cephalosporins, carbapenems and monobactams

Question 1

1st gen cephalosporins

Answer 1

cefazolin, cephalexin

Question 2

2nd gen cephalosporins

Answer 2

Cefuroxime, Cefoxitin, Cefotetan, Cefprozil

Question 3

3rd gen cephalosporins

Answer 3

Ceftriaxone, Ceftazidime, Cefpodoxime

Question 4

4th gen cephalosporins

Answer 4

Cefepime

Question 5

anti-MRSA cephalosporins

Answer 5

Ceftaroline

Question 6

cephalosporins w B-lactamase inhibitor

Answer 6

Ceftolozane-Tazobactam, Ceftazidime-Avibactam

Question 7

carbapenems

Answer 7

Imipenem, Meropenem, Ertapenem, Doripenem

Question 8

monobactam

Answer 8

aztreonam

Question 9

cephalosporin chemistry

Answer 9

Cephalosporins contain a β-lactam ring where the 5-membered thiazolidine ring of the penicillins is replaced by a 6-membered dihydrothiazine ring. **This structural difference provides stability against some B-lactamase enzymes that may render the penicillins inactive.
Structural modifications at position 7 of the B-lactam ring are associated with changes in antibacterial activity, while changes at position 3 of the dihydrothiazine ring are associated with changes in the pharmacokinetic properties of the cephalosporins.
Cephamycins are cephalosporins with a methoxy group at position 7 of the B-lactam ring, which confers activity against anaerobes such as Bacteroides spp.

Question 10

cephalosporin MOA

Answer 10

Cephalosporins, like penicillins, interfere with cell wall synthesis by binding to and inhibiting enzymes, called penicillin-binding proteins (PBPs), that are located in the cell wall of bacteria.
PBPs include transpeptidases, carboxypeptidases, and endopeptidases that are responsible for peptidoglycan cross-linking. The number, type and location of PBPs vary between bacteria.
Inhibition of PBPs by β-lactam antibiotics leads to inhibition of the final transpeptidation step of peptidoglycan synthesis, exposing a less osmotically-stable cell wall that leads to decreased bacterial growth, bacterial cell lysis, and death.
Cephalosporins, like all β-lactam antibiotics, are bactericidal** in a time-dependent manner.

Question 11

cephalosporin MOR

Answer 11

Production of β-lactamase enzymes
-The most important and most common mechanism of bacterial resistance where the bacteria produces a β-lactamase enzyme that hydrolyzes the cyclic amide bond of the β-lactam ring, inactivating the antibiotic.
-Over 850 different β-lactamase enzymes have been identified. β-lactamase enzymes may be plasmid-mediated or chromosomally-mediated, constitutive or inducible.
-Produced by some Gram-positive aerobes (Staphylococcus aureus), many Gram-negative aerobes (H. influenzae, N. gonorrhoeae, M. catarrhalis, K. pneumoniae, E. coli, Proteus spp., P. aeruginosa, S. marcescens, etc.), and some Gram-negative anaerobes (Bacteroides fragilis).
-In general, cephalosporins are somewhat resistant to degradation by β-lactamases of some bacteria***; 3rd and 4th generation cephalosporins and cephalosporin-β-lactamase inhibitor combinations (ceph-βLI) are resistant to β-lactamase degradation of some Gram-negative bacteria.
-Some bacteria (SPICE) have the ability to produce β-lactamase enzymes when exposed to antibiotics that induce their production - these are inducible β-lactamases (such as during treatment of Enterobacter spp. infections with ceftazidime).
Alterations in PBPs that lead to decreased binding affinity of cephalosporins to PBPs (e.g., methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae).
Inability of the antibiotic to reach the PBP target due to poor penetration through the outer membrane in Gram-negative bacteria (altered porin proteins).

