Cephalosporins Flashcards
Cephalosporin General Facts
Have some cross allergenicity with penicillins
Cross reactivity quoted at 10% but reasonable estimate is 3-5% but less for later generations
Be skeptical of nausea
Take hives and anaphylaxis seriously
Similar side chains may be responsible for cross reactivity
Generally more resistant to betalactamses than penicillins
Cephalosporinases exist and are becoming more prevalent (in contrast to penicillinases)
First Generation Cephalosporins
Oral
Cephalexin
Cefadroxil
IV
Cefazolin
Cephalothin
Used immediately prior to surgery to prevent surgical site infections; most commonly used class in the hospital Ideal because of spectrum, cheap, low incidence of adverse effects Useful for treating skin and skin structure infections
First Generation Cephalosporins Spectrum
Good
MSSA
Streptococci
Moderate
Some enteric GNRs
Poor Enterococci Anaerobes MRSA Pseudomonas
First Generation Cephalosporins Important Facts
Good alternatives to antistaphylococcal penicillins
Cause less phlebitis; infused less frequently
Unlike them, may not cross the blood brain barrier;
Should not be used in CNS infections
Good for Skin and skin structure infections Surgical prophylaxis (usually should not give more than one dose; giving more than 24 hours of therapy is rarely justified-does not lower infection rates but may select for more resistant organisms later in the hospital stay) Staphylococcal bloodstream infections Osteomyelitis Endocarditis (MSSA)
Second Generation Cephalosporins
Oral
Cefaclor
Cefprozil
Loracarbef
IV Cefoxitin Cefotetan Cefmetazole Cefonicid Cefamandole
Oral and IV
Cefuroxime
Better Gram- activity; somewhat weaker Gram+ activity but still used for these organisms
More stable against Gram- betalactamases and particular active against H. influenzae and N. gonorrhoeae
Most numerous cephalosporins but least utilized in the US
Second Generation Cephalosporins Spectrum
Good
Some enteric GNRs
Haemophilus
Neisseria
Moderate
Streptococci
Staphylococci
Anaerobes (only cefmetazole, cefotetan, cefoxitin)
Poor
enterococci
MRSA
Pseudomonas
Second Generation Cephalosporins Adverse Effects
Ceph with N-methylthiotetrazole (MTT) side chain can inhibit vitamin K production and prolong bleeding (cefmetazole, cefotetan, cefamandole)
Can also cause a disulfiram like reaction when given ethanol
Second Generation Cephalosporins Important Facts
Cephamycins (cefmetazole, cefotetan, cefoxitin)
Have activity against many anaerobes in GI tract
Cefoxitin and Cefotetan often used for surgical prophylaxis in abdominal surgery
Loracarbef is a carbacepbem
Do not cross the blood brain barrier well enough to be used in CNS infections (like the first gen ceph)
Good for Upper respiratory tract infections Community acquired pneumonia Gonorrhea Surgical prophylaxis (cephamycins)
Cephamycins have good intrinsic anaerobic activity but resistance is increasing in Bacteroides fragilis group infections
In surgical prophylaxis, limit duration after surgery
If infection develops, use an alternative (beta lactamase inhibitor combination or another Gram- agent with metronidazole)
Third Generation Cephalosporins
Greater Gram- coverage than 1G and 2G
Good strep activity but less staph than previous generations
Considered broad spectrum agents
Ceftriaxone Cefotaxime Ceftazidime Cefdinir Cefpodoxime Cefixime Ceftibuten
Third Generation Cephalosporins Spectrum
Good
Streptococci (ceftazidime is poor)
Enteric GNRs
Pseudomonas (only ceftazidime)
Moderate
MSSA (ceftazidime is poor)
Poor Enterococci Pseudomonas (except ceftazidime) Anaerobes MRSA
Third Generation Cephalosporins Adverse Effects
One of the classes with strongest association with Clostridium difficile associated diarrhea
Cefpodoxime has MTT side chain that can inhibit vitamin K production
Third Generation Cephalosporins Important Facts
Ceftazidime is unique
Is antipseudomonal
Lacks clinically useful activity against Gram+ organisms
Ceftriaxone, cefotaxime, ceftazidime cross the blood brain barrier effectively
