What are cephalosporins and how do they work. Which generations of cephalosporins exist. What are the common uses and side effects of cephalosporins. How do different generations of cephalosporins compare in terms of effectiveness.

Understanding Cephalosporins: Broad-Spectrum Antibiotics

Cephalosporins are a diverse group of antibiotics derived from the Acremonium mold, formerly known as Cephalosporium. These bactericidal agents function similarly to penicillins, targeting the enzymes responsible for peptidoglycan synthesis in bacterial cell walls. Their broad-spectrum effectiveness against various bacteria makes them a valuable tool in modern medicine.

The discovery of the first cephalosporin in 1945 marked the beginning of an era of continuous improvement. Scientists have since refined the structure of these antibiotics, creating new “generations” with enhanced efficacy against a wider range of bacteria. Currently, there are five distinct generations of cephalosporins, each with its unique characteristics and applications.

How do cephalosporins work?

Cephalosporins disrupt the bacterial cell wall synthesis by binding to and inhibiting enzymes crucial for peptidoglycan formation. This action weakens the cell wall, ultimately leading to bacterial death. Their broad-spectrum nature allows them to target both gram-positive and gram-negative bacteria, though the effectiveness varies between generations.

Common Uses of Cephalosporins in Medical Practice

Cephalosporins are prescribed for a variety of bacterial infections, including:

• Bone infections
• Ear infections (e.g., otitis media)
• Skin infections
• Upper respiratory tract infections
• Urinary tract infections

The specific cephalosporin chosen depends on the suspected pathogen, the site of infection, and the drug’s pharmacokinetic properties.

Can cephalosporins treat all bacterial infections?

While cephalosporins are effective against many bacteria, they are not a universal solution. Some bacteria have developed resistance to certain cephalosporins, and others may be naturally resistant. Additionally, the effectiveness of each generation varies against different bacterial species, necessitating careful selection based on the specific infection and susceptibility patterns.

The Five Generations of Cephalosporins: A Comparative Analysis

The classification of cephalosporins into generations reflects their development over time and their expanding spectrum of activity. Each generation brings unique advantages and limitations:

First Generation Cephalosporins

First-generation cephalosporins excel in treating gram-positive bacterial infections, particularly those caused by staphylococci and streptococci. However, their efficacy against gram-negative bacteria is limited. Examples include cephalexin, cefadroxil, and cefazolin.

Second Generation Cephalosporins

The second generation shows improved activity against gram-negative bacteria while maintaining some effectiveness against gram-positive organisms. This generation bridges the gap between the narrow spectrum of the first generation and the broader spectrum of later generations.

Third Generation Cephalosporins

Third-generation cephalosporins offer enhanced gram-negative coverage and variable gram-positive activity. Notable members include cefotaxime, ceftriaxone, and ceftazidime. Some, like ceftriaxone, have unique properties such as a long half-life allowing for once-daily dosing.

Fourth Generation Cephalosporins

Fourth-generation agents, such as cefepime, provide excellent coverage against both gram-positive and gram-negative bacteria. They are particularly effective against β-lactamase producing Enterobacteriaceae, which may resist third-generation cephalosporins.

Fifth Generation Cephalosporins

The fifth generation, represented by ceftaroline in the United States, targets methicillin-resistant Staphylococcus aureus (MRSA) while maintaining broad-spectrum activity against other susceptible bacteria.

Administering Cephalosporins: Routes and Considerations

Cephalosporins can be administered through various routes, depending on the specific drug and the clinical situation:

1. Oral administration: Many first-generation and some later-generation cephalosporins are available in oral form, suitable for outpatient treatment.
2. Intravenous (IV) administration: Used for more severe infections or when rapid drug delivery is necessary.
3. Intramuscular (IM) injection: An alternative route for some cephalosporins when IV access is not available or practical.

The choice of administration route depends on factors such as the severity of the infection, the patient’s condition, and the specific properties of the chosen cephalosporin.

How does the administration route affect cephalosporin efficacy?

The route of administration can significantly impact a cephalosporin’s effectiveness. Intravenous administration typically results in higher and more consistent blood levels, making it preferable for severe infections. Oral cephalosporins, while convenient, may have variable absorption rates and might not achieve the same peak concentrations as their IV counterparts.

Safety Profile and Potential Side Effects of Cephalosporins

Cephalosporins are generally considered safe antibiotics with a favorable risk-benefit profile. However, like all medications, they can cause side effects and adverse reactions in some patients.

