Antimicrobial Drugs – Cephalosporins 4th Generation

Name of the Cephalosporins 4th Generation Drugs

• Cefeprime
• Cefepime
• Ceftaroline
• Ceftobiprole
• Ceftolozane

1.Cefeprime

Mechanism of Action

 Interferes with bacterial cell wall synthesis by inhibiting the final step in the crosslinking of peptidoglycan strands. Peptidoglycan makes cell membranes rigid and protective. Without it, bacterial cells rupture and die.

Pharmacokinetics

• Absorption: IM absorption rapid and complete
• Peak plasma time: 0.5-1.5 hr (IV); 1-2 hr (IM)
• Distribution: Penetrates into inflammatory fluid at concentrations ~80% of serum levels and into bronchial mucosa at concentrations ~60% of plasma levels; crosses blood-brain barrier
• Protein bound: 16-19%
• Vd: 16-20 L (adults)
• Metabolism: Minimally metabolized in liver
• Half-life: 2 hr
• Excretion: Urine (85% as unchanged drug)

Administration

• Don’t mix premixed solution with other drugs. 2Don’t use flexible container in series connections because of risk of air embolism.
• Obtain specimens for culture and sensitivity testing as needed before starting therapy.
• Don’t mix with ampicillin (at concentrations above 40 mg/ml), metronidazole, aminoglycosides, or aminophylline if ordered concurrently. Give each drug separately.
• For I.V. infusion, use small I.V. needle and infuse into large vein over 30 to 60 minutes.
• For I.M. administration, inject deep into large muscle.

Contraindications

Hypersensitivity to cephalosporins or penicillins

 Precautions:

• renal impairment, phenylketonuria
• history of GI disease
• elderly patients 
•  pregnant or breastfeeding patients
• Children

Adverse reactions

• CNS: headache, lethargy, paresthesia, syncope,seizures
• CV: phlebitis, hypotension, palpitations, chest pain, vasodilation, thrombophlebitis
• EENT: hearing loss
• GI: nausea, vomiting, diarrhea, abdominal cramps, oral candidiasis, pseudomembranous colitis
• GU: vaginal candidiasis, nephrotoxicity
• Hematologic: lymphocytosis, eosinophilia, bleeding tendency, hemolyticanemia, hypoprothrombinemia, neutropenia, thrombocytopenia, agranulocytosis, bone marrow depression
• Hepatic: hepatic failure, hepatomegaly
• Musculoskeletal: arthralgia
• Respiratory: dyspnea
• Skin: urticaria, maculopapular or erythematous rash, redness, swelling, induration
• Other: chills, fever, superinfection, pain at I.M. site, phlebitis at I.V. site, anaphylaxis, serum sickness

Patient monitoring

• Assess baseline CBC and kidney and liver function test results.
• Monitor for signs and symptoms of superinfection and other serious adverse reactions.
• Monitor for inflammation at infusion site.
• Be aware that cross-sensitivity to penicillins may occur.

Patient teaching

• Instruct patient to report reduced urinary output, persistent diarrhea, bruising, petechiae, or bleeding.
• Caution patient not to take herbs without consulting prescriber.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.

Nursing Considerations

• Use cefepime cautiously in patients with impaired renal function or a history of GI disease, particularly colitis. Also use cautiously in patients hypersensitive to penicillin because cross-sensitivity has occurred in about 10% of such patients.
• If possible, obtain culture and sensitivity test results, as ordered, before giving drug.
• For I.V. infusion, reconstitute using manufacturer’s guidelines. Give over 30 minutes.
• For I.M. injection, reconstitute 500-mg vial of drug with 1.3 ml of diluent, such as sterile water for injection (or 1-g vial with 2.4 ml of diluent). See drug guidelines for complete list of appropriate diluents.
• Be aware that an allergic reaction may occur a few days after therapy starts.
• Monitor BUN and serum creatinine levels for early signs of nephrotoxicity. Also monitor fluid intake and output; decreasing urine output may indicate nephrotoxicity. Be aware that unadjusted dosages of cefepime in renally impaired patients may cause myoclonus and seizures.
• Assess bowel pattern daily; severe diarrhea may indicate pseudomembranous colitis.
•   Assess for signs of superinfection, such as perineal itching, fever, malaise, redness, pain, swelling, drainage, rash, diarrhea, and cough or sputum changes.
• Assess for pharyngitis, ecchymosis, bleeding, and arthralgia; they may indicate a blood dyscrasia.
• Monitor patient for evidence of encepalopathy, such as changes in level of consciousness, myoclonus, and seizures. Patient will need immediate treatment, and the cefepime dosage will need to be adjusted or the drug discontinued.