Useful for CNS infections
Don’t use ceftazidime for community acquired meningitis where S. Pneumoniae predominates
Notorious for inducing resistance among GNRs
Too much broad spectrum usage can result in harder to treat infections
Ceftriaxone one time IM dose increased from 125 to 250mg for gonnorhea (drug of choice)
Should also receive azithromycin (empiric therapy for chlamydia and may reduce emergence of ceftriaxone resistance
Ceftriaxone has dual modes of elimination (renal and biliary excretion)
Does not need to renally adjusted but does effectively treat UTIs
Cefotaxime is safer than ceftriaxone for neonate for two reasons
- Interacts with calcium containing medications to form crystals; can precipitate in lungs and kidneys leading to fatalities
- Can lead to biliary sludging with resultant hyperbilirubinemia
Give higher doses of ceftriaxone (2-4g per day) for MSSA (especially invasive infections)
Need higher doses due to less activity against this organism
Ceftriaxone is a once daily drug for almost all indications except meningitis
2g IV q12H
High dose used for meningitis mainly and a few more indications
Use vancomycin and ampicillin if indicated
Good for Lower respiratory tract infections Pyelonephritis Nosocomial infections (ceftazidime) Lyme disease (ceftriaxone) Meningitis Gonorrhea Skin and skin structure infections Febrile neutropenia (ceftazidime)
Fourth Generation Cephalosporins
Cefepime
Broadest spectrum ceph
Cefazolin (1st) + Ceftazidime (3rd) = Cefepime (4th)
Has activity against Gram- (including Pseudomonas) and Gram+ organisms
Fourth Generation Cephalosporins Spectrum
Good MSSA Streptococci Pseudomonas Enteric GNRs
Moderate
Acinetobacter
Poor
Enterococci
Anaerobes
MRSA
Fourth Generation Cephalosporins Important Facts
May be associated with more neurotoxicity compared with other agents
May manifest as nonconvulsive status epilepticus
Can occur at any dose; still need to adjust dose in renal dysfunction
Good empiric choice for many nosocomial infections; overkill for community acquired infections
Deescalate if possible
Cefepime is better choice than ceftazidime for mono therapy of febrile neutropenia
Better Gram+ activity
May induce less resistance in GNRs
Initially meta analysis showed increased mortality compared with other drugs
FDA exonerated it
Good for Febrile neutropenia Nosocomial pneumonia Postneurosurgical meningitis Other nosocomial infections
Used primarily for nosocomial infections
Overkill for community acquired urinary tract and lower respiratory tract infections
Fifth Generation Cephalosporins
Ceftaroline
Anti-MRSA cephalosporin
Binds to the penicillin binding protein 2a of MRSA that has low affinity for other beta lactams
Has modest activity against E. faecalis
Less Gram- activity than Cefepime; similar to Ceftriaxone
Similar drug Ceftobiprole was removed from market
Fifth Generation Cephalosporins Spectrum
Good
MSSA; MRSA
Streptococci
Enteric GNRs
Moderate
E. faecalis
Poor P. aeruginosa E. faecium Acinetobacter Anaerobes
Fifth Generation Cephalosporins Important Facts
Initial indications for new drugs are usually low hanging fruit: skin and skin structure, community acquired pneumonia; other agents available
However did outperform Ceftriaxone in 2 of 3 studies in CA-pneumonia
Case series and retrospective studies have shown it to be successful in bloodstream infections, endocarditis, meningitis, osteomyelitis, HA-pneumonia
Approved for treatment of complicated skin and soft tissue infections
CA-pneumonia
Cephalosporin/Betalactamase Inhibitor Combinations
Ceftazidime/Avibactam
Ceftolozane/Tazobactam
Carbapenem resistance mostly seen in 3 organisms
Klebsiella pneumoniae
P. aeruginosa
A. baumannii
Avibactam is new kind of inhibitor; does not structurally resemble a beta lactam but binds to ases and makes them inert
Works against many ases produced by K. pneumo and P. aeruginosa
Restores activity of ceftazidime against many of these organisms
