Antimicrobials Part 1 (Cell Wall Synthesis Inhibitors)

Question 1

What is prophylactic therapy? What groups should you consider for this type of therapy?

Answer 1

Pre-treatment to prevent infection in patients with weakened defenses (immunocompromised states).
Used for individuals on immunosuppressive therapy, cancer patients, and in pre-surgical procedures.

Question 2

What is empiric therapy? How is an antibiotic selected in this case?

Answer 2

Treatment of known or probably infection.

Agent selected based on rational judgement and experience, not just “broad spectrum”.

Question 3

What is definitive therapy? How might this be favored in comparison to empiric therapy?

Answer 3

Pathogen’s identity and antibiotic susceptibility is determined.
Compared to empiric therapy, this reduces risk of resistance emerging to broader-spectrum agents.

Question 4

What are two reasons to choose a narrow-spectrum agent over a broad-spectrum agent?

Answer 4

1. Reduces risk of superinfection and opportunistic infections (C. difficile)
2. Reduces risk of community resistance development

Question 5

What are the two ways cell wall synthesis inhibitors weaken the cell wall of bacteria?

Answer 5

1. Transpeptidase inhibition: Disrupts transpeptidase, which catalyzes the formation of cross-bridges between peptidoglycan polymer strands
2. Autolysin activation: Increases the activity of enzymes critical for breaking down cell wall segments to permit growth and division

Question 6

Transpeptidase and autolysin are also known as _____.

Answer 6

Penicillin-binding proteins

Penicillins bind to them to produce a lytic effect (bactericidal).

Question 7

Where are penicillin-binding proteins (PBPs) located?

Answer 7

On the cell membrane of both gram-positive and gram-negative bacteria.

Question 8

Do penicillins work on bacteria that lack a cell wall?

Answer 8

NO

If bacteria lack a cell wall, they also lack PBPs and therefore, penicillin cannot bind.

Question 9

What are the three steps in which this class of antibiotics can interfere with peptidoglycan synthesis?

Answer 9

1. Inhibition of synthesis of murein monomers (e.g. fosfomycin)
2. Inhibition of polymerization of murein monomers into the glycan backbone (e.g. vancomycin)
3. Inhibition of glycan polymer cross-linking into peptidoglycan (e.g. beta lactams and “others”)

Question 10

Cell wall synthesis inhibitors are primarily effective against ______ ______ bacteria.

Answer 10

Gram-positive

Gram-negative bacteria are intrinsically resistant to many drugs from this class.

Question 11

Some gram-negative species express ______ _______ permeable to some antibiotics (e.g., ampicillin, amoxicillin, but NOT vancomycin)

Answer 11

Porin channels

Note: Some species lack porin channels (Pseudomonas aeruginosa)

Question 12

What are 3 resistance mechanisms that gram-negative and gram-positive bacteria can acquire/develop?

Answer 12

1. Altered PBPs (e.g. MRSA)
2. Expression of efflux pumps (e.g. multidrug-resistance protein; Klebsiella pneumoniae)
3. Beta-lactamase enzymes that degrade beta-lactam drugs (most S. aureus and an increasing number of Streptococci)

Question 13

The ______ ______ ______ is the common core structure of all beta-lactam drugs which ______ penicillin-binding proteins at the penicillin binding site.

Answer 13

Beta-lactam ring, acetylates

Question 14

The acetylation of penicillin-binding proteins at the penicillin-binding site ______ the enzyme.

Answer 14

Inactivates

Question 15

The spectra and specific properties of beta-lactam drugs vary based on identities of the ______ ______.

Answer 15

R groups

Question 16

Penicillinase, cephalosporinase, and AmpC-lactamase are examples of ______ ______.

Answer 16

Beta-lactamases

Question 17

Which subclass of beta-lactams are largely resistant to beta-lactamases?

Answer 17

Carbapenems

Question 18

Name 4 common beta-lactamase inhibitors

Answer 18

1. Clavulanic acid/clavulanate
2. Sulbactam
3. Tazobactam
4. Avibactam

Question 19

Beta-lactamases can be inhibited by ______ beta-lactam drugs with other agents

Answer 19

Co-administering

Question 20

Methicillin is an example of how ______ ______ of drug structure can make beta-lactams more resistant to beta-lactamse inactivation

Answer 20

Chemical modification

Question 21

What is penicillin’s principal adverse drug reaction (ADR)?

