Cephalosporin: An introduction, classification, mechanism, structure, uses, with its effect.

Cephalosporin
Structure-of-cephalosporin

A cephalosporin is a group of semisynthetic antibiotics obtained naturally from “cephalosporin C” that is obtained from a fungus Cephaosporium acremonium. It is the compound that first isolated from cultures of “Cephalosporium acremonium” from a sewer in Sardinia by Italian scientist “Giuseppe Brotzu” in 1948.

Molecular formula-C15H21 N3O7S

Molecular weight-387.4 g/mol

IUPAC Name- (2R)-2-[(R)-[[(6R)-6-amino-6-carboxyhexanoyl] amino]-carboxymethyl]-5-methylidene-2H-1,3-thiazine-4-carboxylic acid

Classification of cephalosporin-         

First-generation cephalosporins-

Parental-Cefazolin

Oral-Cephalexin, Cefadroxil

Second-generation cephalosporins-

Parental-Cefuroxime

Oral– Cefaclor, Cefuroxime axetil, Cefprozil

Third-generation cephalosporins-

Parental-Cefotaxime, Ceftizoxime, Ceftriaxone, Ceftazidime, Cefoperazone

Oral– Cefixime, Cefpodoxime proxetil, Cefdinir, Ceftibuten, Ceftamet pivoxil

Fourth-generation cephalosporins-

Parental-Cefepime, Cefpirome

Mechanism of cephalosporins-

Bacteria synthesize a cell wall that is strengthened by cross-linking peptidoglycan units via penicillin-binding proteins (PBP, peptidoglycan transpeptidase). Initially derived from the fungus Cephalosporium sp., cephalosporins are a large group of bactericidal antibiotics that work via their beta-lactam rings. The beta-lactam rings bind to the penicillin-binding protein and inhibit its normal activity. Unable to synthesize a cell wall, the bacteria die.

CEPHALOSPORINS

BIND TO CBP

INHIBITS TRANSPEPTIDATION IN BACTERIAL CELL WALL SYNTHESIS

IMPERFECT CELL WALL

OSMOTIC DRIVE FROM ECF.

INSIDE HYPERTONIC BACTERIAL CYTOPLASM.

ACTIVATION OF AUTOLYSIN ENZYME LEADS TO

AUTOLYSIS OF BACTERIA.

BACTERIOCIDAL ACTIVITY

Staphylococcus aureus that is initially susceptible to cephalosporins can develop resistance by changing the structure of the penicillin-binding proteins. S. aureus does this by having a gene that encodes a modified penicillin-binding protein, and this prevents the cephalosporin’s beta-lactam rings to inactivate the protein. The bacterium that develops this mechanism of resistance is called methicillin-resistant Staphylococcus aureus (MRSA). As indicated above, out of the five generations of cephalosporin, only the fifth generation ceftaroline has coverage against methicillin-resistant Staphylococcus aureus. Another mechanism of resistance is by having the enzyme beta-lactamase, which cleaves the beta-lactam ring preventing it from attaching to the penicillin-binding proteins, e.g., peptidoglycan transpeptidase 

Pharma co-kinetics of cephalosporins-

Distribution-

All cephalosporins distribute very well into body fluids. However, adequate therapeutic levels in the CSF, regardless of inflammation, are achieved with only a few cephalosporins. For example– ceftriaxone and cefotaxime are effective in the treatment of neonatal and childhood meningitis caused by H. influenzae. Cefazolin is commonly used for surgical prophylaxis due to its activity against penicillinase-producing S. aureus, along with its good tissue and fluid penetration.

Elimination

Cephalosporins are eliminated through tubular secretion and/or glomerular filtration. Therefore, doses must be adjusted in renal dysfunction to guard against accumulation and toxicity. In cephalosporin, one exception is ceftriaxone, which is excreted through the bile into the feces, therefore, it is frequently employed in patients with renal insufficiency.

Fate-

In cephalosporins, the transformation is by the host that is not clinically important.Elimination occurs through tubular secretion or by glomerular filtration.