Ceftolozane is 3G ceph; evades many resistance mechanisms of P. aeruginosa
Neither of these drugs is good against Acinetobacter
Cephalosporin/Betalactamase Inhibitor Combinations Spectrum
Good Pseudomonas Enteric GNRs (ceftazidime/av > ceftolozane/tazo)
Moderate Some streptococci (ceftolozane/tazo)
Poor
Most Anaerobes
MRSA/MSSA
Acinetobacter
Cephalosporin/Betalactamase Inhibitor Combinations Important Facts
Both active against multi-drug resistant Pseudomonas
Only ceftazidime/avi active against carbapenem resistant Klebsiella and other enteric GNRs
Ceftolozane is minimally affected by many Pseudomonas resistance mechanisms including its ases; Tazobactam does little for this bug
Ceftazidime/avi relies on avi to inactivate Pesudomonas ases
Isolates of Pseudomonas may be resistant to one drug but susceptible to the other
There is substantial resistance to these agents by gut anaerobes unlike penicillin based beta lactamase inhibitors
If anaerobic involvement is suspected while on one of these agents, add metronidazole
Both good for
multi drug resistant Pseudomonas infections
Mixed aerobic/anaerobic infections
Infections caused by ESBL producing organisms
Intra-abdominal infections
Only Ceftazidime/avi
Carbapenem resistant Enterobacteriaceae infections
Carbapenems
Broadest spectrum agents
Have a beta lactam ring but are structurally different and unique from penicillins and cephs
Imipenem, Doripenem, and Meropenem have similar spectra
Ertapenem has important differences
Carbapenems Spectrum
Good MSSA Streptococci Anaerobes Enteric GNRs Pseudomonas and Acinetobacter (not Ertapenem) ESBL producing GNRs
Moderate
Enterococci (not Ertapenem)
Poor
MRSA
Penicillin resistant Streptococci
Carbapenems Important Facts
Imipenem has higher propensity to induce seizures (calculate appropriate doses in renal dysfunction; avoid in patient with meningitis- it can cross blood brain barrier more readily)
Imipenem is metabolized in kidney to a nephrotoxic product
Cilastatin blocks the renal dehydropeptidase that catalyze a this reaction and prevents the metabolism from occurring
I-C always coadministered together
Good choices for nosocomial infections, especially people who have received many other classes of antibiotics during their hospital stay
Ertapenem is the exception; poor choice for many nosocomial infections:
Nosocomial pneumonia where Pseudomonas and Acinetobacter are important pathogens
However, administered only once a day; may be a better choice for home infusion therapy for susceptible infections
May uncommonly elicit an allergic reaction in patients with a history of penicillin allergy
Cross reactivity most likely around 1%
Patients with a history of allergy to any drug are more likely to react to another one even if unrelated
CarbapenemASES are becoming more common
Most common in NE US; very common in some parts of the world
All good for
Mixed aerobic / anaerobic infections
Infections caused by ESBL producing organisms
Intra-abdominal infections
All except Ertapenem
Nosocomial pneumonia
Febrile neutropenia
Other nosocomial infections
Monobactams
Aztreonam
Only contains the four membered ring of the basic beta lactam structure
Seems to be safe to administer to patients with allergies to other beta lactams, except a specific allergy to ceftazidime
Both drugs share an identical side chain and spectra of activity (ceftolozane also has the side chain)
Monobactams Spectrum
Good
Pseudomonas
Most GNRs
Moderate
Acinetobacter
Poor
Gram+ organisms
Anaerobes
Monobactams Important Facts
Shares MOA and pharmacodynamic profile with other beta lactams
Often gets confused with aminoglycosides because of its spectrum; chemically unrelated and does not share their toxicities
Can be administered via inhalation in CF to prevent exacerbations of infection
Combining with other beta lactams not useful
Add a non beta lactam to empiric regimen for serious nosocomial infections
Good for
Gram- infections including Pseudomonas, especially in patients with history of beta lactam allergy