Common side effects of cephalosporins:

• Gastrointestinal disturbances (nausea, diarrhea)
• Skin rashes
• Headache
• Dizziness

Rare but serious side effects:

• Allergic reactions, including anaphylaxis
• Seizures (more common in patients with kidney disease)
• Blood clotting disorders
• Kidney or liver damage (with prolonged use)

It’s important to note that up to 10% of individuals with a penicillin allergy may also be allergic to cephalosporins due to structural similarities between these antibiotic classes.

Are cephalosporins safe during pregnancy and breastfeeding?

Most cephalosporins are considered relatively safe during pregnancy and breastfeeding. However, the safety profile can vary between different cephalosporins, and the potential risks and benefits should be carefully evaluated by a healthcare provider. Some cephalosporins may pass into breast milk, so caution is advised for nursing mothers.

Antibiotic Resistance and Cephalosporins: A Growing Concern

The emergence of antibiotic-resistant bacteria poses a significant challenge to the effectiveness of cephalosporins and other antibiotics. Several mechanisms contribute to cephalosporin resistance:

• Production of extended-spectrum β-lactamases (ESBLs)
• AmpC β-lactamase overproduction
• Carbapenemase production
• Alterations in bacterial cell wall porins

These resistance mechanisms have led to the development of multi-drug resistant organisms, complicating treatment options and necessitating the judicious use of antibiotics.

How can we combat cephalosporin resistance?

Strategies to mitigate cephalosporin resistance include:

1. Antibiotic stewardship programs to promote appropriate use
2. Development of new antibiotics and combination therapies
3. Enhanced infection control measures in healthcare settings
4. Increased surveillance and monitoring of resistant organisms
5. Public education on the proper use of antibiotics

Future Directions in Cephalosporin Development and Use

The ongoing evolution of cephalosporins continues to shape their role in modern medicine. Researchers are exploring several avenues to enhance the efficacy and utility of these antibiotics:

Novel cephalosporin formulations

Scientists are developing new cephalosporin derivatives with enhanced stability against β-lactamases and improved penetration into bacterial cells. These innovations aim to overcome existing resistance mechanisms and broaden the spectrum of activity.

Combination therapies

Combining cephalosporins with other antibiotics or β-lactamase inhibitors can potentially restore their effectiveness against resistant bacteria. This approach has already yielded promising results with drugs like ceftazidime-avibactam.

Targeted delivery systems

Research into nanoparticle-based delivery systems and other targeted approaches may improve the pharmacokinetics and tissue penetration of cephalosporins, enhancing their efficacy while minimizing side effects.

What role will cephalosporins play in future antimicrobial therapy?

Cephalosporins are likely to remain a crucial component of antimicrobial therapy. However, their use will likely become more targeted and precise, guided by rapid diagnostic techniques and a deeper understanding of bacterial resistance mechanisms. The development of new generations or modified cephalosporins may help address current limitations and expand their therapeutic potential.

Practical Considerations for Cephalosporin Use in Clinical Practice

When prescribing cephalosporins, healthcare providers must consider several factors to ensure optimal treatment outcomes and minimize the risk of adverse effects:

Patient-specific factors

• Allergies and previous adverse reactions
• Renal and hepatic function
• Age and weight
• Concurrent medications and potential interactions

Infection-specific factors

• Suspected or confirmed pathogen
• Site of infection
• Severity of infection
• Local antimicrobial resistance patterns

Drug-specific factors

• Spectrum of activity
• Pharmacokinetics and pharmacodynamics
• Potential for inducing resistance
• Cost and availability

By carefully considering these factors, clinicians can optimize the use of cephalosporins, improving patient outcomes while minimizing the risk of adverse effects and the development of antibiotic resistance.

How can healthcare providers ensure appropriate cephalosporin prescribing?

To promote responsible cephalosporin use, healthcare providers should:

1. Adhere to evidence-based guidelines for antibiotic prescribing
2. Utilize rapid diagnostic tests when available to guide therapy
3. Consider narrower-spectrum alternatives when appropriate
4. Educate patients on proper antibiotic use and the importance of completing the full course of treatment
5. Regularly review and update institutional antibiotic policies based on local resistance patterns

By implementing these practices, healthcare providers can help preserve the effectiveness of cephalosporins and other antibiotics for future generations.

