A presentation I gave during an internship/Advanced Pharmacy Practice Experience (APPE) in specialty pharmacy at a medical practice.

1. The Pharmacology of Cephalosporins:
A Practical Guide
Paul Pasco, PharmD Candidate
UTHSC College of Pharmacy
Friday, November 19, 2021 1
Source: The End is Nigh: Bioethics and Antibiotic Resistance

2. Objectives
Describe the pharmacology of the cephalosporins,
including:
• Chemical structure
• Mechanism of action
• Available agents, general characteristics (e.g., spectrum of
activity), and niches of each functional class (“generation”)
• Efficacy/toxicity monitoring parameters, ADRs, and example
contraindications
• High-yield and actionable counseling points
2

3. INTRODUCTION
3
Source: The Petri Dish: Where Science Hits the Headlines

4. Presentation Highlights
Antibiotic = A substance that kills or inhibits the growth of bacteria
• Bactericidal = Kills
• Bacteriostatic = Inhibits growth
Cephalosporins = SUBCLASS of the larger beta-lactam class of antibiotics
• Semisynthetic in origin
• Generally, more resistant to beta-lactamases than the penicillin subclass
Some of the most commonly used members of this subclass:
• Cefazolin (Ancef®)
• Cephalexin (Keflex®)
• Ceftriaxone (Rocephin®)
• Cefdinir (Omnicef®)
• Cefepime (Maxipime®) 4

5. Relationship to Other Beta-Lactams
5
Beta-Lactams
Penicillins Cephalosporins Carbapenems
Monobactams
(aztreonam)

6. PHARMACOLOGY
6
Source: PharmaFactz

7. Chemical Structure
7
Source: New Health Advisor: Third Generation Cephalosporin
• Cephalosporins
• 6-membered ring
fused with a 4-
membered ring
• “House with a
basement, garage,
and satellite dish.”

8. Mechanism of Action
All beta-lactams, including cephalosporins, inhibit
transpeptidases
• Transpeptidases form cross-links for peptidoglycan in the bacterial cell wall
• Without transpeptidase activity, cell wall formation stops ➔ contents spill
out of cell ➔ bactericidal
Mechanism is selective for bacterial cells only, compared to
other classes of antibiotics (e.g., aminoglycosides)
Time-dependent bactericidal activity
• Time above MIC (T > MIC)
• Time where the serum level ≥ MIC
• Extended/continuous infusions sometimes utilized for inpatients (versus
shorter dosing intervals)
8
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397
Source: The Vaccine and Stockholm Syndrome

9. Functional Classes (“Generations”)
9
In general, decreasing Gram + and increasing Gram – coverage, as you move up the
generations in chronological order (with some exceptions)
Source: Cephalosporin Antibiotic Mnemonic Made Easy: Generation Drug List, Classes, Coverage, Examples — EZmed

10. First-Generation Cephalosporins
Members of this generation include:
• Cefazolin (Ancef®, Kefzol®) ➔ IV
• Cephalexin (Keflex®) ➔ PO
• Cefadroxil (Duricef®) ➔ PO
• Cephalothin (Keflin®) ➔ IV
Characteristics of class:
• Excellent Gram + coverage (MSSA, strep)
• Partial Gram – coverage of some enteric GNRs (E. coli, Proteus, and Klebsiella ➔ EPK)
• IV members produce less phlebitis and are infused less frequently compared to the antistaphylococcal penicillins
• Do NOT cross the BBB; cannot be used in infections of the CNS
Niches:
• Surgical prophylaxis
• SSTIs
• MSSA septicemia
• Osteomyelitis
• MSSA endocarditis
10
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397