Question 12

cephalosporin classification and spectrum of activity

Answer 12

Currently-available cephalosporins are divided into 4 major groups, called “generations”, based primarily on their antimicrobial activity and stability against β- lactamase enzymes. In addition, ceftaroline, a newly-approved anti-MRSA cephalosporin, and the cephalosporin-β-lactamase inhibitor combination products remain uncategorized at this time.
*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 diminishes with an increase in activity against Gram-negative aerobes. Fourth generation cephalosporins are active against Gram-positive and Gram-negative aerobes. Greater β-lactamase stability occurs as you move through the generations (with 4th generation agents and ceph-βLIs being the most stable).
Overall, cephalosporins are NOT ACTIVE* against methicillin-resistant Staphylococcus aureus (MRSA - except ceftaroline) and coagulase-negative staphylococci, Enterococcus spp., Listeria monocytogenes, Legionella pneumophila*, Clostridium difficile, Stenotrophomonas maltophilia (except ceftazidime), and Campylobacter jejuni.

Question 13

1st gen cephalosporin spectrum of activity

Answer 13

Excellent activity against Gram-positive aerobes - the best activity of all cephalosporins
-Group streptococci
-Viridans streptococci
-Penicillin-susceptible Streptococcus pneumoniae (PSSP)
Methicillin-susceptible Staphylococcus aureus (MSSA)
Also have activity against a limited number of Gram-negative aerobes (PEK):
-Proteus mirabilis -Escherichia coli
-Klebsiella pneumoniae
Examples of 1st generation cephalosporins (most often used): cefazolin, cephalexin

Question 14

2nd gen cephalosporin spectrum of activity

Answer 14

Differences exist in the spectrum of activity among 2nd generation agents because of differences in their chemical structure.
In general, are slightly less active than 1st generation cephalosporins against Gram-positive aerobes such as Staphylococci and Streptococci (MICs are a little higher), but are more active against Gram-negative aerobes. Some 2nd generation agents (cephamycins) are active against anaerobes.
Gram-positive aerobes** - 2nd generation agents have 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-negative aerobes** - display activity against
-Proteus mirabilis
-Escherichia. coli
-and Klebsiella pneumoniae like the 1st generation cephalosporins, but they have expanded coverage including:
-Haemophilus influenzae (only β-lactamase negative strains)
-Moraxella catarrhalis
-Neisseria spp.
-In addition, may be active against some strains of Citrobacter and Enterobacter that are resistant to 1st generation agents (HENPEK).
Anaerobes - only cefoxitin, cefotetan and cefmetazole* (the cephamycins) are active against anaerobes including Bacteroides fragilis (cefoxitin is the best).
Examples of 2nd generation cephalosporins: cefuroxime, cefprozile, cefoxitin

Question 15

3rd gen cephalosporin spectrum of activity

Answer 15

In general, are less active than 1st or 2nd generation agents against Gram-positive aerobes, but have enhanced activity against Gram-negative aerobes.
Gram-positive aerobes** - ceftriaxone* and cefotaxime* have the best activity (less than 1st and 2nd generation cephalosporins) and are among the only cephalosporins that have activity against penicillin-resistant Streptococcus pneumoniae or PRSP; other 3rd generation cephalosporins have relatively poor activity.
Gram-negative aerobes - expanded* spectrum of activity when compared to 2nd generation agents (HENPECKSSS and more) including:
-P. mirabilis, E. coli, K. pneumoniae (better than 1st and 2nd generation agents)
-H. influenzae, M. catarrhalis, Neisseria gonorrhoeae (including β-lactamase producing strains)
-Neisseria meningitidis
-Citrobacter spp., Enterobacter spp. (less with oral agents)
-Morganella spp., Providencia spp., Serratia marcescens
-Salmonella spp., Shigella spp.
-Pseudomonas aeruginosa - ONLY ceftazidime and cefoperazone
Anaerobes - very limited activity (ceftizoxime has marginal activity)
Select 3rd generation cephalosporins (especially ceftazidime) are strong inducers of extended spectrum β-lactamases (type 1, Class C or AmpC) in Gram-negative aerobic bacteria (Enterobacter spp.)
Examples of 3rd generation cephalosporins: ceftriaxone, ceftazidime, cefpodoxime

