Erdman - Cephalosporins

Question 1

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

Answer 1

PBP
bacteriocidal
time

Question 2

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.

Answer 2

• siderophore
• ferric Fe
• actively

Question 3

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

Answer 3

• 6
• stability

Question 4

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 ___

Answer 4

• B-lactamase
• 3rd, 4th, cefiderocol, combos, negative
• PBP
• porin, negative

Question 5

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.

Answer 5

• decreases, increase
• B-lactamase

Question 6

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)

Answer 6

• positive, aerobes
• Methicillin-susceptible Staphylococcus aureus (MSSA)
• negative, aerobes
• Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae

Question 7

1st Generation Cephalosporins (2)

Answer 7

• Cefazolin
• Cephalexin

Question 8

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

Answer 8

• positive
• negative
• cephamycins

Question 9

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)

Answer 9

• positive, aerobes
• negative aerobes

HEN-PEK
- H. influenzae
- Enterobacter
- Neisseria spp.
- P. mirabilis
- E. coli
- K. pneumoniae

Question 10

2nd Generation Cephalosporins (4)

Answer 10

• Cefuroxime
• Cefprozil

Cephamycins
- Cefoxitin
- Cefotetan

Question 11

Third Generation Cephalosporins

In general, are less active than 1st or 2nd generation agents against Gram ___ aerobes, but have enhanced activity against Gram ___ aerobes

Answer 11

• positive, negative

Question 12

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)

Answer 12

• 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

Question 13

3rd Generation Cephalosporins (3)

Answer 13

• Ceftriaxone
• Ceftazidime
• Cefpodoxime

Question 14

Fourth generation cephalosporins

___ is considered a 4th generation because:
- Expanded spectrum of activity, including many Gram-positive and Gram-negative aerobes
- NOT ___

Answer 14

Cefepime
- anaerobes

Question 15

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 ___

Answer 15

• PRSP
• Pseudomonas aeruginosa
• Enterobacter and E. coli

Question 16

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

Answer 16

cefepime, poor

Question 17

4th Generation Cephalosporin (1)

Answer 17

Cefepime

Question 18

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 ___

Answer 18

• PRSP
• MRSA
• P. aeruginosa

Question 19

Anti-MRSA Cephalosporin (1)

Answer 19

Ceftaroline

Question 20

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

Answer 20

carbapenemases

Question 21

T or F: Cefiderocol covers gram postitive and gram negative aerobes

Answer 21

FALSE
just negative

Question 22

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

Answer 22

• Streptococci
• Pseudomonas aeruginosa

Question 23

Cephalosporin with β-Lactamase Inhibitor (2)

Answer 23

• Ceftolozane-Tazobactam
• Ceftazidime-Avibactam

Question 24

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.

Answer 24

• ceftaroline
• Enterococcus
• Legionella pneumophila

Question 25

# 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)

Answer 25

- 1st, 2nd - cefuroxime, 3rd, 4th

Question 26

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 ___

Answer 26

- ceftriaxone, cefoperazone - ceftriaxone

Question 27

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)

Answer 27

- short - repeated - ceftriaxone

Question 28

# 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

Answer 28

- MSSA, Streptococci - Cefazolin - meningitis

Question 29

# 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.

Answer 29

- cefuroxime - cefoxitin, cefotetan, and cefmetazole, anaerobes, B. fragilis

Question 30

# 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

Answer 30

- negative, ceftazidime, cefoperazone - Ceftriaxone - Cefotaxime, ceftriaxone, PRSP

Question 31

# 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

Answer 31

- antipseudomonal

Question 32

# 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

Answer 32

MRSA

Question 33

# 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

Answer 33

Gram (-) only!

Question 34

# 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

Answer 34

negative

Question 35

# 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 ___ %).

Answer 35

- 1st, cefazolin, 10

Question 36

# ADVERSE EFFECTS Some cephalosporins have a 5-NMTT side chain (nitromethylthiotetrazole) that confers unique adverse effects (5) SE are ___ and a ___ reaction

Answer 36

- cefamandole, cefotetan, cefmetazole, cefoperazone, and moxalactam - Hypoprothrombinemia - Disulfiram

Question 37

# ADVERSE EFFECTS Hematologic - Coomb's positive hemolytic anemia - activation of complement system ➡ ___ , ___ , or ___

Answer 37

- leukopenia, neutropenia, thrombocytopenia

Question 38

# 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).

Answer 38

- ceftriaxone - Pseudomembranous colitis - status epilepticus

Question 39

# 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

Answer 39

- time, bacteriocidal - PBPs

Question 40

# Carbapenems MECHANISMS OF RESISTANCE - alterations to outer membrane ___ proteins - hydrolysis by ___ or ___ (KPC, OXA, others) enzymes - alterations in ___

Answer 40

- porin - B-lactamase, carbapenemase - PBPs

Question 41

# Carbapenem SOA The carbapenems are currently the most ___ spectrum antibiotics, displaying activity against many Gram ___ AND Gram ___ aerobes AND ___

Answer 41

- broad - positive, negative, anaerobes

Question 42

# 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 ___ )

Answer 42

- imipenem, doripenem - methicillin-susceptible Staphylococcus aureus (MSSA) - doripenem, meropenem - ESBL, AmpC - Enterobacterales - Pseudomonas aeruginosa, ertapenem

Question 43

# 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

Answer 43

just know that they are broad spectrum - gram +/- and aerobic and anaerobic

Question 44

T or F: carbapenems have activity against MRSA, VRE, C. diff, Stenotrophomonas maltophilia, Nocardia, and atypical bacteria

Answer 44

FALSE do not have activity against any of these

Question 45

T or F: there are oral carbapenems

Answer 45

FALSE

Question 46

# Carbapenemes - ___ dependent, - bacteriocidal but bacteriostatic against ___ spp.

Answer 46

- time - Enterococcus

Question 47

# 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

Answer 47

meropenem

Question 48

T or F: All carbapenems require dosage adjustment in patients with renal dysfunction

Answer 48

TRUE

Question 49

# 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

Answer 49

Imipenem cilastatin

Question 50

T or F: ertapenem has a longer half life than the other carbapenems

Answer 50

TRUE - 4 hrs vs 1 hr t1/2

Question 51

# 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

Answer 51

- polymicrobial - Ertapenem - nosocomial - ESBLs - KPC, Enterobacterales

Question 52

# 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

Question 53

# 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)

Answer 53

- bacteriocidal - negative

Question 54

# Monobactam MOR - hydrolysis by ___ enzymes (but relatively very stable) - alteration in ___ proteins in gram negative bacteria

Answer 54

- B-lactamse - porin

Question 55

# Monobactam SOA Gram ___ ___only - wide range - covers ~60% of ___ strains

Answer 55

negative aerobes P. aeruginosa

Question 56

T or F: aztreonam is only available PO

Answer 56

FALSE only IV

Question 57

T or F: Aztreonam DOES penetrate into the CSF, especially in the presence of inflamed meninges

Answer 57

TRUE

Question 58

# Monobactams T or F: Doses need to be adjusted in patients with renal insufficiency, and aztreonam is removed during hemodialysis

Answer 58

TRUE

Question 59

# 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 ___**

Answer 59

- negative, aerobes, P.aeruginosa - allergy

Question 60

# Monobactam AE - hypersensitivity, but can be used in pts with PCN allergy - GI - __ / __ / __ - Other: neutropenia, thrombocytopenia, eosinophilia, transient LFT increases, phlebitis, drug fever

Answer 60

- N/V/D