11. Second-Generation Cephalosporins
Members of this generation
include:
• Cefuroxime (Ceftin®) ➔PO, IV
• Cefoxitin (Mefoxin®) ➔ IV
• Cefotetan (Cefotan®) ➔ IV
• Ceprozil (Cefzil®) ➔ PO
• Loracarbef (Lorabid®) ➔ PO
• Cefmetazole (Zefazone®) ➔ IV
• Cefonicid (Monocid®) ➔ IV
• Cefamandole (Mandol®) ➔ IV
• Cefaclor (Ceclor®) ➔ PO
Characteristics of class:
• Weaker Gram + activity,
stronger Gram – activity than 1st
generation agents
• Do NOT cross the BBB; cannot
be used in infections of the CNS
• More stable against Gram –
beta-lactamases than 1st
generations agents
• Greatest number of drugs in this
generation but the least utilized
• Dilsulfiram-like reaction with
cefamandole, cefmetazole, and
cefotetan when used
concurrently with ethanol ➔
AVOID
Niches:
• Haemophilus influenzae,
Neisseria gonorrhoeae
• URTIs, CAP, gonorrhea, surgical
prophylaxis (cefotetan, cefoxitin,
and cefuroxime)
11
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397

12. Third-Generation Cephalosporins
Members of this generation include:
• Ceftriaxone (Rocephin®) ➔ IV, IM
• Cefotaxime (Claforan®) ➔ IV
• Ceftazidime (Fortaz®, Tazicef®) ➔ IV
• Cefdinir (Omnicef®) ➔ PO
• Cefpodoxime (Vantin®) ➔ PO
• Cefixime (Suprax®) ➔ PO
• Ceftibuten (Cedax®) ➔ PO
Characteristics of class:
• Considered broad spectrum agents
• Weaker Gram + activity, stronger
Gram – activity than 1st and 2nd
generation agents
• Most have good activity against
strep but less activity against staph
versus 1st and 2nd generation agents
• Strong association with
Clostridioides difficile infection
• Some cross the BBB and can be
used for infections of the CNS
(ceftriaxone, cefotaxime, and
ceftazidime)
• Ceftazidime ➔ covers
Pseudomonas but no Gram +
activity
Niches:
• Pseudomonas, febrile neutropenia,
other nosocomial infections
(ceftazidime)
• Lower RTIs
• Pyelonephritis
• Lyme disease (ceftriaxone)
• SSTIs
• Meningitis
• Gonorrhea
12
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397

13. Fourth-Generation Cephalosporins
Only 1 agent available: cefepime (Maxipime®)
• IV only
Characteristics of class:
• Broadest spectrum cephalosporin
• Excellent Gram +, Gram –, and Pseudomonas activity
• Cefepime may be more neurotoxic
• Nonconvulsive status epilepticus
• May occur at any dose but more likely with renal dysfunction
Niches:
• Good for empiric coverage of nosocomial infections; deescalate following C&S
• MSSA, strep, Pseudomonas, enteric GNRs (EPK, others)
• Febrile neutropenia
13
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397

14. “Fifth-Generation”/Anti-MRSA Cephalosporins
• Only 1 available: ceftaroline fosamil (Teflaro®)
• IV only
• Characteristics of class:
• Lower Gram – activity than cefepime (4th generation)
• Exception
• Similar Gram – activity to ceftriaxone (3rd generation)
• Exception
• Covers MSSA, MRSA, strep, and enteric GNRs ➔ EPK, others
• Niches:
• Treatment of MRSA unresponsive to other therapies
• Newer agent; full utility still being elucidated
• Indicated for complicated SSTIs, CAP
14
Source: Superbug MRSA
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397