Question 16

4th gen cephalosporin spectrum of activity

Answer 16

Cefepime is considered a 4th generation cephalosporin for 2 reasons:
-Extended spectrum of activity, including many Gram-positive and Gram-negative aerobes (NOT anaerobes):
—Gram-positive aerobes: coverage similar to ceftriaxone
–Gram-negative aerobes: displays similar coverage against Gram-negative aerobes as 3rd generation agents, including: Pseudomonas aeruginosa, β-lactamase producing Enterobacter and E. coli
-Excellent stability against β-lactamase hydrolysis; cefepime is a relatively poor inducer of extended spectrum β-lactamases (type 1 or Class C) in Gram-negative aerobic bacteria.
Example of a 4th generation cephalosporin: cefepime

Question 17

anti-MRSA cephalosporin spectrum of activity

Answer 17

ceftaroline
Gram-positive aerobes: coverage against Staphylococci and Streptococci similar to ceftriaxone (including PRSP*); AND has in vitro and clinical activity against MRSA**
Gram-negative aerobes: coverage similar to 3rd generation agents like ceftriaxone

Question 18

ceftolozane-tazobactam spectrum of activity

Answer 18

Gram-positive aerobes: coverage against Streptococci
Gram-negative aerobes: coverage similar to cefepime (the 4th generation cephalosporin), but also includes some ESBL-producing Gram negative bacteria; also covers some AmpC-producing Pseudomonas aeruginosa**

Question 19

ceftazidime-avibactam spectrum of activity

Answer 19

Gram-positive aerobes: coverage against Streptococci
Gram-negative aerobes: coverage similar to cefepime (the 4th generation cephalosporin), but also includes many ESBL-producing Gram negative bacteria, some AmpC-producing bacteria (Pseudomonas aeruginosa**) and some KPC-producing Enterobacteriaceae

Question 20

pharmacodynamic principles of cephalosporins

Answer 20

Cephalosporins display time-dependent* bactericidal activity and the pharmacodynamic parameter that correlates best with clinical efficacy is Time above the MIC (T>MIC)*.
Clinically-useful synergy has been demonstrated:
-Viridans streptococcus: ceftriaxone with gentamicin
-Staphylococcus aureus: cefazolin with gentamicin
-Gram-negative aerobes: ceftriaxone, ceftazidime, or cefepime with gent-amicin, tobramycin or amikacin

Question 21

general pharmacologic principles of cephalosporins

Answer 21

Orally-available cephalosporins are well absorbed from the gastrointestinal tract; however, serum concentrations are lower than those achieved with parenteral dosing. Food may influence absorption (see PK table).
Most cephalosporins are widely distributed into tissues and fluids including pleural fluid, synovial fluid, bone, bile, placenta, pericardial fluid and aqueous humor. Adequate concentrations in the cerebrospinal fluid (CSF) are NOT** obtained with 1st and most 2nd generation cephalosporins. Therapeutic concentrations of parenteral cefuroxime, parenteral 3rd, and parenteral 4th generation cephalosporins are attained in the CSF, especially in the presence of inflamed meninges.
Most cephalosporins are eliminated unchanged by the kidneys via glomerular filtration and tubular secretion and require dose adjustment in renal insufficiency. The exceptions* include ceftriaxone* and cefoperazone*, 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.
Most cephalosporins have relatively short elimination half-lives (under 2 hours), and require repeated daily dosing (3 to 4 times daily) to maintain therapeutic serum concentrations. Exceptions include ceftriaxone (8 hours), cefonicid (4.5 hours), cefotetan (3.5 hours), cefixime (3.7 hours).