Chemistry of cephalosporin-

Structure of cephalosporin-

Structure-of-cephalosporin

They are chemically derived from 7 amino cephalosporic acids and they are structurally and functionally related to penicillin because they shared a common beta-lactam ring. Cephalosporins are composed of a six-membered ring having sulfur atom attached to a beta-lactam ring. Cefixime comes under third-generation semisynthetic beta-lactam antibiotic of the cephalosporin group.

You may read- Beta lactam.

SAR of cephalosporin-

SAR-of-cephalosporin

FIRST GENERATION CEPHALOSPORINS-

The first-generation cephalosporins developed in the 1960s, and act as penicillin G substitutes. They have high activity against gram-positive but weaker against gram-negative bacteria. These are resistant to the staphylococcal penicillinase (that is, they cover MSSA). Isolates of S. pneumoniae resistant to penicillin and it also. Agents in this generation also have modest activity against Proteus mirabilis, E. coli, and K. pneumoniae. Most oral cavity anaerobes like Pepto streptococcus are sensitive, but the Bacteroides fragilis group is resistant.

Cefazolin

It is the prototype of the first-generation cephalosporin that is active against most Penicillin G sensitive organisms, like- Streptococci (pyogenes as well as viridans), gonococci, meningococci, C. diphtheriae, H. influenzae, clostridia and Actinomyces.The activity of cefazolin against Klebsiella, Moraxella catarrhalis, and E. coli is relatively high, but it is quite susceptible to staphylococcal beta-lactamase.It can be given I.M. (less painful) as well as I.V. and has a longer t½ is 2 hours, due to slower tubular secretion, and attains higher concentration in plasma and in bile. It is the preferred parenteral first-generation cephalosporin, especially for surgical prophylaxis.

Dose- 0.5 g 8 hourly (mild cases), 1 g 6 hourly (severe cases), children 25–50 mg/kg/day i.m. or i.v.; surgical prophylaxis 1.0 g 1/2 hour before surgery.

Structure of cefazolin-
Structure-of-cefazolin

Cephalexin

 It is the most commonly used orally effective first-generation cephalosporin, that similar in spectrum to cefazolin, but less active against penicillinase-producing staphylococci and H. influenzae. Plasma protein binding is low, and it attains high concentration in bile and is excreted unchanged in the urine, the t½ ~60 min.

Dose– The oral dose for adults is 250–500 mg every 6 h, for children, the dose is 18-25mg/kg every 6 h.

Structure of cephalexin-
structure-of-cephalexin
Source-internet

Properties and uses- Cephalexin monohydrate is a white crystalline powder, sparingly soluble in water, and practically insoluble in alcohol.

-The α-amino group of cephalexin renders its acid-stable.

-The 3-methyl group is responsible for metabolic stability.

-It is particularly recommended for urinary tract infection.

Cefadroxil

 A close analog of cephalexin; has good tissue penetration—describe more sustained action at the site of infection, because of which it can be given 12 hourly despite a t½ of 1 hour.

It is excreted unchanged in the urine, and the dose needs to be reduced only if creatinine clearance is < 50 ml/min.  The indications and antibacterial activity of cefadroxil are similar to those of cephalexin.

Dose– 0.5–1 g BD.

Structure of cefadroxil-

Structure-of-cefadroxil

Properties and uses- Cefadroxil monohydrate is a white or almost white powder, slightly soluble in water, and sparingly soluble in ethanol.

-The antibacterial spectrum and therapeutic indications of cefadroxil are very similar to cephalexin and cephradine.

-The D-p-hydroxyphenyl glycyl isomer is much more active than the L-isomer.

-It is assayed by adopting liquid chromatography techniques.

SECOND GENERATION CEPHALOSPORINS-

These were developed subsequent to the first-generation compounds and it is more active against gram-negative organisms, such as H. influenzae, Klebsiella species, Proteus species, Escherichia coli, and Moraxella catarrhalis with some members active against anaerobes as well, but none inhibits P. aeruginosa. They are weaker than the first-generation compounds against gram-positive bacteria. Their utility has declined in favor of the 3rd generation agents.