Answer 21

Allergic reactions

Question 22

Osmotic pressure is ______ inside the bacterial cell membrane and cell wall. Disruption of the cell wall makes the cell favor water ______. A functional cell wall ______ the cell from expanding and bursting. Penicillins ______ the cell wall and cause bacteria to ______ ______ water and ______.

Answer 22

High, absorption, prevents, weaken, take up, rupture

Question 23

What are the three groups of penicillins organized by spectrum of activity?

Answer 23

1. Natural penicillins
2. Anti-staphylococcal penicillins
3. Extended-spectrum agents (aminopenicillins and antipseudomonal penicillins)

Question 24

Natural penicillins are ______ spectrum.

Answer 24

Narrow

Question 25

Natural penicillins target gram-______ organisms and are sensitive to penicillinases.

Answer 25

Positive

Question 26

Clinical uses of natural penicillins (5)

Answer 26

1. Pneumococcal infections (S. pneumoniae) - pneumonia and meningitis (can cross the BBB) 2. Gonorrhea (Neisseria) - except penicillinase-expressing strains 3. Gas gangrene (C. perfringens) 4. Syphilis (Treponema pallidum) - single IM dose is curative 5. Pharyngitis (beta-hemolytic Streptococcus)

Question 27

___% of S. aureus strains are resistant to natural penicillins

Answer 27

90%

Question 28

Penicillin G is administered ____ or ____

Answer 28

IV, IM

Question 29

Penicillin V can be administered PO, but use in severe infections is discouraged due to ______ ______.

Answer 29

Poor bioavailability

Question 30

Natural penicillins distribution, half life, and excretion

Answer 30

Distributed throughout the body t 1/2 = 30 minutes Renally excreted

Question 31

Benzathine can ______ penicillin G for IM repository (low but prolonged drug levels).

Answer 31

Stabilize

Question 32

Natural penicillins DDIs (1)

Answer 32

Anti-gout drug, probenecid, blocks renal transporters and increases penicillin half-life

Question 33

Natural penicillin considerations

Answer 33

Dose adjustment required for patients with impaired renal function

Question 34

Pediatric dosage of natural penicillins is determined by the child’s ______ ______.

Answer 34

Body weight

Question 35

Natural penicillins ADRs (5) | Otherwise, usually well-tolerated

Answer 35

1. Hypersensitivity (Type I, immediate due to repeat exposure) - 10% of patients self-report an allergy (rash, angioedema, anaphylaxis) to penicillin (contraindication). All other beta-lactams are contraindicated in patients with a previous allergic reaction to penicillin. 2. Diarrhea: disruption of the normal balance of intestinal microorganisms. Can lead to superinfections caused by C. difficile. 3. Nephrotoxicity: acute interstitial nephritis 4. Neutotoxicity: may provoke seizures. Contraindicated in patients with epilepsy. 5. Hematologic toxicities: decreased coagulation, cytopenias; monitor CBCs

Question 36

Anti-staphylococcal (penicillinase-resistant) Penicillins Drugs (4)

Answer 36

1. Methicillin 2. Nafcillin 3. Oxacillin 4. Dicloxacillin

Question 37

Anti-staphylococcal Penicillins Clinical Use

Answer 37

Narrow-spectrum agent restricted for S. aureus strains that express beta-lactamases Also effective treatment for penicillin-susceptible Streptococci and Pneumococci (MSSA susceptible to this entire class, but MRSA is NOT)

Question 38

Nafcillin and oxacillin route of administration

Answer 38

IV

Question 39

Dicloxacillin route of administration

Answer 39

PO

Question 40

Anti-staphylococcal Penicillins half life and excretion

Answer 40

Short half life that requires frequent dosing | Renally excreted, except for nafcillin (biliary excretion)

Question 41

Extended-Spectrum Penicillins (Aminopenicillins) Drugs

Answer 41

Ampicillin (IV) and amoxicillin (PO) with same spectrum of activity

Question 42

Extended Spectrum Penicillins (Aminopenicillins) Clinical Uses

Answer 42

Broad-spectrum agent effective against some gram-negative organisms (E. coli, H. influenzae, Proteus mirabilis, Salmonella typhi) and most gram-positive organisms 1. Ampicillin for L. monocytogenes 2. Amoxicillin for URIs, bacterio-rhinosinusitis, otitis, and LRIs

Question 43

Extended Spectrum Penicillins (Aminopenicillins) Considerations

Answer 43

Co-administer amoxicillin/clavulanate or ampicillin/sulbactam to treat strain resistance from beta-lactamases