List of Cephalosporins + Uses, Types & Side Effects

Cephalosporins are a large group of antibiotics derived from the mold Acremonium (previously called Cephalosporium). Cephalosporins are bactericidal (kill bacteria) and work in a similar way to penicillins. They bind to and block the activity of enzymes responsible for making peptidoglycan, an important component of the bacterial cell wall. They are called broad-spectrum antibiotics because they are effective against a wide range of bacteria.

After the first cephalosporin was discovered in 1945, scientists improved the structure of cephalosporins to make them more effective against a wider range of bacteria. Each time the structure changed, a new “generation” of cephalosporins were made. There are five generations of cephalosporins. Most cephalosporins start with cef, ceph, or kef. Note that this classification system is not used consistently from country to country.

What are cephalosporins used for?

Cephalosporins may be used to treat infections caused by susceptible bacteria, such as:

• Bone infections
• Ear infections (eg, otitis media)
• Skin infections
• Upper respiratory tract infections
• Urinary tract infections.

What are the differences between cephalosporins?

There are five “generations” of cephalosporins, with each generation differing slightly in their antibacterial spectrum (ie, how effective they are at killing certain types of bacteria). Within each generation, there are differences in terms of administration (such as oral or intravenous administration), absorption, excretion, and how long the activity of the cephalosporin lasts in the body.

First generation cephalosporins

First generation cephalosporins refer to the first group of cephalosporins discovered. Their optimum activity is against gram-positive bacteria such as staphylococci and streptococci. They have little activity against gram-negative bacteria.

Cephalexin and cefadroxil can be given by mouth, whereas cefazolin can only be given by injection (IV/IM). There are also differences with regards to how frequently the different first-generation cephalosporins need to be dosed.

Second generation cephalosporins

Second-generation cephalosporins are more active against gram-negative bacteria, with less activity against gram-positive bacteria.

Third generation cephalosporins

Third generation cephalosporins followed the second-generation cephalosporins. No single third-generation cephalosporin treats all infectious disease scenarios.

Cefotaxime and ceftizoxime (discontinued) offer the best gram-positive coverage out of all the third-generation agents; ceftazidime and cefoperazone (discontinued) are unique in that they provide antipseudomonal coverage.

Ceftriaxone has a long half-life which allows for once daily dosing and may be used for the treatment of gonorrhea, pelvic inflammatory disease, and epididymo-orchitis. It is also an alternative to penicillins for suspected meningitis.

All the third-generation cephalosporins except for cefoperazone (discontinued) penetrate cerebrospinal fluid.

Fourth generation cephalosporins

Fourth generation cephalosporins are structurally related to third-generation cephalosporins but possess an extra ammonium group, which allows them to rapidly penetrate through the outer membrane of gram-negative bacteria, enhancing their activity. They are also active against β-lactamase producing Enterobacteriaceae which may inactivate third-generation cephalosporins.

Some fourth-generation cephalosporins have excellent activity against gram-positive bacteria such as methicillin-susceptible staphylococci, penicillin-resistant pneumococci, and viridans group streptococci.

Cefepime is the only fourth generation cephalosporin available in the United States. Cefpirome is available overseas.

Next (fifth) generation cephalosporins

Ceftaroline is currently the only next-generation cephalosporin available in the United States. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and gram-positive bacteria. It also retains the activity of the later-generation cephalosporins and is effective against susceptible gram-negative bacteria.

Are cephalosporins safe?

Cephalosporins are generally safe, with low toxicity and good efficacy against susceptible bacteria.

Allergic reactions have been reported with cephalosporins and symptoms may include a rash, hives (urticaria), swelling, or rarely, anaphylaxis. Up to 10% of people with a history of penicillin allergy will also be allergic to cephalosporins.

Rarely, seizures have been reported with some cephalosporins; the risk is greatest in those with kidney disease.

Cephalosporins have also been associated with a reduced ability of the blood to clot leading to prolonged bleeding times. People with kidney or liver disease, nutritionally deprived, taking cephalosporins long-term, or concurrently receiving anticoagulant therapy are more at risk.

For a complete list of severe side effects, please refer to the individual drug monographs.

What are the side effects of cephalosporins?

Cephalosporins generally cause few side effects. The most common side effects reported include abdominal pain, diarrhea, dyspepsia, headache, gastritis, and nausea and vomiting. Transient liver problems have also been reported.

Rarely, some people may develop a super-infection due to overgrowth of a naturally occurring bacterium called Clostridium difficile, following use of any antibiotic, including cephalosporins. Symptoms may include severe diarrhea.