Cefuroxime

Cefuroxime is resistant to gram-negative beta-lactamases, and has high activity against organisms producing these enzymes including PPNG and ampicillin-resistant H. influenzae, while retaining significant activity on gram-positive cocci and certain anaerobes, but not B. fragilis. It is well tolerated by i.m. route and attains relatively higher CSF levels, but have been superseded by 3rd generation cephalosporins in the treatment of meningitis.

Dose-The dose is 1.5 g (IM) as a single dose and also available as a powder for injection in strengths of 0.75 and 1.5 g.

Structure of cefuroxime-
structure-of-cefroxime

Cefuroxime axetil

 This ester of cefuroxime is effective orally, though absorption is incomplete.  The activity depends on in vivo hydrolysis and the release of cefuroxime.

Dose– 250–500 mg BD

Structure of cefuroxime axitil-
structure-of-cefroxime-axitil

Cefaclor

Cefaclor is retaining significant activity by the oral route and it is more active than the first-generation compounds against H. influenzae, E. coli, Pr. mirabilis, and some anaerobes. It has chloro group at the C-3 position, and hence, stable in acid and achieves sufficient oral absorption.

Dose– The dose orally for adults is 250–500 mg every 8 hours.

Structure of Cefaclor-
structure-of-cefaclor

Properties and uses- Cefaclor is a white or slightly yellow powder, slightly soluble in water, practically insoluble in methanol and methylene chloride.

-Used in the treatment of upper respiratory tract infections caused by Streptococcus pneumoniae and Haemophilus influenzae.

-It is assayed by adopting liquid chromatography techniques.

Cefprozil

This 2nd generation cephalosporin has good oral absorption (>90%) with augmented activity against Strep. pyogenes, Strep. pneumoniae, Staph. aureus, H. influenzae, Moraxella, and Klebsiella. It is excreted by the kidney, with a t½ of 1.3 hours.

The primary indications are bronchitis, ENT, and skin infections.

Dose– 250–500 mg BD, (child 20 mg/kg/day)

Structure of cefprozil-
structure-of-cefrozil
Source-internet

THIRD GENERATION CEPHALOSPORINS-

These compounds introduced in the 1980s have highly augmented activity against gram-negative Enterobacteriaceae, and few members inhibit Pseudomonas as well. However, these are less active against gram-positive cocci and anaerobes. These cephalosporins have assumed an important role in the treatment of infectious diseases.

Although they are less potent than first-generation cephalosporins against MSSA because they have enhanced activity against gram-negative bacilli, including beta-lactamase producing strains of H. influenzae and Neisseria gonorrhoeae.  The spectrum of activity of this class includes enteric organisms, such as Serratia marcescens and Providencia species.

Third-generation cephalosporins must be used with caution, as they are associated with significant.

Cefotaxime

Cefotaxime is the prototype that exerts potent action on aerobic gram-negative as well as some gram-positive bacteria but is not active on anaerobes particularly Bact. fragilis, and Staph. aureus, Ps. aeruginosa. Prominent indications are meningitis caused by gram-negative bacilli (attains relatively high CSF levels), life-threatening resistant/ hospital-acquired infections, septicemias, and infections in immunocompromised patients.

It is an alternative to ceftriaxone for typhoid fever and can be utilized for single-dose therapy of PPNG urethritis, but is not dependable for Pseudomonas infections.

Cefotaxime is deacetylated in the body, and its metabolite exerts weaker but synergistic action with the parent drug. The plasma t½ of cefotaxime is 1 hour but is longer for the deacetylated metabolite—permitting 12 hourly doses in many situations. Penetration into CSF is good.

Dose– 1–2 g i.m./i.v. 6–12 hourly, children 50–100 mg/kg/day.

