Cell Wall Inhibitors ABX med class- Quiz 2

Question 1

Cell Wall Inhibitors

Answer 1

-Selectively interfere with synthesis of the bacterial cell wall
-Antibiotics that inhibit cell walls require actively proliferating microorganisms

Classes:
Penicillins
Cephalosporins
Carbapenems
Monobactams
ß Lactam Inhibitor + Antibiotic Combinations
Lipoglycopeptides

Question 2

Penicillins

Answer 2

Vary based on the R group side chain attached which influences:
-Spectrum of activity
-Stability in stomach acid
-Cross-sensitivity
-Susceptibility to bacterial enzymes

MOA: Interfere with final stage of cell wall synthesis known as
transpeptidation (PCNs compete for & bind to enzymes called penicillin binding proteins [PBPs] which facilitate cross-linking of the cell wall, resulting in weak cell wall and death)
-Are bactericidal and work in a time-dependent mode

Works against: GRAM POSITIVE

Question 3

Which are the natural Penicillins?

Answer 3

-Penicillin G and Penicillin V

-Despite increasing resistance to PCN, still DOC for treating gas gangrene/ syphilis

-Pen V= ONLY available on oral form (not used for severe infections d/t lack of absorption)

-Pen G= IM injection
(more potent than V)

Question 4

What are the semisynthetic Penicillins?

Answer 4

-Ampicillin and Amoxicillin

-The addition of an R group extends their coverage to gram - as well

-Both of these are used widely in: treatment of RESPIRATORY INFECTIONS (and by dentists to prevent bacterial endo)

-Resistance is a huge problem—this limits the use of these agents with gram - bugs

Question 5

What are the Antistaphylococcal Penicillins?

Answer 5

-Nafcillin, Oxacillin, Dicloxacillin
ß-lactamase [penicillinase]-resistant penicillins

-Their use is restricted for infections caused by PENICILLINASE- PRODUCING STAPHYLOCOCCI including MSSA

-MRSA—source of serious infections and is resistant to most available ß-lactam antibiotics

-Penicillinase-resistant penicillins have minimal to no activity against gram - infections

Question 6

What is the Antipseudomonal Penicillin?

Answer 6

-Piperacillin

-Active against Pseudomonas aeruginosa (GRAM NEGATIVE)

-When combined with Tazobactam [Zosyn] extends the antimicrobial spectrum to cover penicillinase producing organisms

-Mainly used to treat:
-PNA/UTI/Bacteremia
-Skin/soft tissue infections

Question 7

What are the 3 ways resistance can occur in spite of a ß-lactam antibiotic?

Answer 7

1. ßlactamase production
2. Decreased permeability of the drug
3. Altered penicillin binding proteins [PBPs]

Question 8

How does Beta lactamase get produced?

Answer 8

-This family of enzymes breaks
down the bond of the ßlactam ring, which causes loss of bactericidal activity—they are the MAJOR cause of resistance to PCNs and are becoming more of an issue

-Gram + organisms secret BL
extracellularly

-Gram – organisms inactivate BL
drugs in the periplasmic space

Question 9

How does Decreased Permeability of the Drug work?

Answer 9

-Decreased penetration of the antibiotic through the outer cell membrane of the pathogen prevents
the drug from reaching target PBPs

-Reduced penetration of the drug into gram – bugs is more of a problem—they have a complex cell wall that includes aqueous channels [porins]

-Presence of an efflux pump, actively removes the drug from the site of action can also reduce amount
of intracellular drug [Klebsiella pneumoniae]

Question 10

How do Altered Penicillin Binding Proteins [PBPs] happen?

Answer 10

-Antibiotic exposure can prevent cell wall synthesis and lead to changes or lysis of susceptible bacteria

-Modified (PBPs) exhibit reduced affinity for β-lactam antibiotics, requiring impractically high drug concentrations to achieve bacterial killing.

-This mechanism underlies MRSA resistance to most β-lactam antibiotics

Question 11

Pharmacokinetics of PCN’s

Answer 11

-Route of admin is determined by stability of drug to gastric acid and severity of infection

-Acidic environment of stomach is unfavorable for PCN’s

-Distribute well throughout the body

-All cross the BBB but NONE have teratogenic effect

-Primary excretion is through kidney so must renally dose if kidney issues

Question 12

ADE’s of PCN’s

Answer 12

-Among the safest drugs on the market

-Hypersensitivity
-Diarrhea
-Nephritis
-Neurotoxicity
-Hematological effects (decreased coagulation/ cytopenia’s)

Question 13

Cephalosporins

Answer 13

-ß-lactam drugs related structurally and functionally to PCNs

-Same MOA as PCNs and affected by same resistance mechanisms

-Tend to be more resistant than PCNs to certain ß-lactams

Question 14

What 3 pathogens are NEVER covered by Cephalosporins?

