Erdman - Cephalosporins Flashcards
MOA
Cephalosporins, like penicillins, interfere with cell wall synthesis by binding to and
inhibiting enzymes, called ___ , which are located in the cell wall
Cephalosporins, like all B-lactam antibiotics, are ___ in a ___ dependent manner
PBP
bacteriocidal
time
Cefiderocol MOA
Odd ball: Functions as a ___ and binds to extracellular free ___ and, in addition to passive diffusion via porin channels, is ___ transported across the outer cell membrane of bacteria into the periplasmic space using a siderophore iron uptake mechanism.
- siderophore
- ferric Fe
- actively
Cephalosporins contain a B-lactam ring where the 5-membered thiazolidine ring of the penicillins is replaced by a __ membered dihydrothiazine ring. This structural difference provides ___ against some B-lactamase enzymes that may render the penicillins inactive
- 6
- stability
MECHANISMS OF RESISTANCE
Production of ___ enzymes
- ___ and ___ generation cephalosporins, ___ and cephalosporin- ___ (ceph-βLI) are resistant to β-lactamase degradation of some Gram- ___ bacteria
Alterations in ___
Altered ___ proteins
- poor penetration though oter membrane in gram ___
- B-lactamase
- 3rd, 4th, cefiderocol, combos, negative
- PBP
- porin, negative
CLASSIFICATION AND SPECTRUM OF ACTIVITY
- In general, 1st generation cephalosporins have the best activity against Gram- positive aerobes with activity against a limited number of Gram-negative aerobes
- As you move down the generations to 2nd and 3rd, Gram-positive activity ___ with an ___ in activity against Gram-negative aerobes.
- Fourth generation cephalosporins are active against Gram-positive and Gram negative aerobes
- Greater ___ stability is demonstrated with higher
generation (3rd and 4th) cephalosporins, cefiderocol, and cephalosporin-βLI
combinations.
- decreases, increase
- B-lactamase
First Generation Cephalosporins
Excellent activity against Gram- ___ ___ ➡ the best activity of all cephalosporins
- ___
- Group streptococci
- Viridans streptococci
- Penicillin-susceptible Streptococcus pneumoniae (PSSP)
Also have activity against a limited number of Gram- ___ ___
- (PEK)
- positive, aerobes
- Methicillin-susceptible Staphylococcus aureus (MSSA)
- negative, aerobes
- Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae
1st Generation Cephalosporins (2)
- Cefazolin
- Cephalexin
Second Generation Cephalosporins (includes cephamycins and carbacephems)
In general, are slightly less active than 1st generation cephalosporins against Gram ___ aerobes (MICs are a little higher), but are more active against Gram ___ aerobes. Some 2nd generation agents ( ___ ) are active against anaerobes
- positive
- negative
- cephamycins
Second Generation Cephalosporins (includes cephamycins and carbacephems)
Gram ___ ___ - activity against the same bacteria as 1st generation agents, with MICs similar to or slightly higher than 1st generation agents. Cefprozil and cefuroxime are best for Gram-positives while cefoxitin and cefotetan are the worst
Gram ___ ___ - expanded coverage including: (HEN-PEK)
- ___ (only B-lactamase negative strains)
- Moraxella catarrhalis
- ___
- ___
Anaerobes - only ___ , ___ and ___ (the cephamycins) are active against anaerobes including Bacteroides fragilis (cefoxitin is the best but resistance is emerging)
- positive, aerobes
- negative aerobes
HEN-PEK
- H. influenzae
- Enterobacter
- Neisseria spp.