15. Other Cephalosporins
•3rd generation cephalosporin plus a beta-lactamase inhibitor
•The beta-lactamase inhibitor restores the activity of ceftolozane in organisms that produce many beta-lactamases
•Effective against mixed aerobic/anerobic infections, Pseudomonas, GNRs, and ESBLs
Ceftolozane + tazobactam (Zerbaxa®) ➔ IV only
•3rd generation cephalosporin plus a beta-lactamase inhibitor
•Avibactam, a beta-lactamase inhibitor, binds beta-lactamases and inactivates them, preventing breakdown of ceftazidime
•Effective against mixed aerobic/anerobic infections, Pseudomonas, Klebsiella, GNRs, carbapenem-resistant GNRs, and ESBLs
Ceftazidime + avibactam (Avycaz®) ➔ IV only
•Similar to ceftazidime (3rd generation) and cefepime (4th generation) in structure
•Novel MOA
•Utilizes iron uptake mechanisms to permeate bacteria
•Causes cell lysis and death in the same manner as other cephalosporins
•Stable against ALL known beta-lactamases
•Indicated for complicated UTIs and pyelonephritis secondary to GNRs, Pseudomonas in patients who have limited or no alternative
options for treatment
•Increase in all-cause mortality when used in a multidrug regimen (often containing colistin) in patients with carbapenem-resistant
Gram – infections
Cefiderocol (Fetroja®) ➔ IV only
15
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397
Shionogi & Co., Ltd. Highlights of Prescribing Information: Fetroja (Cefiderocol). Shionogi & Co., Ltd.; 2020. Accessed November 18, 2021. https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf
Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. 2019;79(3):271-289. doi:10.1007/s40265-019-1055-2

16. Efficacy/Toxicity Monitoring Parameters
Resolution of s/sx of infection
• If patient does not improve after several days of empiric treatment, agent is likely ineffective
Renal function
• Almost universally renally eliminated and require renal dose adjustments based on level of dysfunction (exception: ceftriaxone)
• Accumulation with impaired renal function ➔ seizures
Rash
• Very likely NOT indicative of a true allergy to cephalosporins (and beta-lactams in general), but assess the patient’s prior history
when dispensing or before IV administration
• May be mild and self-limiting
• Can more rarely progress to a blistering skin rash (SJS)
Concomitant medications
• Avoid ceftriaxone with medications that contain calcium in neonates ➔ can precipitate in lungs and kidneys
Age
• Ceftriaxone is contraindicated in neonates due to biliary sludging ➔ increased risk of gallstones, acute pancreatitis, and acute
cholangitis, sometimes requiring a cholecystectomy
16
Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed November 16, 2021. vbk://9781284129397
Shaffer EA. Gallbladder sludge: what is its clinical significance? Current Gastroenterology Reports. 2001;3(2):166-173. doi:10.1007/s11894-001-0015-6

17. COUNSELING POINTS
17
Source: ASHP Online Training

18. Counseling Points
• Take the full course of the drug
• Do NOT skip doses if you feel better
• If you do not take the full prescription as written, the bug may come back
• Take the correct dose
• Do NOT use household teaspoons or tablespoons to measure liquid doses
• Use a graduated, clearly marked dose cup or oral syringe to measure liquid preparations
• Antibiotics ONLY treat BACTERIAL infections
• N/V/D
• Take with food to reduce GI upset
• Mild, self-limiting rashes
• Can progress up to SJS (rarely); assess if patient is at risk based on history
• Ensure patient is aware of storage requirements for liquid antibiotics
• Most liquid cephalosporin preparations require refrigeration (e.g., cephalexin, cefuroxime,
others)
• Liquid preparations of cefdinir should NOT be refrigerated
18

19. QUESTIONS?
19

20. REFERENCES
20
1. Shionogi & Co., Ltd. Highlights of Prescribing Information: Fetroja (Cefiderocol). Shionogi & Co., Ltd.; 2020.
Accessed November 18, 2021. https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf
2. Zhanel GG, Golden AR, Zelenitsky S, et al. Cefiderocol: A Siderophore Cephalosporin with Activity Against
Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs. 2019;79(3):271-289.
doi:10.1007/s40265-019-1055-2
3. Shaffer EA. Gallbladder sludge: what is its clinical significance? Current Gastroenterology Reports.
2001;3(2):166-173. doi:10.1007/s11894-001-0015-6
4. Gallagher J. Antibiotics Simplified, 4th Edition. 4th ed. Jones & Bartlett Learning; 2016:78-98. Accessed
November 16, 2021. vbk://9781284129397

21. The Pharmacology of Cephalosporins:
A Practical Guide
Paul Pasco, PharmD Candidate
UTHSC College of Pharmacy
Friday, November 19, 2021 21
Source: The End is Nigh: Bioethics and Antibiotic Resistance