Question 22

clinical uses of 1st gen cephalosporins

Answer 22

Orally-administered 1st generation cephalosporins achieve lower serum concentrations than parenteral agents and should only be used for the treatment of mild to moderate skin infections or uncomplicated urinary tract infections.
Treatment of infections due to MSSA, Group and viridans Streptococci such as skin/soft tissue infections, septic arthritis, osteomyelitis, and endocarditis.
*Cefazolin is the drug of choice for surgical prophylaxis** against surgical site infections for many surgical procedures because of its activity against Staphylococci and usefulness as a single preoperative dose.
First generation cephalosporins have activity against a few Gram-negative aerobes and can be used for the treatment of urinary tract infections (oral or intravenous) or bacteremias (intravenous) due to susceptible organisms (PEK).
First generation cephalosporins do not penetrate the central nervous system, and should NOT be used for meningitis.

Question 23

clinical uses of 2nd gen cephalosporins

Answer 23

Due to their activity against Gram-positive aerobes and expanded spectrum of activity against Gram-negative bacteria including H. influenzae and M. catarrhalis, oral 2nd generation agents, such as cefuroxime, are useful for the treatment of pharyngitis, tonsillitis, sinusitis, otitis media, bronchitis and mild to moderate community-acquired pneumonia.
Oral 2nd generation cephalosporins are also useful for the treatment of mild to moderate skin and soft tissue infections, and uncomplicated urinary tract infections due to susceptible bacteria.
Although cefuroxime does penetrate the central nervous system, adequate CSF bactericidal activity is not routinely achieved so that it is no longer recommended for the treatment of meningitis.
The cephamycins, cefoxitin, cefotetan, and cefmetazole, have activity against Gram-negative aerobes and anaerobes, including Bacteroides fragilis, and are useful for prophylaxis in abdominal surgical 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.

Question 24

clinical uses of 3rd gen cephalosporins

Answer 24

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-negative bacteria (including nosocomial infections). If Pseudomonas aeruginosa is known or suspected, ceftazidime or cefoperazone should be used. If anaerobes are known or suspected, metronidazole or clindamycin should be added.
Ceftriaxone* is used as a single IM dose for uncomplicated gonorrhea.
Cefotaxime and ceftriaxone have good activity against Gram-positive aerobes, and may be used for the treatment of infections due to Group streptococci, viridans streptococci (endocarditis), and penicillin-resistant Streptococcus pneumoniae** (meningitis, pneumonia). Ceftriaxone is often used for outpatient parenteral therapy in appropriate situations.
Oral third generation cephalosporins are used for the treatment of uncomplicated urinary tract infections, acute otitis media, minor soft tissue infections, and acute sinusitis.

Question 25

clinical uses of 4th gen cephalosporins

Answer 25

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 antipseudomonal activity**. If anaerobes are known or suspected, metronidazole or clindamycin should be added.

Question 26

clinical uses of anti MRSA cephalosporins

Answer 26

Ceftaroline
Ceftaroline is currently FDA-approved for the treatment of skin and soft tissue infections (including those caused by MRSA) and community-acquired pneumonia.

Question 27

clinical uses of cephalosporin-B-lactamase inhibitor combination

Answer 27

Ceftazidime-avibactam and ceftolozane-tazobactam are currently FDA-approved for the treatment of complicated urinary tract infections (including pyelonephritis) and complicated intra-abdominal infections (with metronidazole). Both agents are expensive; use limited to infections due to resistant Gram negative bacteria (ESBL-, AmpC- or KPC-producing bacteria), where appropriate.