Question 44

Extended Spectrum Penicillins (Antipseudomonal Penicillins) Clinical Uses

Answer 44

``` Piperacillin is the only drug of this class in use in the USA Little gram-positive activity Primarily targets gram-negative species (Enterobacter, E. coli, H. influenzae, Proteus mirabilis, Proteus [indole positive], Pseudomonas aeruginosa) Co-administered with tazobactam as combination therapy to broaden spectrum against beta-lactamase-producing organisms (Pseudomonas, Klebsiella pneumoniae) ```

Question 45

Cephalosporins are ______-resistant drugs that consist of ______ generations

Answer 45

Penicillinase, five

Question 46

First Generation Cephlosporins

Answer 46

Cefazolin, cephalexin, cefadroxil

Question 47

First Generation Cephalosporins Spectrum of Activity

Answer 47

Similar spectrum to anti-staphylococcal penicillins, but better tolerated Effective definitive therapy against MSSA, streptococcal, and other penicillinase-producing staphylococcal strains (NOT MRSA)

Question 48

First Generation Cephalosporins Clinical Uses

Answer 48

UTIs, staphylococcal/streptococcal infections (cellulitis/soft tissue abscesses) Cefazolin is used for surgical prophylaxis and severe staph infections (bacteremia)

Question 49

First Generation Cephalosporins Excretion

Answer 49

``` Renal elimination (probenecid can increase half-life) Dose adjustment required for patients with renal impairment ```

Question 50

Second Generation Cephalosporins

Answer 50

Cefaclor, cefuroxime, cefprozil, cefoxitin, and cefotetan

Question 51

Second Generation Cephalosporins Spectrum of Activity

Answer 51

Spectum generally includes organisms susceptible to first generation cephalosporins, plus an extended gram-negative coverage

Question 52

Second Generation Cephalosporins Clinical Uses

Answer 52

URIs (sinusitis, otitis media), soft tissue infections, gynecologic infections, perioperative surgical procedures

Question 53

Second Generation Cephalosporins Excretion

Answer 53

Renally eliminated (probenecid increases half-life)

Question 54

Third Generation of Cephalosporins

Answer 54

Cefotaxime, ceftazidime, ceftriaxone, cefdinir, cefpodoxime

Question 55

Third Generation of Cephalosporins Spectrum of Activity

Answer 55

Less potent gram-positive activity (very potent against pneumococci), but have much greater gram-negative activity. Used to treat serious infections caused by organisms resistant to most other drugs. Effective against beta-lactamase-producing Haemophilus and Neisseria gonorrhoeae.

Question 56

Third Generation Cephalosporins Pharmokinetics

Answer 56

Ceftriaxone t1/2 = 7-8 hours

Question 57

Third Generation Cephalosporins Clinical Uses

Answer 57

Ceftriaxone used for severe infections, meningitis, endocarditis Ceftazidime/avibactam approved for complicated, resistant intra-abdominal or UTIs Can penetrate body fluids and tissues, including CSF

Question 58

Third Generation Cephalosporins Excretion

Answer 58

Renally eliminated, except for ceftriaxone (biliary excretion)

Question 59

Four Generation Cephalosporins

Answer 59

Cefepime (IV only)

Question 60

Fourth Generation Cephalosporins Spectrum of Activity

Answer 60

Spectrum comparable to 3rd generation, plus Pseudomonas aeruginosa multi-drug resistant strains More resistant to hydrolysis by beta-lactamases

Question 61

Fourth Generation Cephalosporins Clinical Uses

Answer 61

Useful in treatment of Enterobacter infections Also treats gonorrhea, community-acquired pneumonia, meningitis, UTIs, Lyme disease, and encephalopathy Distributes well into CSF

Question 62

Fourth Generation Cephalosporins Excretion

Answer 62

Renally eliminated

Question 63

Fifth Generation Cephalosporins

Answer 63

Ceftaroline (IV)

Question 64

Fifth Generation Cephalosporins MOA

Answer 64

Binds to the mutated PBP that confers resistance to almost all other beta-lactams

Question 65

Fifth Generation Cephalosporins Spectrum of Activity and Clinical Uses

Answer 65

Active against organisms susceptible to third-generation cephalosporins Mostly reserved for MRSA

Question 66

Cephalosporins Major ADRs (2)

Answer 66

1. Cross-reactivity with penicillins | 2. Some cephalosporins have anti-vitamin K (bleeding) - cefotetan

Question 67

Monobactams

Answer 67

Aztreonam (IV or nebulized)

