Cephalosporin drugs belong to the class of antibiotics known as beta-lactam antibiotics. These antibiotics were first discovered in the 1940s from a mold called Cephalosporium. Initially only a few generations of cephalosporins were developed but now seven generations of cephalosporins have been developed with expanded spectra of activity against both Gram-positive and Gram-negative bacteria.
First Generation Cephalosporins
The first generation cephalosporins were among the earliest cephalosporin drugs to be developed in the 1960s. Examples of first generation cephalosporins include cefazolin and cephalexin. These drugs have a narrow spectrum of activity and are primarily effective against Gram-positive cocci such as Staphylococcus aureus. They are generally used for relatively minor bacterial infections affecting the skin, respiratory tract, urinary tract etc. Due to their narrow spectrum, first generation cephalosporins have limited use today and have been replaced by newer generations with broader activity.
Second Generation Cephalosporins
Developed in the 1970s to address the need for broader spectrum antibiotics, second generation Cephalosporins Drugs were more effective against Gram-negative bacteria in addition to Gram-positive cocci. Some examples of second generation cephalosporins are cefuroxime, cefotetan and cefoxitin. These drugs found more use in treating infections caused by Escherichia coli, Klebsiella, Proteus in addition to Staphylococcus. However, they had limited activity against Gram-negative bacilli like Pseudomonas aeruginosa and Enterobacter. Second generation cephalosporins remain useful for respiratory tract infections, skin and soft tissue infections, urinary tract infections, etc.
Third Generation Cephalosporins
Released in the 1980s, third generation cephalosporins like cefotaxime, ceftriaxone and ceftazidime had an even broader spectrum covering additional Gram-negative bacteria including Pseudomonas aeruginosa. They demonstrate good activity against Enterobacteriaceae family of bacteria and have little activity against methicillin-resistant Staphylococcus aureus (MRSA). Third generation cephalosporins are used for treating pneumonia, bloodstream infections, complicated urinary tract infections, bacterial meningitis, pelvic inflammatory disease etc. Injectable formulations like ceftriaxone are commonly used for treating common infections in outpatient setting.
Fourth Generation Cephalosporins
Fourth generation cephalosporins were developed to combat emerging resistance, specifically against Pseudomonas species. Examples include cefepime and cefpirome. These drugs demonstrate activity against Pseudomonas aeruginosa in addition to routine Gram-positive and Gram-negative bacteria covered by previous generations. Due to their broader spectrum, fourth generation cephalosporins are primarily used for hospital-acquired pneumonia, complicated urinary tract infections, intra-abdominal infections etc. They are generally reserved for use against multi-drug resistant infections.
Fifth Generation Cephalosporins
Compared to previous generations, fifth generation cephalosporins have an even broader spectrum of activity against Gram-positive as well as Gram-negative bacteria, including MRSA. Examples of fifth generation cephalosporins are ceftaroline and ceftobiprole. They are useful for treating complex bacterial infections involving MRSA, penicillin-resistant Streptococcus pneumoniae and so on. These drugs are indicated for community-acquired pneumonia, skin and soft tissue infections caused by MRSA. Their use has helped address the increasing resistance developed by bacteria against previous generations of cephalosporins.
Spectrum of Activity
The spectrum of activity of cephalosporins has increased with each successive generation as modifications were made to their chemical structure. First generation cephalosporins are only active against Gram-positive cocci whereas later generations demonstrate activity against both Gram-positive and Gram-negative organisms including Pseudomonas and Enterobacteriaceae. Fifth generation cephalosporins have the broadest coverage effective against MRSA in addition to routine bacteria. However, cephalosporins as a class have no clinically relevant activity against anaerobic bacteria. They are also not useful for treating bacterial infections caused by Chlamydia, Mycoplasma etc since these are not affected by beta-lactam antibiotics.
Uses of Cephalosporins
Depending on their generation and spectrum, cephalosporins are used to treat a variety of bacterial infections:
- Lower respiratory tract infections - Pneumonia
- Skin and soft tissue infections - Cellulitis, abscesses
- Urinary tract infections - Cystitis, pyelonephritis
- Bone and joint infections - Osteomyelitis
- Intra-abdominal infections - Peritonitis
- Sexually transmitted diseases - Gonorrhea, pelvic inflammatory disease
- Septicemia/bloodstream infections
- Bacterial meningitis
Infections caused during surgeries are also treated with appropriate cephalosporins. Combination therapy may be used for serious illnesses like endocarditis, osteomyelitis etc.
Mechanism of Action
Cephalosporins exert their antibacterial action through inhibition of bacterial cell wall synthesis. They function like penicillins in inhibiting the transpeptidase or penicillin-binding proteins (PBPs) which are necessary for cross-linking peptidoglycan polymers during cell wall formation. This leads to cell wall weakening, lysis and death of bacteria. However, the binding affinity of cephalosporins is higher than penicillin for PBPs, thus they are effective against penicillin-resistant bacteria as well. Their beta-lactam ring must remain intact and available to bind PBPs for retaining antibacterial activity.
Adverse Effects and Interactions
Being beta-lactam antibiotics, cephalosporins can cause similar side effects like penicillin allergies. Common adverse effects reported include hypersensitivity reactions, nausea, vomiting, diarrhea and allergic reactions. More serious effects may include anaphylaxis, blood disorders and Stevens-Johnson syndrome. They may worsen seizure disorders and should be used cautiously in kidney disease patients. Oral contraceptives may have reduced effectiveness when administered with cephalosporins and tube ligation can become ineffective as well. Drug interaction potential exists with probenecid and drugs eliminated by kidneys like cyclosporine. Blood concentrations of methotrexate may elevate dangerously when used with cephalosporins.
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