Question 28

adverse effects of cephalosporins

Answer 28

hypersensitivity, 5-NMTT side chain, hematologic, GI, other

Question 29

hypersensitivity with cephalosporins

Answer 29

1. Reactions include pruritus, rash (maculopapular, erythematous, or morbilloform), hives, urticaria, angioedema, laryngeal edema, hypotension, vasodilation, shock, and anaphylaxis.
   Hypersensitivity reactions to cephalosporins occur most frequently in patients with a history of penicillin allergy. The degree of cross-reactivity is 5 to 15%, and clinicians must consider the allergic reaction to the penicillin (? IgE-mediated) and the degree of cross-reactivity when deciding if a cephalosporin can be used in a patient with a history of allergy to penicillin.
   -Immediate or accelerated hypersensitivity reactions (anaphylaxis, laryngeal edema, hives, bronchospasm) → avoid other cross-reactive β-lactams, such as cephalosporins
   -Delayed hypersensitivity reactions (rash, pruritus) → give cephalosporins with caution considering the degree of cross-reactivity
   Other skin reactions include Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and exfoliative dermatitis.

Question 30

5-NMTT side chain AEs with cephalosporins

Answer 30

Some cephalosporins have a 5-NMTT side chain (nitromethylthiotetrazole) that confers unique adverse effects. Cephalosporins with the NMTT side chain include cefamandole, cefotetan, cefmetazole, cefoperazone, and moxalactam.

• Hypoprothrombinemia with or without bleeding due to reduction of vitamin K-producing bacteria in the GI tract. Moxalactam also reduces platelet aggregation that significantly increased the incidence of bleeding.
• Disulfiram reaction (ethanol intolerance).

Question 31

hematologic AEs with cephalosporins

Answer 31

β-lactam-specific cytotoxic IgG or IgM antibodies may be developed that bind to circulating RBCs, WBCs, or platelets.

• In the case of RBCs, intravascular hemolysis (Coomb’s positive hemolytic anemia) rarely occurs when the antigen (cephalosporin) is encountered; anemia may also develop when the cells are removed by the reticuloendothelial system.
• In the case of WBCs and platelets, cell lysis may occur through activation of the complement system when the antigen (cephalosporin) is encountered leading to leukopenia, neutropenia or thrombo- cytopenia. Occurs primarily in patients receiving long-term (over 2 weeks) therapy; reversible upon discontinuation.

Question 32

GI side effects with cephalosporins

Answer 32

Transient increases in liver enzymes.
Biliary sludging – especially with ceftriaxone* therapy (especially in neonates).
Nausea, vomiting.
Pseudomembranous colitis (Clostridium difficile colitis). Some cephalosporins may cause diarrhea that is not due to C. difficile.

Question 33

other AEs of cephalosporins

Answer 33

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 status epilepticus** (cefepime, ceftazidime).

Question 34

carbapenem chemistry

Answer 34

Carbapenems are β-lactam antibiotics that contain a β-lactam ring fused to a 5-membered ring, like the penicillins. However, the 5-membered ring of the carbapenems contains a carbon atom at position one (hence the name, carbapenem) instead of a sulfur atom, and the addition of a double bond.
All carbapenems contain a hydroxyethyl group in the trans configuration at position 6 as compared to an acylamino group in the cis configuration of the penicillins and cephalosporins. This structural difference results in increased antibacterial activity and greater stability against most β-lactamase enzymes.

Question 35

carbapenem MOA

Answer 35

Like other β-lactam antibiotics, carbapenem antibiotics display time-dependent bactericidal** activity (except against Enterococcus), and cause bacterial cell death by covalently binding to PBPs that are involved in the biosynthesis of bacterial cell walls.
Each carbapenem displays different affinities for specific PBPs, which appear to be genus-specific. The highest binding affinity for imipenem, meropenem and doripenem is PBP-2.

Question 36

carbapenem MOR

Answer 36

Decreased permeability as a result of alterations to outer membrane porin proteins is an important mechanism of resistance in Gram-negative bacteria, particularly Pseudomonas aeruginosa.
Hydrolysis of carbapenem antibiotics by β-lactamase or carbapenemase enzymes. However, all of the carbapenems display intrinsic resistance to nearly all β-lactamases (are very stable and not destroyed), including both plasmid- and chromosomally- mediated enzymes.
Alterations in PBPs that lead to decreased binding affinity of the carbapenem.