Uncommonly, an overgrowth of the yeast, Candida albicans, may occur following cephalosporin use, resulting in the symptoms of thrush.

For a complete list of side effects, please refer to the individual drug monographs.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

What are Cephalosporins? Uses, Warnings, Side Effects, and More

Common Questions & Answers

What drugs are cephalosporins?

Cephalosporins are a large group of beta-lactam antibiotics. These drugs are used to treat a wide variety of bacterial infections. There are five generations of cephalosporins, grouped according to their range of coverage against bacteria and when the drugs were developed.

What are examples of cephalosporins?

Examples of cephalosporins include first-generation drugs cefazolin and cephalexin; second-generation drugs cefuroxime and cefoxitin; third-generation drugs ceftriaxone and ceftazidime; fourth-generation drug cefepime; and fifth-generation drug ceftaroline.

Is a cephalosporin a penicillin?

Cephalosporins are similar to penicillins on a molecular level, and as a result, they might lead to an allergic reaction in people who are allergic to penicillins. If your penicillin allergy is not severe, you may still be able to take cephalosporins, but probably not first- or second-generation drugs.

What are the most common cephalosporins?

The first-generation cephalosporins (such as cefazolin and cephalexin) are commonly used to treat skin and soft tissue infections. Second-generation cephalosporins, including cefaclor, cefprozil, loracarbef, and cefpodoxime, are commonly used to treat sinus, lung, and ear infections.

What are the five generations of cephalosporins?

First and second generation cephalosporins (such as cefazolin and cefuroxime) treat skin and soft tissue infections. Cefuroxime also treats respiratory infections and UTIs. Third-generation cephalosporins (ceftriaxone and ceftazidime) are typically for serious infections. Fourth-generation cefepime treats staphylococcal infections. Fifth-generation ceftaroline is effective against MRSA and pneumonia.

Because of their long history of development, there are numerous cephalosporins on the market. According to the Nelson Textbook of Pediatrics, the five generations of cephalosporins break down as follows:

• First-generation cephalosporins are commonly used to treat skin and soft tissue infections. Examples include cefazolin and cephalexin. Doctors also use these drugs to treat bone, respiratory, urinary, genital, biliary tract, ear, and bloodstream infections, per StatPearls.
• Second-generation cephalosporins are used to treat respiratory tract infections, UTIs, skin and soft tissue infections, and Lyme disease. Examples include cefuroxime and cefoxitin. Other second-generation cephalosporins (cefaclor, cefprozil, loracarbef, cefpodoxime) are commonly used to treat sinus, lung, and ear infections.
• Third-generation cephalosporins are typically used for serious infections, including meningitis and sepsis. Examples include ceftriaxone and ceftazidime. Ceftriaxone is also used to treat gonorrhea and Lyme disease, per StatPearls.
• A fourth-generation cephalosporin called cefepime is used to treat staphylococcal infections.
• A fifth-generation cephalosporin called ceftaroline is effective against MRSA (methicillin-resistant Staphylococcus aureus) and community-acquired pneumonia.

Precautions and Warnings

People who are allergic to cephalosporins, or any inactive ingredients found in these drugs, shouldn’t take them.

Cephalosporins share a molecular similarity with penicillins, and so might lead to an allergic reaction in people who are allergic to penicillins. Depending on the severity of your penicillin allergy, you may still be able to take cephalosporins, but most likely not first- or second-generation drugs, notes StatPearls.

You should also avoid cephalosporins if you’ve had an anaphylactic reaction to other beta-lactams.

The third-generation cephalosporin ceftriaxone is contraindicated in some newborns, because it could increase the risk of jaundice.

Make sure your doctor or pharmacist is monitoring your kidney function when you are taking cephalosporins, because that could potentially warrant a change in the dose or dosing frequency of your medication.

An overdose of the fourth-generation cephalosporin cefepime can lead to seizures and encephalopathy (brain disease). If you have a history of seizures, especially with poor kidney function, use caution when taking cephalosporins.

As with all antibiotics, it’s important that you finish the entire course you were prescribed — even if you feel better. This is the only way to ensure that the infection is completely gone. Otherwise, the infection could return and be much more difficult to treat the second time around.

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Cephalosporins: pharmacological group

Depending on the characteristics of the antimicrobial spectrum, 5 generations of cephalosporins are isolated.

First generation cephalosporins: parenteral – cefazolin, oral – cephalexin.