- P. mirabilis
- E. coli
- K. pneumoniae
2nd Generation Cephalosporins (4)
- Cefuroxime
- Cefprozil
Cephamycins
- Cefoxitin
- Cefotetan
Third Generation Cephalosporins
In general, are less active than 1st or 2nd generation agents against Gram ___ aerobes, but have enhanced activity against Gram ___ aerobes
- positive, negative
Third Generation Cephalosporins
Gram-positive aerobes - ___ and ___ have the best activity (less than 1st and 2nd generation cephalosporins) and are among the only cephalosporins that have activity against ____
Gram-negative aerobes - expanded spectrum of activity when compared to 2nd generation agents
- HEN-PECK-SSS (including B-lactamase producing strains)
- AND Pseudomonas aeruginosa - ONLY ___ and ___
Anaerobes - very limited activity (ceftizoxime has marginal activity)
- ceftriaxone and cefotaxime
- PRSP
HEN-PECK-SSS
- H. influenzae
- Enterobacter
- Neisseria spp.
- P. mirabilis
- E. coli
- Citrobacter spp.
- K. pneumoniae
- Seratia, Salmonella, Shigella
ceftazidime and cefoperazone
3rd Generation Cephalosporins (3)
- Ceftriaxone
- Ceftazidime
- Cefpodoxime
Fourth generation cephalosporins
___ is considered a 4th generation because:
- Expanded spectrum of activity, including many Gram-positive and Gram-negative aerobes
- NOT ___
Cefepime
- anaerobes
Fourth generation cephalosporins
Gram-positive aerobes: coverage similar to ceftriaxone ( ___ )
Gram-negative aerobes: displays similar coverage against Gram- negative aerobes as 3rd generation agents, including:
- ___
- B-lactamase producing ___ and ___
- PRSP
- Pseudomonas aeruginosa
- Enterobacter and E. coli
Fourth generation cephalosporins
Excellent stability against B-lactamase hydrolysis; also ___ is a relatively ___ inducer of extended spectrum B-lactamases (type 1/Amp C) in Gram negative aerobic bacteria
cefepime, poor
4th Generation Cephalosporin (1)
Cefepime
Anti-MRSA Cephalosporins - Ceftaroline
Gram-positive aerobes: coverage against Staphylococci and Streptococci similar to ceftriaxone (including ___ )
- AND has in vitro and clinical activity against ___
Gram-negative aerobes: coverage similar to 3rd generation agents like
ceftriaxone (HENPECKSSS)
- does NOT cover ___
- PRSP
- MRSA
- P. aeruginosa
Anti-MRSA Cephalosporin (1)
Ceftaroline
Cefiderocol
Gram-negative aerobes: coverage against Enterobacterales, P. aeruginosa, and A. baumannii, and S. maltophilia including some MDR strains that produce ESBLs {TEM, SHV, CTX-M, OXA}, AmpCs, and ___ {KPCs, OXA-48, VIM and NDM-1}
NO GRAM POSITIVE
carbapenemases
T or F: Cefiderocol covers gram postitive and gram negative aerobes
FALSE
just negative
Ceftolozane-tazobactam
Gram-positive aerobes: coverage against ___
Gram-negative aerobes: coverage similar to cefepime (HENPECKSSS and more), but includes some ESBL-producing Gram negative bacteria; also covers some AmpC-producing ___
- for Ceftazidime-avibactam: and some KPC-producing and OXA-48 producing Enterobacterales
- Streptococci
- Pseudomonas aeruginosa
Cephalosporin with β-Lactamase Inhibitor (2)
- Ceftolozane-Tazobactam
- Ceftazidime-Avibactam
SoA
Overall, cephalosporins are NOT ACTIVE against:
- methicillin-resistant Staphylococcus aureus (MRSA) - except ___
- coagulase-negative staphylococci
- __ spp.
- Listeria monocytogenes
- ___
- Clostridium difficile
- Stenotrophomonas maltophilia (except ceftazidime and cefiderocol)
- Campylobacter jejuni.
- ceftaroline
- Enterococcus
- Legionella pneumophila
CSF?
- adequate concentrations in the CSF are NOT obtained with ___ and most ___ generation cephalosporins or the β-lactamase inhibitors.
