Adverse effects of cephalosporins

Cephalosporins

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.

Since the first cephalosporin was discovered in 1945, scientists have been improving the structure of cephalosporins to make them more effective against a wider range of bacteria. Each time the structure changes, a new “generation” of cephalosporins are made. So far there are five generations of cephalosporins. All 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.

Cephalosporins are not usually used as a first-choice antibiotic. They tend to be reserved for use when other antibiotics (often penicillins) cannot be used.

What are the differences between cephalosporins?

There are currently 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 for 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.

Generic name Brand name examples
cefadroxil Duricef
cefazolin Ancef, Kefzol
cephadrine Discontinued
cephalexin Daxbia, Keflex

Second generation cephalosporins

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

Generic name Brand name examples
cefotetan Cefotan
cefoxitin Mefoxin
cefprozil Cefzil
cefuroxime Ceftin, Zinacef
loracarbef Discontinued

Third generation cephalosporins

Third generation cephalosporins followed the second-generation cephalosporins. No one 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.

Generic name Brand name examples
cefdinir Omnicef
cefditoren Spectracef
cefixime Suprax
cefoperazone Discontinued
cefotaxime Claforan
cefpodoxime Generic
ceftazidime Fortaz, Tazicef
ceftibuten Cedax
ceftriaxone Generic

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.

Generic name Brand name examples
cefepime Maxipime

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.

Generic name Brand name examples
ceftaroline Teflaro

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.

What Are Cephalosporins?

This group of antibiotics is used to treat a wide range of bacterial infections.

Cephalosporins are a large group of antibiotics that belong to a class known as beta-lactams.

These drugs are used to treat bacterial infections including:

  • Ear infections
  • Pneumonia
  • Skin infections
  • Kidney infections
  • Sexually transmitted infections such as gonorrhea
  • Bone infections
  • Strep throat and other throat infections
  • Meningitis

Cephalosporins are bactericidal drugs, meaning they kill bacteria directly. They do this by interfering with how bacteria build their cell walls.

Cephalosporins are grouped into five generations based on when the drugs were developed. In general, each generation is effective against certain types of bacteria.

First-generation cephalosporins work primarily against infections that are considered easy to treat, while later-generation cephalosporins tend to be reserved for more severe bacterial infections.

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 your penicillin allergy, you may still be able to take cephalosporins, but most likely not first- or second-generation drugs.

Because of their long history of development, there are numerous cephalosporins on the market.

Examples of cephalosporins include:

  • Ancef and Kefazol (cefazolin)
  • Ceclor and Cefaclor (cefaclor)
  • Cefdinir
  • Ceftin and Zinacef (cefuroxime)
  • Duricef (cefadroxil)
  • Keflex and Keftabs (cephalexin)
  • Maxipime (cefepime)
  • Rocephin (ceftriaxone)
  • Suprax (cefixime)
  • Teflaro (ceftaroline fosamil)

Warnings and Precautions

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

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.

Common Side Effects

Taking a cephalosporin may lead to the following side effects:

  • Stomach discomfort
  • Nausea or vomiting
  • Diarrhea
  • Thrush (white fungus in the mouth), yeast infection, or other fungal infection
  • Blood abnormalities
  • Rash or itching

Drug Interactions

Don’t take a cephalosporin if you’re taking Theracrys (BCG live intravesical).

Ask your doctor about taking a cephalosporin if you’re taking:

  • Drugs for acid reflux like Pepcid (famotidine), Tagamet (cimetidine), or Zantac (ranitidine)
  • Other heartburn medications like Aciphex (rabeprazole), Dexilant (dexlansoprazole), Nexium (esomeprazole)
  • Vivotif (live typhoid vaccine)

Microbiology:
Mode of Action:
Ceftaroline is a cephalosporin within vitroactivity against Gram-positive and -negative bacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs). Ceftaroline is bactericidal againstS. aureusdue to its affinity for PBP2a and againstStreptococcus pneumoniaedue to its affinity for PBP2x.

Mechanisms of Resistance:
Ceftaroline is not active against Gram-negative bacteria producing extended spectrum beta-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-beta-lactamases, or class C (AmpC cephalosporinases).

Cross-Resistance:
Although cross-resistance may occur, some isolates resistant to other cephalosporins may be susceptible to ceftaroline.

Interaction with Other Antimicrobials
In vitrostudies have not demonstrated any antagonism between ceftaroline or other commonly used antibacterial agents (e.g., vancomycin, linezolid, daptomycin, levofloxacin, azithromycin, amikacin, aztreonam, tigecycline, and meropenem).

Ceftaroline has been shown to be active against most of the following bacteria, bothin vitro and in clinical infections.