Question 37

carbapenem spectrum of activity

Answer 37

The carbapenems are currently the most broad-spectrum antibiotics, displaying activity against many Gram positive AND Gram-negative aerobes AND anaerobes.
Gram-positive aerobes - imipenem and doripenem exhibit the best activity; meropenem and ertapenem are generally 2 to 4 times less active than imipenem
-Group streptococci
-Viridans streptococci
-penicillin-susceptible Streptococcus pneumoniae (PSSP)
-Enterococcus faecalis only** (most strains of E. faecium are resistant)
methicillin-susceptible Staphylococcus aureus (MSSA)
Gram-negative aerobes – the carbapenems display excellent activity against many Gram-negative aerobes (doripenem and meropenem are the best, followed by imipenem and ertapenem); differences in susceptibility exist between the agents and are species-dependent; carbapenems display activity against β-lactamase producing strains that display resistance to other β-lactam antibiotics (they are the DRUGS OF CHOICE for ESBL- and AmpC-producing bacteria)
-E. coli, Citrobacter freundii, Klebsiella spp., Enterobacter spp., Serratia marcescens, Proteus spp., Morganella morganii, Providencia spp., Yersinia spp., Acinetobacter spp. (not ertapenem), Neisseria spp. , Haemophilus influenzae, Moraxella catarrhalis, Campylobacter jejuni, Salmonella spp., Shigella spp., Pseudomonas aeruginosa (NOT ertapenem)
Anaerobes – ALL carbapenems display excellent activity against clinically significant Gram-positive and Gram-negative anaerobes including:
-Gram-positive anaerobes: Peptostreptococcus spp., Peptococcus spp., Veillonella parvula, Clostridium perfringens and tetani
-Gram-negative anaerobes: Bacteroides fragilis, Bacteroides vulgatus, Bacteroides distasonis, Bacteroides thetaiotamicron, Bacteroides ovatus, Prevotella bivia, Fusobacterium spp.
The carbapenems do NOT have activity against methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, some enterococci (VRE), Clostridium difficile, Stenotrophomonas maltophilia, Nocardia, and atypical bacteria*.

Question 38

pharmacodynamic principles of carbapenems

Answer 38

Carbapenems display time-dependent* bactericidal activity and the pharmacodynamic parameter that correlates best with clinical efficacy is Time above the MIC** (T>MIC).
Carbapenems are bactericidal, but only display bacteriostatic activity against Enterococcus spp. (imipenem)
Clinically-useful synergy has been demonstrated:
-Gram-negative aerobes: carbapenems with gentamicin, tobramycin or amikacin

Question 39

distribution of carbapenems

Answer 39

all carbapenems are widely distributed in various body tissues and fluids including saliva, sputum, aqueous humor, skin, soft tissue, bone, bile, endometrium, heart valves, placenta; pleural, peritoneal, and wound fluids; and the urinary tract.
CSF penetration - only low concentrations of imipenem diffuse into the CSF following IV administration, with CSF concentrations approximately 1 to 10% of concurrent serum concentrations; meropenem penetrates into the CSF better than imipenem and ertapenem, with CSF concentrations up to 52% of simultaneous serum concentrations in patients with inflamed meninges

Question 40

elimination of carbapenems

Answer 40

The major route of elimination of the carbapenems is urinary excretion of unchanged drug involving both glomerular filtration and tubular secretion.
-Imipenem* undergoes hydrolysis in the kidney by an enzyme called dihydropeptidase (DHP) to microbiologically inactive and potentially nephrotoxic metabolites. A DHP inhibitor called cilastatin* is added to commercially-available preparations of imipenem to prevent renal metabolism and protect against potential nephrotoxicity.
The elimination half-life of imipenem, meropenem and doripenem is approximately 1 hour in patients with normal renal function; the elimination half-life of ertapenem is approximately 4 hours.
All carbapenems require dosage adjustment in patients with renal dysfunction and are removed during hemodialysis procedures so they are usually dosed after hemodialysis.