- therapeutic concentrations of parenteral ___ , ___ , and ___ generation cephalosporins are attained in the CSF (especially in the presence of inflamed meninges)
- 1st, 2nd
- cefuroxime, 3rd, 4th
Most cephalosporins are eliminated unchanged by the kidneys via glomerular
filtration and tubular secretion and require dose adjustment in renal
insufficiency. The exceptions include ___ and ___, which are eliminated by the biliary system and the liver, respectively
Most cephalosporins are removed during hemodialysis and require supplemental
dosing after a hemodialysis procedure, with the exception of ___
- ceftriaxone, cefoperazone
- ceftriaxone
Most cephalosporins have relatively ___ elimination half-lives (< 2 hours), and require ___ daily dosing (3 to 4 times daily) to maintain therapeutic serum concentrations
Exceptions include:
- ___ (8 hours)
- cefonicid (4.5 hours)
- cefotetan (3.5 hours)
- cefixime (3.7 hours)
- short
- repeated
- ceftriaxone
CLINICAL USES - 1st gen
- oral - mild-moderate skin, UTI
- Treatment of infections due to ___, Group and viridans ___ such as skin/soft tissue infections, septic arthritis, osteomyelitis, and endocarditis
- ___ is the drug of choice for surgical prophylaxis
- should NOT be used for ___
- bacteremia (IV)
positive = MSSA, negative = PEK
- MSSA, Streptococci
- Cefazolin
- meningitis
CLINICAL USES - 2nd gen
- oral = mild-moderate skin, UTI
- although ___ does penetrate the CSF, adequate bactericidal activity is not routinely achieved so that it is no longer recommended for the treatment of meningitis.
- the cephamycins ( ___ , ___ , and ___ ), have activity against Gram-negative aerobes and ___, including ___, and are useful for surgical prophylaxis in abdominal/pelvic procedures and for the treatment of polymicrobial infections such as intraabdominal infections (diverticulitis, appendicitis, bowel perforation), pelvic infections (pelvic inflammatory disease), and skin and soft tissue infections in patients with
diabetes.
- cefuroxime
- cefoxitin, cefotetan, and cefmetazole, anaerobes, B. fragilis
Clinical Uses - 3rd Gen
- Due to expanded activity against Gram-negative aerobes, parenteral 3rd generation cephalosporins are used for the treatment of bacteremia, pneumonia, complicated urinary tract infection, peritonitis, intraabdominal infections, skin and soft tissue infections, bone and joint infections, and meningitis (those that penetrate the CSF) caused by Gram ___ bacteria (including nosocomial infections). If Pseudomonas aeruginosa is known or suspected, ___ or ___ should be used. If anaerobes are known or suspected, metronidazole or clindamycin should be added.
- ___ is used as a single IM dose for uncomplicated gonorrhea
- ___ and ___ have good activity against Gram-positive aerobes, and may be used for the treatment of infections due to Group streptococci, viridans streptococci (endocarditis), and ___ (meningitis, pneumonia). Ceftriaxone is often
used for outpatient parenteral therapy in appropriate situations
- negative, ceftazidime, cefoperazone
- Ceftriaxone
- Cefotaxime, ceftriaxone, PRSP
Clinical Uses - 4th Gen
Cefepime is used for the treatment of community- and hospital-acquired
pneumonia, bacteremia, uncomplicated and complicated urinary tract
infections, skin and soft tissue infections, intraabdominal infections, and
empiric therapy for febrile neutropenia. Cefepime also has ___ activity. If anaerobes are known or suspected, metronidazole or clindamycin
should be added
- antipseudomonal
Clinical Uses - Anti-MRSA cephalosporin - Ceftaroline
Ceftaroline is currently FDA-approved for the treatment of skin and soft tissue infections (including those caused by ___ ) and community- acquired bacterial pneumonia
MRSA
Clinical Uses: Cefiderocol
Cefiderocol is currently FDA-approved for the treatment of complicated
urinary tract infections (including pyelonephritis) and hospital acquired
bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia
(VABP) in adult patients due to multidrug resistant Gram negative bacteria
who have limited or no therapeutic options
Gram (-) only!