Skin Infections
Gram-positive bacteria
Staphylococcus aureus(including methicillin-susceptible and -resistant isolates)
Streptococcus pyogenes
Streptococcus agalactiae

Gram-negative bacteria
Escherichia coli
Klebsiella pneumoniae
Klebsiella oxytoca

Community-Acquired Bacterial Pneumonia (CABP)
Gram-positive bacteria
Streptococcus pneumoniae
Staphylococcus aureus(methicillin-susceptible isolates only)

Gram-negative bacteria
Haemophilus influenzae
Klebsiella pneumoniae
Klebsiella oxytoca
Escherichia coli

The following in vitro data are available, but their clinical significance is unknown. Ceftaroline exhibitsin vitro MICs of 1 mcg/mL or less against most (>/= 90%) isolates of the following bacteria; however, the safety and effectiveness of Teflaro in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria
Streptococcus dysgalactiae

Gram-negative bacteria
Citrobacter koseri
Citrobacter freundii
Enterobacter cloacae
Enterobacter aerogenes
Moraxella catarrhalis
Morganella morganii
Proteus mirabilis
Haemophilus parainfluenzae

INDICATIONS AND USAGE:
Teflaro® (ceftaroline fosamil) is indicated for the treatment of patients with the following infections caused by susceptible isolates of the designated microorganisms.

Acute Bacterial Skin and Skin Structure Infections
Teflaro is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms:Staphylococcus aureus(including methicillin-susceptible and -resistant isolates),Streptococcus pyogenes,Streptococcus agalactiae,Escherichia coli,Klebsiella pneumoniae, and Klebsiella oxytoca.

Community-Acquired Bacterial Pneumonia
Teflaro is indicated for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms:Streptococcus pneumoniae(including cases with concurrent bacteremia),Staphylococcus aureus(methicillin-susceptible isolates only),Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca,andEscherichia coli.

Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Teflaro and other antibacterial drugs, Teflaro should be used to treat only ABSSSI or CABP that are proven or strongly suspected to be caused by susceptible bacteria. Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to ceftaroline. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION:
Recommended Dosage
The recommended dosage of Teflaro is 600 mg administered every 12 hours by intravenous (IV) infusion over 1 hour in patients ≥ 18 years of age. The duration of therapy should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress.

The recommended dosage and administration by infection is:
Dosage of Teflaro by Infection:

Infection Dosage Frequency Infusion Time
(hours)
Recommended Duration of Total Antimicrobial Treatment
Acute Bacterial Skin and Skin Structure Infection (ABSSSI) 600 mg Every 12 hours 1 5-14 days
Community-Acquired Bacterial Pneumonia (CABP) 600 mg Every 12 hours 1 5-7 days

Renal Dosing:
Dosage of Teflaro in Patients with Renal Impairment:

Estimated CrCla (mL/min) Recommended Dosage Regimen for Teflaro
>50 No dosage adjustment necessary
>30 to </=50 400 mg IV (over 1 hour) every 12 hours
≥ 15 to </=30 300 mg IV (over 1 hour) every 12 hours
End-stage renal disease,
including hemodialysisb
200 mg IV (over 1 hour) every 12 hoursc

a. Creatinine clearance (CrCl) estimated using the Cockcroft-Gault formula.
b. End-stage renal disease is defined as CrCl < 15 mL/min.
c. Teflaro is hemodialyzable; thus Teflaro should be administered after hemodialysis on hemodialysis days.

DOSAGE FORMS AND STRENGTHS:
600 mg or 400 mg of sterile Teflaro powder in single-use 20 mL vials.

SOURCE:
Package insert data:

Cephalosporins: A Guide

Cephalosporins are grouped together based on the type of bacteria that they’re most effective against. These groups are referred to as generations. There are five generations of cephalosporins.

To understand the differences between the generations, it’s important to understand the difference between Gram-positive and Gram-negative bacteria.

One of the main distinctions between the two is their cell wall structure:

  • Gram-positive bacteria have thicker membranes that are easier to penetrate. Think of their cell wall as a chunky, loose-knit sweater.
  • Gram-negative bacteria have thinner membranes that are harder to penetrate, making them more resistant to some antibiotics. Think of their wall as a piece of fine chain mail.

First-generation cephalosporins

First-generation cephalosporins are very effective against Gram-positive bacteria. But they’re only somewhat effective against Gram-negative bacteria.

First-generation cephalosporins might be used to treat:

  • skin and soft tissue infections
  • UTIS
  • strep throat
  • ear infections
  • pneumonia

Some first-generation cephalosporins are used as prophylactic antibiotics for surgery involving the chest, abdomen, or pelvis.

Examples of first-generation cephalosporins include:

  • cephalexin (Keflex)
  • cefadroxil (Duricef)
  • cephradine (Velosef)

summary

First-generation cephalosporins are more effective against Gram-positive bacteria, though they also work against some Gram-negative bacteria.

Second-generation cephalosporins

Second-generation cephalosporins also target some types of Gram-positive and Gram-negative bacteria. But they’re less effective against certain Gram-positive bacteria than first-generation cephalosporins are.

They’re often used to treat respiratory infections, such as bronchitis or pneumonia.

Other infections sometimes treated with second-generation cephalosporins include:

  • ear infections
  • sinus infections
  • UTIs
  • gonorrhea
  • meningitis
  • sepsis

Examples of second-generation cephalosporins include:

  • cefaclor (Ceclor)
  • cefuroxime (Ceftin)
  • cefprozil (Cefzil)

summary

Second-generation cephalosporins target both Gram-positive and Gram-negative bacteria. But they’re a little less effective against Gram-positive bacteria compared to first-generation cephalosporins

Third-generation cephalosporins

Third-generation cephalosporins are more effective against Gram-negative bacteria compared to both the first and second generations. They’re also more active against bacteria that may be resistant to previous generations of cephalosporins.