Question 41

dosing of the carbapenems in patients with normal renal function

Answer 41

Adult dosing:
Imipenem: 250 to 500 mg IV q6h
Meropenem: 1-2 grams q8h
ertapenem: 1 gram q24h
doripenem: 500 mg q8h

pediatric dosing:

imipenem: 15-25 mg/kg q6h
meropenem: 20-40 mg/kg q8h
ertapenem: 15 mg/kg q12h

Question 42

clinical uses of carbapenems

Answer 42

very expensive
The carbapenems are very broad-spectrum antibiotics that are typically used for polymicrobial infections* where they can be employed as monotherapy including intraabdominal infections or skin and skin structure infections in diabetic patients. Ertapenem does not have activity against Pseudomonas aeruginosa.
Empiric therapy for nosocomial infections* such as serious lower respiratory tract infections, septicemia, and complicated urinary tract infections due to Gram-negative bacteria, while waiting for the results of culture and susceptibility data. Ertapenem does not have activity against Pseudomonas aeruginosa. Once results of the cultures and susceptibilities are known, therapy is often changed to a less broad spectrum (more targeted) and less costly antimicrobial agent.
Infections due to resistant Gram-negative bacteria, especially those organisms that produce ESBLs or type 1/class C/AmpC β-lactamase enzymes.
Febrile neutropenia – imipenem or meropenem
Meningitis (children) - meropenem

Question 43

AEs of carbapenems

Answer 43

hypersensitivity, GI, CNS

Question 44

hypersensitivity of carbapenems

Answer 44

Reactions include rash, fever, pruritus, hives, urticaria, angioedema, laryngeal edema, hypotension and anaphylaxis.
Cross reactivity (5 to 15%) can occur in patients who have a history of hypersensitivity to penicillins, so clinicians must consider the degree of cross reactivity and reaction to penicillin before using a carbapenem in a penicillin-allergic patient.
-Immediate or accelerated hypersensitivity reactions (anaphylaxis, laryngeal edema, hives, bronchospasm) - avoid other cross-reactive β-lactams, such as carbapenems.
-Delayed hypersensitivity reactions (rash, pruritus) - give carbapenems with caution keeping in mind the degree of cross-reactivity.

Question 45

GI AEs of carbapenems

Answer 45

Nausea, vomiting, and diarrhea have been reported in up to 5% of patients receiving carbapenems.
Antibiotic-associated pseudomembranous colitis (C. difficile).

Question 46

CNS AEs of carbapenems

Answer 46

direct toxic effect
Insomnia, agitation, confusion, dizziness, hallucinations, and depression.
Seizures** - have been reported in patients receiving imipenem (1.5%), meropenem (0.5%), ertapenem (0.5%), and doripenem (under 0.5%).
-Historically, initial imipenem dosage recommendations were 1 gram every 6 hours without specific guidelines for dose adjustment in renal insufficiency, which may have led to the initial increased incidence of seizures. Today, 500 mg every 6 hours is used with dosage adjustments in renal dysfunction, and the incidence of seizures has decreased.
-Risk factors** for the development of seizures during carbapenem therapy include preexisting CNS disorders (e.g. history of seizures, brain lesions, recent head trauma), high doses (> 2 grams imipenem per day), and the presence of renal dysfunction.

Question 47

other AEs of carbapenems

Answer 47

Other adverse effects associated with carbapenems include thrombophlebitis, neutropenia, thrombocytopenia, transient LFT increases, and yeast infections.

Question 48

monobactam chemistry

Answer 48

Aztreonam is a synthetic monocyclic, β-lactam antibiotic (monobactam). Unlike other currently available β-lactam antibiotics that are bicyclic and contain a ring fused to the β-lactam ring, aztreonam contains only a β-lactam ring with side chains.