Clinical Uses: Cephalosporin-β-lactamase inhibitor combination
Ceftazidime-avibactam and ceftolozane-tazobactam are FDA-approved for the
treatment of complicated UTI (including pyelonephritis), complicated IAI (with metronidazole), and HABP/VABP.
- Both are expensive (Avycaz $1,194/day, Zerbaxa $460-$920/day)
- use limited to infections caused by resistant Gram ___ bacteria (ESBL/AmpC {both} or KPC/OXA-48
{Avycaz}producing bacteria), where appropriate
negative
ADVERSE EFFECTS
Hypersensitivity
- Cross reactivity between penicillins and cephalosporins is associated with similarities in the R1 side chain
- The rate of cross-reactivity is estimated to be 1 to 5%
- ___ generation cephalosporins (except ___ because it has a unique R1 side chain) demonstrate the highest risk (up to ___ %).
- 1st, cefazolin, 10
ADVERSE EFFECTS
Some cephalosporins have a 5-NMTT side chain (nitromethylthiotetrazole) that
confers unique adverse effects (5)
SE are ___ and a ___ reaction
- cefamandole, cefotetan, cefmetazole, cefoperazone, and moxalactam
- Hypoprothrombinemia
- Disulfiram
ADVERSE EFFECTS
Hematologic
- Coomb’s positive hemolytic anemia
- activation of complement system ➡ ___ , ___ , or ___
- leukopenia, neutropenia, thrombocytopenia
ADVERSE EFFECTS
GI
- Transient increases in liver enzymes.
- Biliary sludging – especially with ___ therapy (especially in neonates)
- N/V
- ___ ___ (Clostridium difficile colitis) Some cephalosporins may cause diarrhea that is not due to C. difficile.
- Precipitation of ceftriaxone with IV calcium products – avoid coadministration.
Other adverse effects include phlebitis; drug fever; interstitial nephritis (rare); neurotoxicity such as seizures, encephalopathy, nonconvulsive ___ ___ (cefepime, ceftazidime, cefiderocol).
- ceftriaxone
- Pseudomembranous colitis
- status epilepticus
Carbapenem MOA
Like other B-lactam antibiotics, carbapenem antibiotics display ___ dependent ___ activity (except against ___ )
- Cause bacterial cell death by covalently binding to ___ that are involved in the biosynthesis of bacterial cell walls
- time, bacteriocidal
- PBPs
Carbapenems MECHANISMS OF RESISTANCE
- alterations to outer membrane ___ proteins
- hydrolysis by ___ or ___ (KPC, OXA, others) enzymes
- alterations in ___
- porin
- B-lactamase, carbapenemase
- PBPs
Carbapenem SOA
The carbapenems are currently the most ___ spectrum antibiotics, displaying
activity against many Gram ___ AND Gram ___ aerobes AND ___
- broad
- positive, negative, anaerobes
Carbapenem SOA - aerobes
Gram-positive aerobes - ___ and ___ exhibit the best activity
- Group streptococci
- Viridans streptococci
- penicillin-susceptible Streptococcus pneumoniae (PSSP)
- Enterococcus faecalis only (imipenem, most strains of E. faecium are resistant)
- ____
Gram-negative aerobes – ___ and ___ are the best
- carbapenems display activity against B-lactamase producing strains
- DRUGS OF CHOICE for ___ and ___ producing bacteria
- Meropenem-vaborbactam and imipenem-relebactam also have activity against KPC-producing ___
- cover ___ and Acinetobacter spp (not ___ )
- imipenem, doripenem
- methicillin-susceptible Staphylococcus aureus (MSSA)
- doripenem, meropenem
- ESBL, AmpC
- Enterobacterales
- Pseudomonas aeruginosa, ertapenem
Carbapenem SOA - Anaerobes
Gram-positive anaerobes
- Peptostreptococcus spp
- Peptococcus spp
- Clostridium perfringens and tetani
Gram-negative anaerobes
- Bacteroides fragilis
- Bacteroides vulgatus
- Bacteroides distasonis
- Bacteroides thetaiotamicron
- Bacteroides ovatus
- Prevotella bivia
- Fusobacterium spp
- Veillonella parvula
just know that they are broad spectrum
- gram +/- and aerobic and anaerobic
T or F: carbapenems have activity against MRSA, VRE, C. diff, Stenotrophomonas maltophilia, Nocardia, and atypical bacteria
FALSE
do not have activity against any of these
T or F: there are oral carbapenems
FALSE
Carbapenemes
- ___ dependent,
- bacteriocidal but bacteriostatic against ___ spp.