The third generation also tend to be less active than previous generations against Gram-positive bacteria, including Streptococcus and Staphylococcus species.

One third-generation cephalosporin, ceftazidime (Fortaz), is often used to treat pseudomonas infections, including hot tub folliculitis.

Third-generation cephalosporins may also be used to treat:

  • skin and soft tissue infections
  • pneumonia
  • UTIs
  • gonorrhea
  • menigitis
  • Lyme disease
  • sepsis

A few examples of third-generation cephalosporins include:

  • cefixime (Suprax)
  • ceftibuten (Cedax)
  • cefpodoxime (Vantin)

Summary

Third-generation cephalosporins are effective against many Gram-negative bacteria and bacteria that haven’t responded to first- or second-generation cephalosporins.

Fourth-generation cephalosporins

Cefepime (Maxipime) is the only fourth-generation cephalosporin that’s available in the United States. While effective against a variety of Gram-positive and Gram-negative bacteria, it’s usually reserved for more severe infections.

Cefepime can be used to treat the following types of infections:

  • skin and soft tissue infections
  • pneumonia
  • UTIs
  • abdominal infections
  • meningitis
  • sepsis

Cefepime can be administered intravenously or with an intramuscular injection. It may also be given to people with a low white blood cell count, which can increase the risk of developing a severe infection.

Summary

Fourth-generation cephalosporins work against both Gram-positive and Gram-negative bacteria. They’re generally used for more severe infections or for those with weakened immune systems.

Fifth-generation cephalosporins

You may hear fifth-generation cephalosporins referred to as advanced- generation cephalosporins. There’s one fifth-generation cephalosporin, ceftaroline (Teflaro), available in the United States.

This cephalosporin can be used to treat bacteria, including resistant Staphylococcus aureus (MRSA) and Streptococcus species, that are resistant to penicillin antibiotics.

Otherwise, ceftaroline’s activity is similar to that of third-generation cephalosporins, although it isn’t effective against Pseudomonas aeruginosa.

Summary

Ceftaroline is the only fifth-generation cephalosporin available in the United States. It’s often used to treat infections, including MRSA infections, that are resistant to other antibiotics.

REVIEW

Pharmacokinetics of cephalosporins in the neonate: a review

Gian Maria Pacifici

University of Pisa, Department of Neurosciences, Section of Pharmacology, Medical School, Pisa, Italy

ABSTRACT

The aim of this work was to review the published data on the pharmacokinetics of cephalosporins in neonates to provide a critical analysis of the literature as a useful tool for physicians. The bibliographic search was performed for articles published up to December 3, 2010, using PubMed. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum was consulted. The cephalosporins are mainly eliminated by the kidneys, and their elimination rates are reduced at birth. As a consequence, clearance is reduced and t1/2 is more prolonged in the neonate than in more mature infants. The neonate’s substantial body water content creates a large volume of distribution (Vd) of cephalosporins, as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, the clearance of cephalosporins increases. The maturation of the kidney governs the pharmacokinetics of cephalosporins in the infant. Clearance and t1/2 are influenced by development, and this must be taken into consideration when planning a cephalosporin dosage regimen for the neonate.

Keywords: Cephalosporins; Pharmacokinetics; Neonate.

INTRODUCTION

Cephalosporins are the most common class of antibiotics used to treat bacterial infection. These drugs have proven to be safe, clinically effective, and easy to use.1,2 The expanded-spectrum cephalosporins (e.g., cefotaxime, ceftriaxone, and ceftazidime), either alone or in combination with other antibiotics, are the most common antibiotics used as initial empiric therapy for treating serious infections.3

The first generation of cephalosporins has good activity against Gram-positive bacteria and relatively modest activity against Gram-negative bacteria. The second generation of cephalosporins has increased activity against Gramnegative microorganisms but tends to be much less active than the third-generation agents. The fourth generation of cephalosporins is particularly useful for the empirical treatment of serious infections in hospitalized patients when Enterobacteriaceae and pseudomonas are potential etiologies.4 Cephalosporins are minimally toxic, with the exception of ceftriaxone, which displaces bilirubin from albumin5,6 and precipitates calcium, resulting in serious adverse effects.7,8 The aim of this paper was to review the literature on the kinetics of cephalosporins in the neonate and provide a critical analysis of the literature as a useful tool for physicians.

Bibliographic search

The bibliographic search was performed electronically, using PubMed to find articles published up to December 3, 2010. First, a Medline search was performed with the key words “pharmacokinetics of cephalosporins in neonates,” with the limit of “human”. Other Medline searches were performed with the key words “pharmacokinetics of……… in neonates,” followed by the names of single cephalospor-ins. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum9 was consulted. The bibliographic search produced 37 original articles, four review articles and two book chapters. The publication years of this material ranged from 1977 to 2010.