Structure of cefotaxime-
structure-of-cefotaxime

Properties and uses- Cefotaxime sodium exists as white solid and soluble in water, exhibits broad-spectrum activity against both gram-positive and gram-negative bacteria.

-Used in genitourinary infection and lower respiratory infection.

Ceftizoxime

Ceftizoxime is similar in antibacterial activity and indications to cefotaxime but inhibits B. fragilis also. It is not metabolized— excreted by the kidney at a slower rate; t½ 1.5–2 hours.

Dose– 0.5–2.0 g i.m./i.v. 8 or 12 hourly.

Structure of ceftizoxime-
structure-of-ceftizxime
Source-internet

Ceftriaxone

Ceftriaxone has a distinguishing feature because of its longer duration of action with t½ 8 hours, that permitting once, or at the most twice-daily dosing. Penetration into CSF is good and elimination occurs equally in urine and bile.

Ceftriaxone has shown high efficacy in a wide range of serious infections including bacterial meningitis (especially in children), multi-resistant typhoid fever, complicated urinary tract infections, abdominal sepsis, and septicemias.

A single dose of 250 mg i.m. has proven curative in gonorrhea including PPNG, and in chancroid. Hypoprothrombinemia and bleeding are specific adverse effects. Hemolysis is reported. To overcome resistance, it has been combined with sulbactam or tazobactam.

Structure of ceftriaxone-
structure-of-ceftriaxone

Ceftazidime

Ceftazidime has high activity against Pseudomonas aeruginosa and the specific indications are—febrile neutropenic patients with hematological malignancies, burn, etc. The activity of ceftazidime is against the Enterobacteriaceae that is similar to that of cefotaxime, but it is less active on Staph. aureus, other gram-positive cocci, and anaerobes like Bact. fragilis. Its plasma t½ is 1.5–1.8 hour. Neutropenia, thrombocytopenia, rise in plasma transaminases, and blood urea have been reported.

Dose– 0.5–2 g i.m. or i.v. every 8 hours, children 30 mg/kg/day.

Structure of ceftazidime-
structure-of-ceftazidime

Cefoperazone

Cefoperazone also differs from other third-generation compounds like- ceftazidime, because it has a stronger activity on Pseudomonas and weaker activity on other organisms. It is good for S. typhi and B. fragilis also, but more susceptible to beta-lactamases. The indications are—severe urinary, biliary, respiratory, skin-soft tissue infections, typhoid, meningitis, and septicemias. It is primarily excreted in bile, and the t½ is 2 hours.

Dose– 1–3 g i.m./i.v. 8–12 hourly

Structure of Cefoperazone-

structure-of-cefoperazone

Properties and uses– It exists as a white powder.

-It resembles piperacillin, chemically, and microbiologically.

-It is less active than cephalothin against gram-positive bacteria and less active than cefamandole against most of the enterobacteria.

Cefixime

Cefixime is an orally active compound and highly active against Enterobacteriaceae, H. influenzae, Strep. pyogenes, and is resistant to many beta-lactamases. However, it is not active on Staph. aureus, most pneumococci, and Pseudomonas. It is longer acting t½ of 3 hours and it has been used in a dose of 200–400 mg BD for the respiratory, urinary, and biliary infections. Stool changes and diarrhea are the most prominent side effects of it.

Structure of cefixime-

structure-of-cefixime
Source-internet

Cefpodoxime proxetil

Cefpodoxime proxetil is an orally active ester prodrug of cefpodoxime. It is highly active against Enterobacteriaceae and streptococci and also inhibits Staph. aureus. It is used mainly for respiratory, urinary, skin, and soft tissue infections.

Dose- 200 mg BD (max 800 mg/day)

Structure of Cefpodoxime proxetil-

structure-of-cefodoxime-proxetil

Cefdinir

Cefdinir is orally active third-generation cephalosporin, that has good activity against many beta-lactamases producing organisms. Most respiratory pathogens including gram-positive cocci are susceptible. Its indications are pneumonia, acute exacerbations of chronic bronchitis, ENT, and skin infections.

