CEPHALOSPORINS

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Cephalosporins are beta-lactam antibiotics that are penicillinase-resistant, and with related mode of action to the penicillins. Drugs in this category are clinical substitutes for penicillins due to the development of resistance to the later by pathogenic bacteria. Cephalosporins are classified into five (5) major generations based on their spectrum of activity, side chain modifications and clinical applications. These five major generations of cephalosporins include first-, second-, third-, fourth-, and fifth- generation cephalosporins.

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  • FIRST GENERATION CEPHALOSPORINS

The 1st-generation cephalosporins are active against Gram-positive bacteria. They include cephalexin, cephalothin, cephapirin, cefazolin, cephadrine and cefadrox. They have a narrow-spectrum of activity against pathogenic bacteria especially the Gram-negative rods (e.g. Klebsiella species and Escherichia coli). Though their activity is mainly against penicillinase-resistant Gram-positive bacteria, antibiotics in this group are also active against some Enterobacteriaceae.   

  • SECOND GENERATION CEPHALOSPORINS

The 2nd-generation cephalosporins were designed to counter the resistance of Gram-negative bacteria (mediated by beta-lactamase production) to the 1st-generation cephalosporins. They have expanded antibacterial activity against pathogenic bacteria in the family Enterobacteriaceae (e.g. Klebsiella species and E. coli), Haemophilus speciesand even against some anaerobic bacteria (e.g. Bacteroides species). Antibiotics that are 2nd-generation cephalosporins include cefaclor, cefotetan, cefuroxime, and cefoxitin. Second (2nd)-generation cephalosporins generally have expanded Gram-negative activity than the 1st-generation cephalosporins that are more susceptible to beta-lactamase enzymes secreted by these pathogens.  

  • THIRD GENERATION CEPHALOSPORINS

The 3rd-generation cephalosporins include ceftazidime, cefotaxime, and ceftriaxone. Antibiotics in this category are more effective against Gram-negative rods than the 2nd-generation cephalosporins. They have antibacterial activity against a wide variety of Enterobacteriaceae and non-enteric bacteria (e.g. Pseudomonas aeruginosa). Third (3rd)-generation cephalosporins have enhanced systemic activity against a wide variety of Gram-negative rods including those that penetrate the central nervous system (CNS) such as Neisseria meningitidis. They are the preferred antibiotic of choice in life-threatening bacterial diseases or infections of yet unknown cause (i.e. infections in which the causative agents are yet to be isolated from patients specimen in the microbiology laboratory).      

  • FOURTH GENERATION CEPHALOSPORINS

The 4th-generation cephalosporins have extended antibacterial spectrum or activity against pathogenic bacteria (especially the Gram-negative rods) to which the 3rd-generation cephalosporins are least effective. They include cefepime and cefpirome. Fourth (4th)-generation cephalosporins have activity against Enterobacter species, Citrobacter species, Neisseria species, Haemophilus species, Enterobacteriaceae and a wide variety of Gram-negative bacteria. Antibiotics in this category have more outer membrane (OM)-penetrating potential than the other generations of cephalosporins. They are more stable to beta-lactamase enzymes secreted by Gram-negative bacteria.       

  • FIFTH GENERATION CEPHALOSPORINS

The 5th-generation cephalosporins are usually administered intravenously (IV). They are active against a variety of multidrug resistant bacteria pathogens including the dreaded methicillin resistant Staphylococcus aureus (MRSA). The 5th-generation cephalosporins include Ceftaroline Fosamil (IV) and Ceftobiprole (IV) – which are both administered parenterally.

SOURCES OF CEPHALOSPORINS

Cephalosporins are naturally sourced from the fungus Cephalosporium (e.g. C. acremonium). The cephalosporins were originally produced in the early 1940s from moulds (i.e. Cephalosporium species). However, cephalosporins can also be produced semi-synthetically in the laboratory by the addition of substituent groups to the side chains of the 7-aminocephalosporanic acid structure (Figure 1).  

STRUCTURE OF CEPHALOSPORINS

The basic structure of the cephalosporins is known as 7-aminocephalosporanic acid (Figure 1). Addition of substituent groups to this basic structure result in the production of different variants of cephalosporins as aforementioned.

Figure 1. Basic structure of cephalosporins (7-aminocephalosporanic acid, 7-ACA). The beta-lactam ring is fused with the dihydrothiazine ring. Cephalosporins unlike the penicillins have a six-membered ring (the dihydrothiazine ring); and group substitution occurs in two places or at both sides of the 7-aminocephalosporanic acid nucleus. The cephalosporins work in the same manner as the penicillins by inhibiting the cross-linking of peptidoglycan during bacterial cell wall synthesis. Photo courtesy: https://www.microbiologyclass.com

CLINICAL APPLICATION OF CEPHALOSPORINS

Clinically, the cephalosporins are effective against a wide variety of pathogenic bacteria especially the Gram-negative rods to which the penicillins have little or no activity against. 1st-generation cephalosporins are very active against Gram-positive bacteria (e.g. Staphylococcus species). Second (2nd)-generation cephalosporins are effective against Gram-negative rods (e.g. Klebsiella species and Proteus species) but not against Pseudomonas species. Third (3rd)-generation cephalosporins are active against Pseudomonas species and a variety of Enterobacteriaceae and other Gram-negative rods. Fourth (4th)-generation cephalosporins are active against a variety of pathogenic bacteria including those that are resistant to the antibacterial onslaught of 3rd-generation cephalosporins.              