II generation cephalosporins: parenteral – cefuroxime, oral – cefuroxime axetil, cefaclor.

III generation cephalosporins: parenteral – cefotaxime, ceftriaxone, cefoperazone, cefoperazone / sulbactam, ceftazidime, oral – cefditoren, cefixime, cefpodoxime, ceftibuten.

IV generation cephalosporins: parenteral – cefepime, cefpirome.

V generation cephalosporins (anti- MRSA -cephems): parenteral – ceftaroline, ceftobiprole.

I generation cephalosporins have predominant activity against gram-positive cocci – staphylococci and streptococci. Gram-negative bacteria are resistant, with the exception of some community-acquired strains E. coli and P. mirabilis. Used for infections of the skin and soft tissues, bones and joints, for perioperative prophylaxis. As an alternative means, it is used for endocarditis and sepsis caused by methicillin-sensitive staphylococci and viridescent streptococci. Cefazolin does not penetrate well through the BBB. Excreted mainly in the urine, T _1/2 – 2 hours, administered 2-3 times a day. Cephalexin has a high oral bioavailability. The main indications for the use of cephalexin: streptococcal pharyngitis, streptococcal and staphylococcal uncomplicated community-acquired infections of the skin and soft tissues.

II generation cephalosporins, having activity similar to the first generation cephalosporins against gram-positive cocci, surpass them in their effect on gram-negative bacteria, primarily H. influenzae. Well distributed (except for the central nervous system), excreted mainly by the kidneys, have close T _1/2 (about 1 hour). Used for the treatment of community-acquired infections, for perioperative prophylaxis.

III generation parenteral cephalosporins have a high natural activity against gram-negative bacteria (family Enterobacteriaceae, H. influenzae, N. gonorrhoeae, N. meningitidis), are not inactivated by many β-lactamases. Degraded by extended spectrum β-lactamases and class C β-lactamases (AmpC). Ceftazidime and cefoperazone are active against P. aeruginosa. In terms of activity against staphylococci, they are significantly inferior to drugs of the first and second generations, but against streptococci and pneumococci, cefotaxime and ceftriaxone are superior to other cephalosporins and act on many penicillin-resistant strains. Ceftazidime is practically inactive against Gram-positive bacteria. All drugs of this group are well distributed in the body, penetrate (except for cefoperazone) through the BBB and can be used to treat infections of the central nervous system. Cefotaxime and ceftazidime are excreted by the kidneys, while cefoperazone and ceftriaxone are excreted by the kidneys and liver. All III generation cephalosporins have similar T _1/2 (1.2-2 hours), except for ceftriaxone (about 7 hours). It is used to treat severe community-acquired and nosocomial infections caused by gram-negative microorganisms. Cefoperazone / sulbactam, a combination of a third-generation cephalosporin with the β-lactamase inhibitor sulbactam, has an extended spectrum of activity compared to cephalosporins, including anaerobes and many nosocomial bacterial strains, incl. most strains producing extended spectrum β-lactamase.

Third-generation oral cephalosporins cefixime and ceftibuten are active against Enterobacteria and Haemophilus influenzae, but are not very active against Gram-positive organisms, including pneumococci, streptococci, and staphylococci; therefore, they should not be used in Gram-positive infections, especially community-acquired pneumonia. Cefditoren, unlike cefixime and ceftibuten, has high activity against staphylococci and streptococci (including pneumococci), and therefore does not have the above limitations.

IV generation cephalosporins are characterized by high activity against Gram-negative bacteria, including P. aeruginosa, and increased activity against Gram-positive flora compared to III generation drugs (ceftazidime). Active against some nosocomial strains Enterobacteriaceae, resistant to III generation cephalosporins. Destroyed by extended spectrum β-lactamases, but resistant to class C β-lactamases. Used to treat severe nosocomial infections, incl. in the intensive care unit and in neutropenic patients. Cefpirome is inferior to cefepime in activity against most pathogens.

Fifth generation cephalosporins (anti- MRSA -cephems) include parenteral preparations ceftaroline and ceftobiprole only. The main distinguishing feature of the fifth generation cephalosporins is the highest in vitro activity among β-lactams against gram-positive bacteria, including most strains of MRSA . The activity of ceftaroline and ceftobiprole against gram-negative bacteria is generally equivalent to that of cefotaxime and ceftriaxone.

The most common side effects are allergic reactions. Approximately 10% of patients with hypersensitivity to penicillin have cross-allergic reactions to cephalosporins of the first generation.