Question 68

Monobactams Spectrum of Activity

Answer 68

Narrow-spectrum No gram-positive activity Gram-negative spectrum similar 3rd generation cephalosporins Highly resistant to beta-lactamases

Question 69

Monobactams Clinical Uses

Answer 69

Used to treat serious infections (pneumonia, meningitis, and sepsis) caused by susceptible gram-negative pathogens

Question 70

Monobactams Pharmokinetics

Answer 70

t1/2 = 1-2 hours Renally eliminated Penetrated the BBB

Question 71

Monobactams ADRs

Answer 71

Major toxicity uncommon | Skin rashes, elevations of serum aminotransferases

Question 72

Monobactams Considerations

Answer 72

Safe for patients with penicillin allergies, EXCEPT ceftazidime

Question 73

Carbapenems

Answer 73

Imipenem/cilastatin, doripenem, ertapenem, meropenem | All administered IV

Question 74

Carbapenems Spectrum of Activity

Answer 74

Broad-spectrum agents | Important in empiric therapy and against resistant organisms

Question 75

Carbapenems Clinical Uses

Answer 75

UTIs, LRIs, intra-abdominal and gynecological infections, skin, soft tissue, bone, joint infections

Question 76

Carbapenems Pharmokinetics

Answer 76

``` Renally eliminated (70%) Imipenem/cilastatin t1/2 = 1 hour Ertapenem t1/2 = 4 hours Imipenem is hydrolyzed to a toxic metabolite in the proximal tubular epithelium by a renal dipeptidase; cilastatin inhibits renal dipeptidase ```

Question 77

Cabapenems ADRs

Answer 77

Nausea and vomiting common | Cross-reactivity with beta-lactams

Question 78

Glycopeptides

Answer 78

Vancomycin, dalbavancin, oritacancin, teicoplanin, and telavancin

Question 79

Glycopeptides Spectrum of Activity

Answer 79

Effective against gram-positive organisms and some anaerobes

Question 80

Glycopeptides MOA

Answer 80

Inhibits cell wall synthesis by preventing polymerization into glycan strands and prevents cross-linking via transpeptidase (PBP)

Question 81

Glycopeptides Clinical Uses

Answer 81

Primary use is Staph/Strep infection in patients with penicillin/cephalosporin hypersensitivities

Question 82

Glycopeptides Pharmokinectics

Answer 82

Administered IV Poor oral distribution (oral formulation limited to treat C. difficile) Renally excreted

Question 83

Glycopeptides ADRs

Answer 83

ADRs are frequent with parenteral administration, though most are minor and reversible Phlebitis at injection site Ototoxicity is rare, but dose-related, especially with other ototoxic drugs like aminoglycosides (tinnitus, high-tone deafness, hearing loss, and possible deafness) Nephrotoxicity is encountered regularly, especially with other nephrotoxic drugs (aminoglycosides) Histamine-mediated “red (neck) man syndrome” with sudden infusion; can prolong infusion or pretreat with an antihistamine

Question 84

Lipopeptides

Answer 84

Daptomycin

Question 85

Lipopeptides MOA

Answer 85

Cyclic compounds with lipophilic “tails” that insert into the plasma membrane and disrupt the cell wall through membrane depolarization leading to cell death

Question 86

Lipopeptides Spectrum of Activity

Answer 86

Similar to vancomycin Effective against some gram-positive, vancomycin-resistant strains (VRSA) Used to treat skin and soft tissue infections, bacteremia, endocarditis

Question 87

Lipopeptides Excretion

Answer 87

Renally eliminated

Question 88

Lipopeptides ADRs

Answer 88

Can cause myopathy (monitor creatine phosphokinase levels) | Can also cause allergic pneumonitis in patients with prolonged therapy

Question 89

Fosfomycin MOA

Answer 89

Inhibits one of the first steps in the synthesis of peptidoglycan by inhibiting enolpyruvyl transferase: prevents formation of UDP-N-acetylmuramic acid, the precursor of N-acetylmuramic acid

Question 90

Fosfomycin Spectrum of Activity

Answer 90

Active against gram-positive and gram-negative organisms | Used for uncomplicated UTIs

Question 91

Fosfomycin Pharmokinetics

Answer 91

40% oral bioavailability t1/2 = 4 hours Renally eliminated

Question 92

Fosfomycin ADRs

Answer 92

Diarrhea, vaginitis, nausea, headache