RESULTS

The demographic data for the neonates and the pharmacokinetic parameters of different cephalosporins are presented in four tables. Information relative to the first-generation cephalosporin, cefazolin, and the second-generation cephalosporins, cefoxitin, and cefuroxime, is provided in Table 1. Table 2 summarizes the results relative to the third-generation cephalosporins. Table 3 shows the results relative to cefepime, a fourth-generation cephalosporin, and Table 4 shows the concentrations of various cephalosporins in the cerebrospinal fluid (CSF) and serum.

Clearance (Cl) is expressed in different units by different authors. This makes comparisons between studies difficult. To overcome this difficulty, Cl was converted into ml/min/ kg. SD cannot be converted; therefore, Cl values are reported without SDs.

First generation cephalosporin

Cefazolin. The pharmacokinetics of cefazolin (Table 1) in 11 neonates were studied by Deguchi et al.10 There was marked interindividual variability in the distribution volume (Vd). This parameter ranged from 0.21 to 0.37 L/ kg. The unbound fraction of cefazolin in neonatal plasma ranged from 0.22 to 0.83. The Vd of cefazolin highly correlated (r = 0.936; p<0.001) with the unbound fraction of this drug.

Young and Mangum9 suggested administering 25 mg/kg cefazolin every 8 to 12 h according to the neonate’s postmenstrual age and postnatal age. When the postmenstrual age is >45 weeks, the interval between doses should be six hours.

Second-generation cephalosporins

Cefoxitin. Regazzi et al11 studied the pharmacokinetics of cefoxitin in 15 neonates. Their reported kinetic parameters are summarized in Table 1. The half-life (t1/2) negatively correlated with postnatal age (r = -0.58; p<0.05). Young and Mangum9 suggested administering 25 to 33 mg/ kg cefoxitin every 8 to 12 h according to the neonate’s postmenstrual age and postnatal age. When the post-menstrual age is >45 weeks, the interval between doses should be six hours.

Cefuroxime. Renlund and Pettay12 studied the pharmacokinetics of cefuroxime in 104 neonates, and their reported kinetic parameters are summarized in Table 1. The serum concentration of cefuroxime decreased with body weight from 25.6 ± 9.9 µg/ml (<1 kg body weight) to 19.5 + 6.8 µg/ml (>4 kg body weight) because of the increase in GFR with neonatal maturation. t1/2 showed similar behavior, decreasing from 5.6 h (2.83 kg body weight) to 4.0 h (3.83 kg body weight). Cefuroxime did not accumulate over a period of 8 days and was excreted in the urine by more than 70%.

Third-generation cephalosporins

Cefotaxime. The kinetic parameters of cefotaxime are summarized in Table 2. Kafetzis et al13 described treating infections with cefotaxime in 32 neonates. The pathogens that sustained the infection were Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Serratia marcescens Staphylococcus aureus, Staphylococcus epidermidis, and β-hemolytic streptococcus. All of the isolated pathogens were susceptible to cefotaxime. These authors clustered the pharmacokinetic parameters of cefotaxime into four groups according to the neonates’ gestational age and postnatal age. With neonatal maturation, t]y2 decreased and Cl increased. For brevity, Table 2 shows the two extremes of the cohort. In five patients with meningitis who received 50 mg/kg cefotaxime twice daily, the concentration of the drug was simultaneously measured in the CSF and serum 1 to 2 h after cefotaxime administration. The CSF and serum concentrations (mean±SD) were 18.2 ± 7.4 and 38.6 ± 10.3 µg/ml, respectively. The CSF-to-serum ratio was 45 ± 0.12%.

McCracken et al14 compared the kinetic parameters of cefotaxime in two groups of neonates; the first had an average body weight of 1,103 g, and the second had an average body weight of 2,561 g (p<0.0001). Vd and t1/2 were greater in the former than the latter group, whereas Cl was greater in the latter group and AUC was not different in the two groups.

Cefotaxime is converted into desacetyl cefotaxime in the neonate, and the peak concentration of desacetyl cefotaxime is about one-tenth of that of cefotaxime.15-1 The t1/2 of desacetyl cefotaxime is 9.4 h in very low-body-weight neonates.18 After 50 mg/kg cefotaxime, 50 to 60% of the dose is excreted unchanged in the urine, and approximately 20% is excreted as desacetyl cefotaxime.18 The renal Cl of cefotaxime is quantitatively more important than its metabolic Cl. Gouyon et al15 observed that the t1/2 of cefotaxime was negatively correlated with gestational age (r =-0.8954; p<0.01) and body weight (r =-0.8500; p<0.01). In contrast, Cl was positively correlated with gestational age (r = 0. 280; p<0.02) and body weight (r = 0.8667; p<0.02). The AUC of cefotaxime was negatively correlated with gestational age (r =-0.7950; p<0.01), but it did not correlate with body weight.

One recent study examined cefotaxime in neonates undergoing extracorporeal membrane oxygenation (ECMO).19 Doses of 50 mg/kg of body weight twice a day (postnatal age <1 week), 50 mg/kg three times a day (postnatal age 1 to 4 weeks) or 37.5 mg/kg four times a day (postnatal age >4 weeks) were found to provide sufficient periods of supra-MIC concentrations to give adequate treatment of infants on ECMO.

Young and Mangum9 suggested intravenously administering 25 to 33 mg/kg of cefotaxime every 8 or 12 h according to the postmenstrual age. When the postmenstr-ual age is >45 weeks, the interval between doses should be six hours.

