/min)
Cefazolin	Horses	45	188	5.5
Cefotaxime	Sheep	25	134	9.0
Cefpodoxime	Dog	300	150
Cefovecin	Dog	5.5 days	90
Cephalexin	Dogs	84	—	—
Cefadroxil	Dogs	120	—	—
	Cats	150–180	—	—
Ceftiofur	Cattle	∼360	—	—

Therapeutic uses

When Gm +ve bacteria is involved a 1^st generation agents is preferable.

When the pathogen is gm –ve and the infection is serious parentral use of a 3^rd generation agent is recommended.

First generation cephalosporins are Excellent agents for skin and soft tissue infections due to S. aureus and S. Pyogenes. A single dose of cefazolin just before surgery is the preferred as prophylaxis

Second-generation cephalosporins  The second generation agents have inferior activity against  penicillin-resistant S. pneumoniae compared to either the 3^rd generation agents or ampicillin and therefore should not be used for treatment of meningitis or pneumonia. In case where Gm -ve bacteria and anaerobes are involved such as intraabdominal infections, pelvic inflammatory disease and diabetic foot infection, cefoxitin and cefotetan have been shown to be effective. For colorectal surgery where prophylaxis for intestinal anaerobes is desired, cefoxitin or cefotetan (2^nd generation)   are preferred.

Third generation cephalosporins - Third generation cephalosporins have been considered to be  the drugs of choice for serious infections caused by: Klebsiella, Enterobacter, Proteus, Haemophilus species. Ceftriaxone is now the drug of choice for all form of gonorrhea. Cefotaxime or ceftriaxone (as part of a 3-drug combination with vancomycin and ampicillin) are used for the initial treatment of  meningitis in nonimmunocompromised adults and children older than 3 months.  Ceftazidime + aminoglycoside is the drug of choice for Pseudomonas meningitis. The antimicrobial spectrum of cefotaxime and ceftriaxone is excellent for the treatment of community acquired pneumonia, i.e. that caused by pneumococci, H. influenzae, S. aureus.

The fourth generation - The fourth generation are indicated for the empirical treatment of nosocomial infections where antibiotic resistance due to extended spectrum β-lactamases are anticipated. e.g. cefepime has superior activity against nosocomial isolates of Enterobacter, Citrobacter compared to ceftazidime and piperacillin

Therapeutic Indications and Dose Rates

First-generation cephalosporins have proved useful, particularly for infections involving Staphylococcus spp (eg, oral cephalexin for dermatitis) and for surgical prophylaxis (eg, cefazolin). However, their efficacy appears to be declining because of emerging resistance, including methicillin-resistant organisms.

Ceftiofur is approved for use in bovine respiratory disease principally caused by Pasteurella spp and in urinary tract infections in dogs. Use of ceftiofur for treatment of soft-tissue infections in dogs is not recommended because proper dosages and safety have not been documented.

Cefpodoxime (PO) and cefovecin (SC) also have been approved for use in dogs and dogs and cats, respectively.

Cephalosporins are particularly useful for treating infections of soft tissue and bone due to bacteria that are resistant to other commonly used antibiotics.

Cefazolin (IV) has been used prophylactically 1 hr before surgery.

More than most penicillins, cephalosporins may penetrate tissues and fluids sufficiently (CSF being an exception for most), to be effective in the management of osteomyelitis, prostatitis, and arthritis.

Oral cephalosporins are also usually effective in the management of urinary tract infections, except those due to Pseudomonas aeruginosa.

Cephapirin benzathine is used for dry-cow therapy, and cephapirin sodium is used in treatment of mastitis.

 

Adverse reactions

The approved cephalosporins are relatively nontoxic. IM injections can be painful, and repeated IV administration may lead to local phlebitis. Nausea, vomiting, and diarrhea may occasionally be seen. Hypersensitivity reactions of several forms have been seen, with cross-reactivity to penicillin allergies possible. Superinfection may arise with the use of cephalosporins, and Pseudomonas or Candida spp are likely opportunistic pathogens.

The most common adverse reactions are:

                1- Allergic and hypersensitivity reactions

                2- A disulfiram-like effect

                3-Bleeding: Bleeding can occur with cefamandole, cefotetan, cefmetazole , moxalactam and cefoperazone (containing an N-methyl-5-       thiotetrazole moiety at the 3 position) b/c of  antivitamin K     effects,                 administration of the vitamin corrects the problem.

                4- Nephrotoxicity.   

Interactions

In vitro incompatibilities are quite common for cephalosporin and cephamycin preparations; an exception exists when mixing with weak bases such as aminoglycosides.

Potential pharmacokinetic interactions are similar to those of the penicillin group.