Question 49

monobactam MOA

Answer 49

Like bicyclic β-lactam antibiotics, aztreonam is bactericidal** because of its ability to bind to and inhibit PBPs and ultimately inhibit peptidoglycan synthesis, which is essential for the synthesis, assembly and maintenance of bacterial cell walls.
Aztreonam binds preferentially to PBP-3 in aerobic Gram-negative bacilli, interfering with cell wall synthesis. Aztreonam has poor affinity for PBPs of Gram-positive and anaerobic bacteria.

Question 50

monobactam MOR

Answer 50

Hydrolysis by bacterial β-lactamase enzymes: aztreonam is relatively stable against hydrolysis by some plasmid- and chromosomally-mediated β-lactamases; aztreonam is hydrolyzed by some β-lactamase enzymes produced by Klebsiella spp., Enterobacter spp., and Pseudomonas aeruginosa.
Alteration in outer membrane porin proteins in Gram-negative bacteria leading to decreased permeability.

Question 51

monobactam spectrum of activity

Answer 51

Aztreonam preferentially binds to PBP-3 in Gram-negative aerobic bacteria; therefore, aztreonam only* has activity against Gram-negative aerobes.
Gram-positive aerobes - inactive
Gram-negative aerobes - aztreonam is active against a wide range of Gram-negative aerobes including: Haemophilus influenzae, Moraxella catarrhalis, Citrobacter spp., Enterobacter spp., E. coli, Klebsiella pneumoniae, Proteus spp., Morganella morganii, Providencia spp., Serratia marcescens, Salmonella spp., Shigella spp., Pseudomonas aeruginosa (≈ 60% of strains)*
Anaerobes - inactive

Question 52

pharmacodynamic principles of aztreonam

Answer 52

Aztreonam displays time-dependent bactericidal activity and the pharmacodynamic parameter that correlates with efficacy is Time>MIC**
Clinically-useful synergy has been demonstrated: P. aeruginosa and other Gram-negative aerobes: aztreonam with gentamicin, tobramycin or amikacin

Question 53

distribution of monobactams

Answer 53

Aztreonam is widely distributed into body tissues and fluids including skeletal muscle, adipose tissue, skin, bone, gallbladder, liver, lungs, prostatic tissue, endometrium, sputum, bronchial secretions, aqueous humor, bile, pleural fluid, peritoneal fluid, and synovial fluid. Aztreonam DOES penetrate into the CSF, especially in the presence of inflamed meninges.

Question 54

elimination of monobactams

Answer 54

Aztreonam is excreted principally in the urine as unchanged drug. The half- life of aztreonam is 1.3 to 2.2 hours in patients with normal renal function. Doses need to be adjusted in patients with renal insufficiency, and aztreonam is removed during hemodialysis.

Question 55

dosing of monobactams in normal renal function

Answer 55

adults: 0.5-2 grams IV q8h
peds: 30-50 mg/kg q8h

Question 56

clinical uses of monobactams

Answer 56

Aztreonam can only be used for the treatment of infections caused by Gram-negative aerobes** (including Pseudomonas aeruginosa**) such as complicated and uncomplicated urinary tract infections, lower respiratory tract infections, meningitis, bacteremia, skin and skin structure infections, intraabdominal infections, and gynecologic infections. If anaerobes are known or suspected, metronidazole or clindamycin should be added.
Aztreonam is especially useful for the treatment of Gram-negative infections in patients with a history of a severe penicillin or β-lactam allergy.

Question 57

AEs of monobactams

Answer 57

Hypersensitivity - rash, pruritus, urticaria, angioedema, anaphylaxis (rare). Studies in rabbits and humans suggest that antibodies directed against penicillin show negligible cross-reactivity with aztreonam. Because of a low to negligible incidence of cross- reactivity, aztreonam can be used in a patient with a history of penicillin allergy.
Gastrointestinal - diarrhea, nausea, vomiting in 1 to 2% of patients
Other: neutropenia, thrombocytopenia, eosinophilia, transient LFT increases, phlebitis, drug fever