Ceftazidime. The pharmacokinetic parameters of cefta-zidime are summarized in Table 2. The ceftazidime concentration was measured after intravenous administration to seven neonates and after intramuscular administration to 9 infants.20 Ceftazidime concentrations after intravenous injection declined biexponentially, and the postdistributive phase occurred 30 to 60 min after administration. The peak ceftazidime concentration was 109 ± 19.9 (intravenously) and 53.0 ± 22.4 (intramuscularly; p<0.05). The t1/2 of ceftazidime was 4.7 ± 1.5 (intravenously) and 3.8 ± 1.1 (intramuscularly; NS).

McCracken et al21 described the pharmacokinetics of ceftazidime in three groups of neonates with gestational ages of <32, 33-37, and >38 weeks. Cl increased with gestational age, whereas t1/2, AUC and the trough concentrations decreased with gestational age.

Blumer et al22 described ceftazidime’s pharmacokinetics and penetration into CSF in ten children aged 12 to 540 days. Ceftazidime at 50 mg/kg was intravenously administered once per day. The t1/2 of ceftazidime was 1.8 ± 0.8 h, which was 2- to 4-fold lower than that reported in neonates during the first week of life (see Table 2). The two youngest children, aged 12 and 23 days, had a t1/2 of 3.6 and 2.18 h, respectively. The Cl of ceftazidime varied by more than 300%; such a large variation makes it inappropriate to report the average Cl, so the data from Blumer et al22 are not shown in Table 2. In contrast, Vd showed little variation and ranged from 0.27 to 0.38 L/kg, with a mean ± SD of 0.34 ± 0.07 L/kg. The ceftazidime concentrations in the CSF and serum were 4.7 ± 2.5 and 145 ± 30.4 µg/ml, respectively. The CSF-to-serum concentration of ceftazidime was 3.5 ± 1.8%. The ratio of CSF to serum ceftazidime concentration showed a time-dependent increase, suggesting that ceftazidime was eliminated more slowly from the CSF than from the vascular compartment. The MIC of the isolated pathogens ranged from 0.0156 µg/ml (Neisseria meningitidis) to 0.125 µg/ml (Haemophilus influenzae, Type B).

Prenatal exposure to indomethacin resulted in significantly lower GFR and ceftazidime Cl values.23 The Cl of ceftazidime was 0.46 ml/min/kg (n = 23) in neonates who were prenatally exposed to indomethacin and 0.68 ml/ min/mg (No = 84) in infants who were not exposed to indomethacin (p<0.05). The Cl of ceftazidime increased with gestational age (r = 0.83; p<0.001), whereas t1/2 showed an opposite trend (r = -0.54; p<0.001).23 The positive relationship between the Cl of ceftazidime and the Cl of inulin (r = 0.73; p<0.001) indicated that glomular filtration had an important effect on the Cl of ceftazidime. The Cl of ceftazidime correlated with the reciprocal of the serum concentration of creatinine (r = 0.72; p<0.001), suggesting that this compound may interfere with the renal Cl of ceftazidime.

The ceftazidime Cl increased from days 3 to 10 of life24 (Table 2). Such increases are due to an increase in GFR. The inulin Cl was 0.72 (day 3) and 0.91 ml/min (day 10; p<0.05). The Cl of ceftazidime correlated with GFR (r = 0.81; p< 0.001). This correlation indicates the important role of GFR in the clearance of ceftazidime. The Vd of ceftazidime decreased between days 3 and 10 of life. During the first week of life, there was a significant decrease in extracellular water. Ceftazidime is mainly distributed in the extracellular water component, and a decrease of extracellular water may cause a decrease in the Vd during this period. Postnatal exposure to indomethacin prevented the pharmacokinetic modification seen from days three to ten of life. This may be explained by renal function’s dependence on postnatal changes in extracellular water24 and the GFR impairment associated with indomethacin use.

Once-daily versus twice-daily administration of ceftazidime was studied by van den Anker et al.25 After 25 mg/kg twice daily, the trough concentration of ceftazidime was 42.0 ± 13.4 µg/ml, which was higher than the target value of 10 µg/ml. After once-daily dosing, the trough concentration was 13.1 ± 4.7 µg/ml, higher than the target value of 10 µg/ ml and higher than major neonatal pathogen MIC99 values such as those for Streptococcus agalactiae and Escherichia coli26,27 (MIC99 <0.25 µg/ml). Therefore, these authors suggested that once-daily 25 mg/kg ceftazidime is the appropriate therapeutic schedule for ceftazidime in the neonate. This administration schedule conflicts with the one suggested by Young and Mangum.9 They suggested administering 30 mg/kg of ceftazidime every 8 or 12 h according to the postmenstrual and postnatal age. When the postmenstrual age is >45 weeks, ceftazidime should be administered every eight hours.