SPECTRUM OF ACTIVITY OF CEPHALOSPORINS

Cephalosporins (including the 1st, 2nd, 3rd, 4th, and 5th-generations) have a broader spectrum of activity. They are bactericidal in action. Cephalosporins have activity against both Gram-positive and Gram-negative bacteria.  

MECHANISM OR MODE OF ACTION OF CEPHALOSPORINS

Cephalosporins like the penicillins are cell wall synthesis inhibitors. They bind to the PBPs on bacterial cell wall. Cephalosporins interfere with the synthesis of peptidoglycan in growing bacteria. They have similar mode of action like the penicillins but the former have increased stability to beta-lactamases produced by Gram-negative bacteria than the penicillins.

BACTERIAL RESISTANCE TO CEPHALOSPORINS

Though very effective against a wide variety of pathogenic bacteria, most cephalosporins are fast becoming susceptible to some antibiotic-degrading enzymes such as the ESBLs and other multidrug resistance factors produced by bacteria. The production of ESBLs aside other antibiotic-hydrolyzing enzymes by Gram-negative bacteria have significantly compromised the clinical use of the cephalosporins for treating some bacterial-related infections or diseases.  

PHARMACOKINETICS AND SIDE EFFECT OF CEPHALOSPORINS

Cephalosporins are generally well tolerated by the body when administered orally or parenterally. They have a wider systemic distribution in the body. Untoward effects due to the usage of cephalosporins are attributed to the host’s allergic reactions to the drug as is applicable to the use of penicillins. But hypersensitivity to cephalosporins is fewer compared to that produced by penicillins.

OTHER BETA-LACTAM ANTIBIOTICS AND NON-BETA-LACTAMS THAT

INTERFERE WITH BACTERIAL CELL WALL SYNTHESIS

Aside penicillins and cephalosporins, other beta-lactam antibiotics used for clinical applications also exist. These beta-lactam antibiotics have expanded antibacterial activity. They are often used to treat infections caused by bacterial pathogens that are resistant to the penicillins and cephalosporins. Antibiotics in this category are generally cell wall synthesis inhibitors. They possess similar mechanisms of action like the penicillins and cephalosporins. They have broader spectrum of activity and are very effective against Gram-positive and Gram-negative bacteria. These other beta-lactam antibiotics and non-beta lactams that interrupt the synthesis of peptidoglycan in bacteria are highlighted in this section.

  • Carbapenems: Carbapenems are active against a wide variety of bacteria including Gram-positive and Gram-negative bacteria as well as against anaerobic bacteria. Examples of antibiotics in this class include: imipenem, meropenem, ertapenem and doripenem. They have the broadest spectrum of antibacterial activity than all the other beta-lactam drugs including penicillins and cephalosporins. Carbapenems are clinically used to treat infections caused by multidrug resistant bacteria including those that produce ESBLs.     
  • Monobactams: Monobactams are effective for treating infections caused by Gram-negative bacteria. They are the drug of choice for patients who are allergic to penicillins or cephalosporins. Monobactams are least effective against Gram-positive bacteria. Aztreonam is a typical example of monobactams.  
  • Cephamycins: Cephamycins areβ-lactamswitha wider antibacterial spectrum than the cephalosporins. They are more stable to beta-lactamase hydrolysis. Examples include cefotetan, cefmetazole and cefoxitin. The cephamycins are very similar to the cephalosporins and are sometimes classified as cephalosporins. Though naturally sourced from Streptomyces, cephamycins can now be produced synthetically.  
  • Glycopeptides: Glycopeptides are produced by Streptomyces species. Vancomycin is a typical example of glycopeptides. Vancomycin is more effective against Gram-positive bacteria than Gram-negative organisms because the drug cannot penetrate the OM of the latter. The existence of vancomycin-resistant bacteria has compromised the clinical use of vancomycin. Vancomycin is not a beta-lactam drug like the penicillins even though they interrupt peptidoglycan synthesis in Gram-positive bacteria.
  • Bacitracin: Bacitracin is a polypeptide antibiotic naturally synthesizedby Bacillus licheniformis. Bacitracin is mainly used for topical applications (e.g. for ointment) because of their very high toxicity which prohibittheir usage for systemic administration.They are not beta-lactam antibiotics but interfere with the synthesis of peptidoglycan in pathogenic bacteria.

Carbapenems, monobactams, bacitracin and the glycopeptides inhibit the synthesis of bacterial cell wall by interfering with the transpeptidation reaction (required for the formation of peptidoglycan or murein) the same way that the cephalosporins and penicillins operate in vivo.

FURTHER READING

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India. 

Block S.S (2001). Disinfection, sterilization and preservation. 5th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Ejikeugwu Chika, Iroha Ifeanyichukwu, Adikwu Michael and Esimone Charles (2013). Susceptibility and Detection of Extended Spectrum β-Lactamase Enzymes from Otitis Media Pathogens. American Journal of Infectious Diseases. 9(1):24-29.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg.

Russell A.D and Chopra I (1996). Understanding antibacterial action and resistance. 2nd edition. Ellis Horwood Publishers, New York, USA.

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