2.Cefepime

Mechanism of Action

Interferes with bacterial cell wall synthesis by inhibiting the final step in the crosslinking of peptidoglycan strands. Peptidoglycan makes cell membranes rigid and protective. Without it, bacterial cells rupture and die.

Pharmacokinetics

• Absorption: IM absorption rapid and complete
• Peak plasma time: 0.5-1.5 hr (IV); 1-2 hr (IM)
• Distribution: Penetrates into inflammatory fluid at concentrations ~80% of serum levels and into bronchial mucosa at concentrations ~60% of plasma levels; crosses blood-brain barrier
• Protein bound: 16-19%
• Vd: 16-20 L (adults)
• Metabolism: Minimally metabolized in liver
• Half-life: 2 hr
• Excretion: Urine (85% as unchanged drug)

Administration

•   Don’t mix premixed solution with other drugs. 2Don’t use flexible container in series connections because of risk of air embolism.
• Obtain specimens for culture and sensitivity testing as needed before starting therapy.
• Don’t mix with ampicillin (at concentrations above 40 mg/ml), metronidazole, aminoglycosides, or aminophylline if ordered concurrently. Give each drug separately. For I.V. infusion, use small I.V. needle and infuse into large vein over 30 to 60 minutes.
• For I.M. administration, inject deep into large muscle.

Contraindications

Hypersensitivity to cephalosporins or penicillins

Precautions:

• renal impairment, phenylketonuria 
•  history of GI disease
• elderly patients
• pregnant or breastfeeding patients
• Children

Adverse reactions

• CNS: headache, lethargy, paresthesia, syncope,seizures
• CV: phlebitis, hypotension, palpitations, chest pain, vasodilation, thrombophlebitis
• EENT: hearing loss
• GI: nausea, vomiting, diarrhea, abdominal cramps, oral candidiasis, pseudomembranous colitis
• GU: vaginal candidiasis, nephrotoxicity
• Hematologic: lymphocytosis, eosinophilia, bleeding tendency, hemolytic anemia, hypoprothrombinemia, neutropenia, thrombocytopenia, agranulocytosis, bone marrow depression
• Hepatic: hepatic failure, hepatomegaly
• Musculoskeletal: arthralgia
• Respiratory: dyspnea
• Skin: urticaria, maculopapular or erythematous rash, redness, swelling, induration
• Other: chills, fever, superinfection, pain at I.M. site, phlebitis at I.V. site, anaphylaxis, serum sickness

Patient monitoring

• Assess baseline CBC and kidney and liver function test results.
• Monitor for signs and symptoms of superinfection and other serious adverse reactions.
• Monitor for inflammation at infusion site.
• Be aware that cross-sensitivity to penicillins may occur.

Patient teaching

• Instruct patient to report reduced urinary output, persistent diarrhea, bruising, petechiae, or bleeding.
• Caution patient not to take herbs without consulting prescriber.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.

Nursing Considerations

• Use cefepime cautiously in patients with impaired renal function or a history of GI disease, particularly colitis. Also use cautiously in patients hypersensitive to penicillin because cross-sensitivity has occurred in about 10% of such patients.
• If possible, obtain culture and sensitivity test results, as ordered, before giving drug.
• For I.V. infusion, reconstitute using manufacturer’s guidelines. Give over 30 minutes.
• For I.M. injection, reconstitute 500-mg vial of drug with 1.3 ml of diluent, such as sterile water for injection (or 1-g vial with 2.4 ml of diluent). See drug guidelines for complete list of appropriate diluents.
• Be aware that an allergic reaction may occur a few days after therapy starts.
• Monitor BUN and serum creatinine levels for early signs of nephrotoxicity. Also monitor fluid intake and output; decreasing urine output may indicate nephrotoxicity. Be aware that unadjusted dosages of cefepime in renally impaired patients may cause myoclonus and seizures.
• Assess bowel pattern daily; severe diarrhea may indicate pseudomembranous colitis.
• Assess for signs of superinfection, such as perineal itching, fever, malaise, redness, pain, swelling, drainage, rash, diarrhea, and cough or sputum changes.
•   Assess for pharyngitis, ecchymosis, bleeding, and arthralgia; they may indicate a blood dyscrasia.
• Monitor patient for evidence of encepalopathy, such as changes in level of consciousness, myoclonus, and seizures. Patient will need immediate treatment, and the cefepime dosage will need to be adjusted or the drug discontinued.