Ceftriaxone. Ceftriaxone is contraindicated in neonates because it displaces bilirubin from albumin binding sites, resulting in a higher free bilirubin serum concentration with subsequent accumulation of bilirubin in the tissues.5,6 Even more dangerous is ceftriaxone’s interaction with calcium. This interaction precipitates calcium, which results in serious adverse effects.7,8

Nonetheless, the literature on ceftriaxone was reviewed to provide a comprehensive study of cephalosporin use. The kinetic parameters of ceftriaxone are summarized in Table 2. The MIC90 of ceftriaxone ranged between 0.06 and 2 µg/ml for Escherichia coli, Klebsiella species, Proteus species, Enterobacter species, and Staphylococcus aureus, whereas Enterococci and Listeria monocytogenes are resistant.28 Ceftriaxone reached CSF concentrations of 5.4 and 6.4 µg/ml after intravenous doses of 50 and 75 mg/kg, respectively, and the CSF-to-peak serum concentration was 2.2-2.3%.29 Sixty percent of ceftriaxone is eliminated by the kidneys, and Mulhall et al30 have described the pharmaco-kinetics of this drug in the neonate (Table 2).

McCracken et al31 stratified the kinetic parameters of ceftriaxone based on neonatal body weight. The longest t1/2, 7.7 to 8.4 h, was found in neonates weighing <1,500 g, compared with 5.2 to 7.4 h in those weighing >1,500 g. The shortest t1/2 (3.5 and 4.8 h) was found in two neonates aged 45 to 33 days, respectively. Vd ranged between 0.50 and 0.61 l/kg; the smaller value was found in larger and older infants. Of nine neonates who received multiple ceftriaxone doses of 50 mg/kg every 12 h, five showed evidence of drug accumulation in the plasma. The concentrations of ceftriazone increased from 20 to 208% (mean 82%) at 0.5 h and from 15 to 165% (mean 53%) at 6 h after dosing. The ceftriaxone concentration in randomly collected urine ranged from 113 to 3,350 µg/ml (median 618 µg/ml).

Young and Mangum9 suggested administering 50 mg/kg every 24 h. To treat meningitis, they suggested a 100-mg/kg loading dose and then 80 mg/kg once daily.

Cefoperazone. The kinetic parameters of cefoperazone are summarized in Table 2. Gestational age correlated with Cl (r = 0.67; p = 0.01) and with a constant rate of elimination32 (Ke; r = 0.57; p = 0.05), while t1/2 decreased with advancing gestational age33 (r = -0.81; p<0.001). Rosenfeld et al34 studied the pharmacokinetics of cefoperazone (50 mg/kg) in 25 infants with a postnatal age of 1 to 2 days. The neonates were divided into three groups according to their gestational age. These authors repeated the cefoperazone treatment in 14 neonates aged 5 to 7 days, and the kinetic parameters were similar to those obtained at a postnatal age of 1 to 2 days. The percentage of the cefoperazone dose excreted in the urine on days 1 and 2 after birth was highest in the most premature patients (55%) but was not statistically different from that of full-term infants (37%). In infants 5 to 7 days old, cefoperazone excretion decreased in the full-term neonates (27%) and was 55% in the most premature infants (p<0.03). These data suggest that cefoperazone is partially metabolized and that its rate of metabolism depends on neonatal maturation. In adults, 69% of cefoperazone administered orally is eliminated by hepatic routes.35

A study based on seven neonates with body weights ranging from 1,540 to 3,600 g determined that cefoperazone penetrates the CSF.34 The cefoperazone concentration (µg/ ml) in the CSF and serum was 5.3 ± 3.6 and 89 ± 58, respectively. The CSF-to-serum ratio was 10.9 ± 9.6% and ranged from 1.4 to 31.7%.

Ceftizoxime. The kinetic parameters of ceftizoxime are summarized in Table 2. The pharmacokinetics of ceftizoxime were studied in 52 infants whose postnatal age ranged from 0.1 to 189 days.36 t1/2 diminished steadily as the postnatal aged increased, whereas Cl showed the opposite trend. In this study, Vd remained relatively constant37, and ceftizoxime was excreted essentially unchanged via the kidney.36

Fourth-generation cephalosporins

Cefepime. The kinetic parameters of cefepime are summarized in Table 3. The serum creatinine concentration was negatively correlated (r = -0.79) with cefepime Cl in neonates.38 The serum concentration of creatinine was a strong predictor of cefepim Cl.38 The relationship between cefepime Cl and gestational age was not significant. The maturation of the renal excretory function is an important dosing determinant for cephalosporins, including cefepime. In premature infants, renal function is impaired. Because cefepime is mainly excreted unchanged, the premature and term neonates clear cefepime more slowly than more mature infants. In neonates, the cefepime Cl value was approximately 40% of that of more mature infants, which results in a longer t1/2 and a higher trough concentration. Vd was greater in infants with less than 30 weeks of postconceptional life.38 This is consistent with the greater total body water content in the extremely premature neonate.

Reed et al39 described the pharmacokinetics of cefepime in 37 infants and children aged between 2 months and 16 years. The data were grouped by age; the youngest patients ranged between two and six months of age, and the pharmacokinetic parameters of cefepime in these patients are reported in Table 3. Ninety percent of cefepime was recovered in the urine during 24-h urine collection; thus, the elimination of cefepime is in large part via the kidneys. The data for cefepime reveal disposition parameters similar to those of third-generation cephalosporins, including linearity over a broad dose range (250-2,000 mg), limited disposition and Cl mainly by the kidneys.