- time
- Enterococcus
CSF?
___ penetrates into the CSF better than imipenem and ertapenem, with CSF concentrations up to 52% of simultaneous serum concentrations in patients with inflamed meninges
meropenem
T or F: All carbapenems require dosage adjustment in patients with renal
dysfunction
TRUE
Carbapenems
___ undergoes hydrolysis in the kidney by an enzyme called dihydropeptidase (DHP) to microbiologically inactive and potentially nephrotoxic metabolites. A DHP inhibitor called ___ is added to commercially-available preparations of imipenem to prevent renal metabolism and protect against potential nephrotoxicity
Imipenem
cilastatin
T or F: ertapenem has a longer half life than the other carbapenems
TRUE
- 4 hrs vs 1 hr t1/2
Clical Uses: Carbapenems
The carbapenems are very broad-spectrum antibiotics that are typically used for ___ infections where they can be employed as monotherapy including intraabdominal infections or skin and skin structure infections in diabetic patients
- ___ does not have activity against Pseudomonas aeruginosa
Empiric therapy for ___ infections
Infections due to resistant Gram-negative bacteria, especially those organisms that produce ___ or type 1/class C/AmpC β-lactamase enzymes
Complicated urinary tract infections including pyelonephritis caused by ___ -
producing ___ -meropenem/vaborbactam and imipenem-
relebactam
- polymicrobial
- Ertapenem
- nosocomial
- ESBLs
- KPC, Enterobacterales
ADVERSE EFFECTS - Carbapenems
Hypersensitivity
Gastrointestinal
CNS – direct toxic effect
- Insomnia, agitation, confusion, dizziness, hallucinations, and depression
- ___
- risk factors: preexisting CNS disorders, high doses, presence of renal dysfunction
Monobactams MOA
Like bicyclic B-lactam antibiotics, aztreonam is ___ because of its ability to bind to and inhibit PBPs
- Aztreonam binds preferentially to PBP-3 in aerobic Gram ___ bacill (poor affinity for Gram positive anaerobic)
- bacteriocidal
- negative
Monobactam MOR
- hydrolysis by ___ enzymes (but relatively very stable)
- alteration in ___ proteins in gram negative bacteria
- B-lactamse
- porin
Monobactam SOA
Gram ___ ___only
- wide range
- covers ~60% of ___ strains
negative aerobes
P. aeruginosa
T or F: aztreonam is only available PO
FALSE
only IV
T or F: Aztreonam DOES penetrate into the CSF, especially in the presence of inflamed meninges
TRUE
Monobactams
T or F: Doses need to be adjusted in patients with renal insufficiency, and aztreonam is removed during hemodialysis
TRUE
Clinical Uses: Monobactams
- Aztreonam can only be used for the treatment of infections caused by Gram ___ ___ (including ___ )
- especially useful for the treatment of Gram-negative infections in patients with a history of a severe penicillin or β-lactam ___
- negative, aerobes, P.aeruginosa
- allergy
Monobactam AE
- hypersensitivity, but can be used in pts with PCN allergy
- GI - __ / __ / __
- Other: neutropenia, thrombocytopenia, eosinophilia, transient LFT increases, phlebitis, drug fever
- N/V/D