3.Ceftobiprole

Mechanism of Action

New generation of extended-spectrum cephalosporin with activity against clinically important gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP)

Pharmacokinetics

• Peak plasma concentration: 33 mcg/mL
• AUC(0-8h): 102 mcg⋅h/mL
• Protein bound: 16%
• Vd: 18 L
• Metabolism: Minimally metabolized
• Half-life: 3.3 hr
• Clearance: 4.98 L/hr
• Excretion: Urine 83%

Contraindications

History of severe hypersensitivity to ceftobiprole or other cephalosporins

Adverse Reactions/Side Effects

• GI: PSEUDOMEMBRANOUS COLITIS, diarrhea, nausea. 
• Derm: rash. 
• Hemat: hemolytic anemia. 
• Local: phlebitis at injection site. 
• Misc: HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLAXIS.

Precautions

Known hypersensitivity to other beta-lactams; Renal impairment (dosage reduction required for CCr ≤50 mL/min); Geri: dose adjustment may be necessary for age-related ↓ in renal function; OB: Use in pregnancy ..

4.Ceftaroline

Mechanism of Action

Beta-lactam cephalosporin with activity against aerobic and anaerobic gram-positive and aerobic gram-negative bacteria

Demonstrates activity in vivo against resistant methicillin-resistant Staphylococcus aureus (MRSA) strains and in vitro against vancomycin-resistant and linezolid-resistant S aureus

Pharmacokinetics

• Peak plasma concentration: 21.3 mcg/mL
• Peak plasma time: 1 hr
• Vd: 20.3 L
• Protein bound: 20%
• Metabolism: Ceftaroline fosamil converted to bioactive ceftaroline in plasma by phosphatase enzyme; undergoes hydrolysis
• Clearance: 9.6 L/hr
• Half-life: 2.6 hr
• Excretion: urine (88%)

Contraindications

Hypersensitivity to drug, excipients or other cephalosporins

Adverse Reactions/Side Effects

• GI: PSEUDOMEMBRANOUS COLITIS, diarrhea, nausea. 
• Derm: rash.
• Hemat: hemolytic anemia. 
• Local: phlebitis at injection site. 
• Misc: HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLAXIS.

Precautions

Known hypersensitivity to other beta-lactams; Renal impairment (dosage reduction required for CCr ≤50 mL/min); Geri: dose adjustment may be necessary for age-related ↓ in renal function; OB: Use in pregnancy ..

5.Ceftolozane

Mechanism of Action

Ceftolozane: Cephalosporin that has demonstrated potent in vitro activity against Pseudomonas aeruginosa

Pharmacokinetics

• Peak plasma time: 1.02 hr
• Peak plasma concentration: 65.7/17.8 mcg/mL (cIAI, cUTI); 105/26.4 mcg/mL (HABP/VABP)
• AUC: 186/35.8 mcg•h/mL (cIAI, cUTI); 392/73.3 mcg•h/mL (HABP/VABP)
• Protein bound: 16-21/30%
• Vd: 13.5/18.2 L
• Ceftolozane: Not metabolized to any appreciable extent
• Half-life: 2.77/0.91 hr
• Renal clearance (ceftolozane): 3.41-5.59 L/hr
• Ceftolozane: >95% excreted unchanged in urine

Contraindications

Hypersensitivity to any of the components

Side –Effects

• Hives
• difficulty breathing
• swelling of the face, lips, tongue, or throat
• severe stomach pain
• diarrhea that is watery or bloody (even if it occurs months after the last dose),
• little or no urination
• swelling in the feet or ankles
• tiredness
• shortness of breath
• sudden numbness,
• weakness, and
• problems with vision or speech

REFERENCES

1. Robert Kizior, Keith Hodgson, Saunders Nursing Drug handbook,1st edition 2024, Elsevier Publications. ISBN-9780443116070
2. McGraw Hill- Drug Handbook, Seventh Edition, 2013, McGraw Hill Education Publications,9780071799430.
3. April Hazard, Cynthia Sanoski, Davi’s Drug Guide for Nurses -Sixteenth Edition 2019, FA Davis Company Publications,9780803669451.
4. Jones and Bartlet, Pharmacology for Nurses, Second Edition, 2020, Jones and Bartlet Learning Publications, ISBN 9781284141986.
5. Nursebro.com, Search – Nursebro

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