Lima-Rogel et al40 compared their own results on the pharmacokinetics of cefepime in neonates with those of Capparelli et al38 and Reed et al.39 The kinetic parameters of cefepime measured by Lima-Rogel et al40 and those of Capparelli et al38 were obtained in infants with similar demographic data, and t1/2 and Cl were comparable in these two studies. Reed et al39 described the pharmacoki-netics of cefepime in older infants and children. In this last study, t1/2 was one-half and Cl was double the values in the neonates.

Information on the penetration of cephalosporins in the CSF is limited. Table 4 summarizes the concentrations of cefotaxime, ceftazidime, ceftriaxone, cefoperazone, and cefepime in the CSF and serum and the CSF-to-serum ratio. Information on the penetration in the CSF is available only for these cephalosporins. A relevant CSF-to-serum ratio was observed for cefotaxime13 and it was 45 ± 12%. Another relevant penetration rate in the CSF was observed for cefoperazone,34 which was 10.9 ± 9.6%. This figure seems to be overestimated, as it ranged from 1.4% to 37.1%. The rate of penetration of cefepime in the CSF was variable. In two preterm infants, the CSF-to-serum ratio was 30% and 87%, whereas in 7 term infants, it ranged from 3.6% to 59%, with a mean ± SD of 16.7 ± 21.4%. Table 4 shows the data for all nine neonates.

DISCUSSION

A common feature in the reviewed literature is the remarkable interindividual variability of the kinetic parameters of cephalosporins in the neonate. Such variability is due to renal maturation, as cephalosporins are fairly water soluble and are mainly eliminated with the urine.

The pharmacokinetic parameters of cephalosporins are development dependent; the t1/2 of cefotaxime,13,14 ceftazidime24-26 and ceftizoxime37 decrease with increasing gestational and postnatal age, whereas Cl shows an opposite trend. With prenatal and postnatal maturation, GFR increases, and consequently, the Cl of drugs that are mainly eliminated by kidneys increases.41,42 Vd is only slightly influenced by neonatal maturation, although it tends to decrease with the maturation of the neonate. This has been observed for cefotaxime.20,24 Preterm infants have a higher water content than term infants,40 and because cephalos-porins are fairly water soluble, they are distributed at a larger volume in preterm infants than in term infants.

The hypersensitivity, resistance and toxicology of cepha-losporins have been studied in adults, but little is known about these characteristics in the neonate. Cephalosporin resistance may be related to the drug’s inability to reach its sites of action, alterations in the penicillin-binding proteins that are the targets of cephalosporins or hydrolysis of the β-lactam ring by β-lactamase.4 The most common side effects of cephalosporins are hypersensitivity reactions. The reactions appear to be identical to those caused by penicillins and may be related to the shared β-lactam structure of both groups of antibiotics. Immediate reactions, such as anaphy-laxis, bronchospasm, and urticaria, are typically observed.4 The cephalosporins have been implicated as potentially nephrotoxic agents, although they are not nearly as toxic to the kidneys as the aminoglycosides or polymyxins. In adults, renal tubular necrosis has followed the administration of cephaloridine in doses greater than 4 g/day.4

With the exception of cefotaxime15,16 and cefoperazone,34 which are partially metabolized, cephalosporins are mostly eliminated by the renal route, and maturation of the excretory renal function increases with development. Cl correlates with gestational age for cefotaxime,15 cefoper-azone,32 and ceftazidime.23 The Cl of cefotaxime is 2- to 3-fold higher in term than preterm infants.13,14 With increasing Cl, t1/2 clearly decreases. The Cl of ceftazidime negatively correlates with the reciprocal of serum concentration of creatinine; thus, the serum creatinine concentration negatively influences the Cl of ceftazidime.23

Little is known about the AUC, although this parameter for cefotaxime is similar in preterm and term infants.14 In contrast, the AUC for ceftazidime is greater in neonates with a gestational age <32 weeks than in term infants.21 This finding is due to the reduced renal excretory function in preterm infants compared with term infants. In premature subjects, the Cl of ceftazidime is reduced; therefore, the ceftazidime serum concentration slowly decreases, and AUC tends to increase.

Most of the available information about the kinetics of cephalosporins deals with the third generation of these antibiotics. A considerable body of information is available on cefotaxime, ceftazidime, and ceftriaxone.

The Cl of ceftazidime increases between days 3 and 10 of life.24 This increase is due to the increase in GFR. The Cl of ceftazidime is also correlated with GFR (r = 0.81; p<0.001). This correlation indicates the important effect of GFR on ceftazidime Cl. Intravenous administration of ceftazidime yields double the peak concentration of intramuscular administration.20

Ceftriaxone is active against Escherichia coli, Klebsiella species, Proteus species, Enterobacter species, and Staphylococcus aureus.28 Cefepime is a fourth-generation cephalosporin and little is known about this drug, as it is the latest cephalosporin to enter clinical use. Creatinine negatively influences the Cl of cefepime.39 Cefepime is primarily excreted unchanged. Preterm infants clear cefepime more slowly than full-term infants, as the renal excretory function rate is reduced in preterm subjects. Consequently, cefepime has a longer t1/2 and a higher trough concentration in the preterm infant than the term infant.38

Meningitis can be treated with cephalosporins, so the penetration of these drugs in the CSF is important. Information on the concentration of cephalosporins in CSF is available for cefotaxime, ceftazidime, ceftriaxone, cefo-perazone, and cefepime. Cefotaxime reaches a considerable CSF concentration, and the CSF-to-serum concentration ratio is relevant.13 Only one study is available on the penetration of cefepime in CSF.43 The concentration of this drug varies considerably in serum and CSF, and consequently, the CSF-to-serum ratio ranges widely.