Dose- 300 mg BD

Structure of cefdinir-

structure-of-cefdinir

Ceftibuten

Ceftibuten is active against gram-positive and few gram-negative bacteria, but not Staph. aureus.  It is stable to beta-lactamases and is indicated in respiratory and ENT infections with the t½ 2–3 hours.

Dose– 200 mg BD or 400 mg OD.

Structure of ceftibuten-

structure-of-ceftibuten

Ceftamet pivoxil

Ceftamet pivoxil is an ester prodrug of ceftamet, it has high activity against gram-negative bacteria, especially Enterobacteriaceae and N. gonorrhea, and used in respiratory, skin-soft tissue infections, etc.

Dose– 500 mg BD–TDS.

Structure of ceftamet pivoxil-

structure-of-ceftamet-pivoxil
Source-internet

FOURTH GENERATION CEPHALOSPORINS-

The distinctive feature of this last developed subgroup of cephalosporins is non-susceptibility to inducible chromosomal beta-lactamases. In addition, these have high potency against Enterobacteriaceae and spectrum of activity resembling the third-generation compounds.

Cefepime

Cefepime is developed in the 1990s, it has an antibacterial spectrum similar to that of third-generation compounds but is highly resistant to beta-lactamases, and hence active against many bacteria resistant to the earlier drugs. Ps. aeruginosa and Staph. aureus is also inhibited but not MRSA.

Due to high potency and extended-spectrum, it is effective in many serious infections like hospital-acquired pneumonia, febrile neutropenia, bacteremia, septicemia. Higher concentrations are attained in the CSF, and it is excreted by the kidney with a t½ of 2 hours.

Dose- 1–2 g i.v. 8–12 hourly.

Structure of cefepime-

structure-of-cefepime
Source-internet

Properties and uses- It must be administered parenterally.

-It has a wide antibacterial spectrum, with the activity against streptococci and staphylococci (but only those that are methicillin-susceptible).

-It is also effective against aerobic gram-negative organisms, like- Enterobacter species, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa.

Cefpirome

The zwitterion character of cefpirome is permitting better penetration through porin channels of gram-negative bacteria. It is resistant to many beta-lactamases and inhibits type 1 beta-lactamase-producing Enterobacteriaceae. It is more potent against gram-positive and some gram-negative bacteria than the third-generation compounds.

Dose- 1–2 g i.m./i.v. 12 hourly;

Structure of cefpirome-

structure-of-cefpirome

Properties and uses– Cefpirome is used to treat susceptible infections, including urinary and resistant hospital-acquired infections including lower respiratory tract infections, skin infections, septicemia, and infections in immune-compromised patients.

You may read- anti microbial agent.

Uses of cephalosporins-

Cephalosporins are now extensively used antibiotics. Their indications are:

-As alternatives to penicillin for ENT.

-Surgical prophylaxis

-Meningitis

-Typhoid

-In penicillinase-producing staphylococcal infections.

-In septicemias caused by gram-negative organisms.

-Gonorrhea caused by penicillinase-producing organisms.

-Prophylaxis and treatment of infections in neutropenic patients.

-As an alternative to fluoroquinolones (especially in children) for empirical therapy.

-For mixed aerobic-anaerobic infections in cancer patients.

-Respiratory, urinary, and soft tissue infections are caused by gram-negative organisms, like- Klebsiella, Proteus, Enterobacter, Serratia.

Adverse Effects of cephalosporins-

Cephalosporins have low toxicity and are generally safe. The most common adverse reactions from cephalosporins are-

-Nausea

-Vomiting

-lack of appetite

-abdominal pain

The less common adverse reaction includes-

-Hypersensitivity reaction

-Drug-induce immune hemolytic anemia (DIIHA)

-Disulfiram-like reaction

-Vitamin K deficiency

-Increase nephrotoxicity of aminoglycosides

-Pseudo membranous colitis


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