The penetration of other cephalosporins into the CSF should be studied, and we feel that further research is required to ensure that the doses recommended for treating sepsis in neonates are entirely evidence-based.

ACKNOWLEDGEMENTS

This work was supported by the Ministry of University and Scientific and Technological Research (Rome, Italy).

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4. Petri WA Jr. Penicillins, cephalosporins, and other β-lactam antibiotics. In “The pharmacological basis of therapeutics”. Brunton LL, Lazo JS, Parker KL editors. 11th edition, 2006 pp 1127-1154. New York USA.

8. Park HZ, Lee SP, Schy AL. Ceftriaxone-associated gallbladder sludge. Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate. Gastroenterology. 1991;100:1665-70.

9. Young TE, Mangum B. Antimicrobials pp 1-99. Neofax: A Manual of Drugs used in neonatal care. Edition 23rd. Thomson Reuters, Montvale 07645, New Jersey, USA 2010.

10. Deguchi Y, Koshida R, Nakashima E, Watanabe R, Taniguchi N, Ichimura F, et al. Interindividual changes in volume of distribution of cefazolin in ewborn infants and its prediction based on physiological pharmacokinetic concepts. J Pharm Sci. 1988;77:674-8, doi: 10.1002/jps.2600770807.

12. Relund M, Pettay O. Pharmacokinetics and clinical efficacy of cefurox-ime in the newborn period. Proc roy Soc Med. 1977;70:179-82.

13. Kafetzis DA, Brater DC, Kapiki AN, Papas CV, Dellagrammatics H, Papadotos CJ. Treatment of severe neonatal infections with cefotaxime. Efficacy and pharmacokinetics. J Pediatr. 1982;100:483-9.

14. McCracken GH, Threlkeld NA, Thomas ML. Pharmacokinetics of cefotaxime in newborn infants. Antimicrob Agents Chemother. 1982;21:683-4.

19. Ahsman MJ, Wildschut ED, Tibboel D, Mathot RA. Pharmacokinetics of cefotaxime and desacetylcefotaxime in infants during extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 2010;54:1734-41, doi: 10.1128/AAC.01696-09.

20. Boccazzi A, Rizzo M, Caccamo ML, Assale BM. Comparison of the concentrations of ceftazidime in the serum of newborns infants after intravenous and intramuscular administration. Antimicrob Agents Chemother. 1983;24:955-6.

21. McCracken GH Jr, Threlkeld N, Thomas ML. Pharmacokinetics of ceftazidime in newborn infants. Antimicrob Agents Chemother. 1984;26:583-4.

22. Blumer JI, Aronoff SC, Myers CM, O’Brien CA, Klinger JD, Reed MD. Pharmacokinetics and cerebrospinal fluid penetration of ceftazidime in children with meningitis. Dev Pharmacol Ther. 1985;8:219-31.

24. van den Anker JN, Hop WC, Schoemaker RC, van der Heijden BJ, Neijens HJ, de Groot R. Ceftazidime pharmacokinetics in preterm infants: effect of postnatal age and postnatal exposure to indomethacin. Br J Clin Pharmacol. 1995;40:439-43.

25. van den Anker JN, Schoemaker RC, van der Heijden BJ, Broerse HM, Neijens HJ, de Groot R. Once-daily versus twice-daily administration of ceftazidime in the preterm infant. Antimicrob Agents Chemother. 1995; 39:2048-50.

26. Gentry LO. Antimicrobial activity, pharmacokinetics, therapeutic indications and adverse reactions of ceftazidime. Pharmacotherapy. 1985;5:254-67.

28. Bint AJ, Yeoman P, Kilburn P, Anderson E, Stansfield E. The in vitro activity of ceftazidime compared with that of the other cephalosporins. J Antimicrob Chemother. 1981;8(Supple B) :47-51.

29. Steele RW, Eyre LB, Bradsher RW, Weinfeld RE, Patel IH, Spicehandler J. Pharmacokinetics of ceftriaxone in pediatric patients with meningitis. Antimicrob Agents Chemother. 1983;23:191-4.

31. McCracken GH Jr, Siegel JD, Threlkeld N, Thomas M. Ceftriaxone pharmacokinetics in newborn infants. Antimicrob Agents Chemother, 1983;23:341-3.

39. Reed MD, Yamashita TS, Knupp CK, Veazey JM Jr, Blumer JL. Pharmacokinetics of intravenously and intramuscularly administered cefe-pime in infants and children. Antimicrob Agents Chemother. 1997;41:1783-7.

Received for publication on December 14, 2010; First review completed on January 21, 2011; Accepted for publication on March 2, 2011

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