Answer 14

Listeria, C. difficile and Enterococcus

Question 15

First generation Cephalosporins

Answer 15

-GRAM POSITIVE coverage

-Like a PCN G substitute (except that cover MSSA)

-Cephalexin= PROTOYPE for 1st gen
-Used orally for PHARYNGITIS

-Other Ex: Cefazolin

Question 16

Second generation Cephalosporins

Answer 16

-More activity against GRAM NEGATIVE

-Cefuroxime Sodium= PROTOTYPE for 2nd gen
-Crosses BBB, used for: BRONCHITIS/PNA IN THE ELDERLY AND IMMUNOCOMPROMISED

Question 17

Third generation Cephalosporins

Answer 17

-IMPORTANT PLAYERS IN TREATING INFECTIOUS DISEASE

-Get gram - and gram + coverage

-Use these drugs cautiously—they can foster bacterial resistance and cause C. difficile infection

-Ceftriaxone and Cefotaxime are
DOC in meningitis

-Ceftriaxone= PROTOYPE for 3rd generation
-Has the longest alf life of any ceph
-Can be used in renal insufficiency and good penetration to bone/ CSF

-Mainly used for:
-MENINGITIS
-Severe resp infections
-Sepsis/Bactermia

Question 18

Fourth Generation Cephalosporins

Answer 18

-Must be given parenterally

-Wide spectrum with coverage of Staph and Strep

-Has greater stability against B-lactamases

-Cefepime= PROTOTYPE for 4th gen
-Active against Pseudomonas aeruginosa

-Mainly used in:
Cefepime is often used in critically ill patients d/t broad coverage and beta-lactamase stability, making it a go-to empiric therapy for SEVERE INFECTIONS.

Question 19

Advanced Generation Cephalosporins

Answer 19

-Broad spectrum—only ß-lactam in the US that covers MRSA

-Twice day dosing limits its use outside of a hospital

• Ceftaroline =PROTOTYPE for advanced gen

-Mainly used in:
-Skin/ skin structure infections
-CAP

THINK MRSA

Question 20

Pearls for Practice for
Cephalosporins

Answer 20

-1 st generation drugs—gram + bugs-

-2 nd generation drugs—gram – bugs

-3rd generation drugs—covers both but you lose some gram + coverage

-4th generation—broader coverage and covers some aerobes and Pseudomonas

Question 21

How does resistance to cephalosporins occur?

Answer 21

1. Hydrolysis of the beta-lactam ring by ß-lactamases
2. Reduced affinity for PBPs

Question 22

Pharmacokinetics for Cephalosporins

Answer 22

-Many have to be given IV or
IM because of poor oral absorption

-Distribute very well into body fluids

-Cephs not thought of to treat CNS inf

-Ceftriaxone and Cefotaxime used
in treating neonatal and childhood meningitis from H. influenzae (WHY DO I FEEL THIS IS A TEST ?)

-Cefazolin used for surgery prevention

-Renal excretion, Dose reduction in
renal disease

-Ceftriaxone is excreted through the
bile into the feces, no dose reduction needed (Only exception)

Question 23

ADE’s of Cephalosporins

Answer 23

-Generally well tolerated like PCN

-Those who have had anaphylaxis, StevensJohnson Syndrome or Toxic Epidermal Necrolysis to PCNs should not be prescribed a Cephalosporin

-Use with caution in those with PCN allergy

-Cross-reactivity between Cephalosporins and PCNs is 5-10% (low)

• Highest chance of cross-sensitivity between PCN is with 1st generation Cephalosporins

Question 24

What are the other B-lactam antibiotics?

Answer 24

1. Carbapenems
   2.Monobactams

Question 25

Carbapenems

Answer 25

-Synthetic ß-lactam antibiotics that
differ from PCNs in that sulfur atom
of one ring has been externalized and replaced by a carbon atom

-Resists breakdown by ß-lactamases, but not metallo-ßlactamases

-Can be used empirically as it is
active against gram +
and gram – ßlactamase producing
pathogens, anaerobes and
Pseudomonas

-Imipenem=PROTOTYPE drug

-Ex: Imipenem, Meropenem,, Doripenem, Ertapenem

-Mainly used in:
Last-resort, used for serious, drug-resistant infections, particularly ESBL-producing and MDR Gram-negative bacteria.

Question 26

Pharmacokinetics of Carbapenems

Answer 26

-All carbapenems are given IV

• Imipenem, Meropenem and Doripenem penetrate well
  into tissues, fluids and CSF [when meninges are inflamed]

-Excreted by glomerular filtration, need to dose reduce in CKD

-Because Imipenem is cleaved by a dehydropeptidase in the proximal tubule, it is combined with cilastin to protect the drug from this cleavage

Question 27

ADE’s of Carbopenems

Answer 27

-Nausea, Vomiting and Diarrhea can be seen with Imipenem

-High levels of Imipenem can cause seizures [less chance with other
carbapenems]

-Because carbapenems and PCNs share a common core cross
sensitivity may occur

-Use carbapenems cautiously in those with PCN allergy (rate is <1%)

Question 28

Monobactams

Answer 28

-Disrupt bacterial cell wall synthesis—
unique because ß-lactam ring is not fused to another ring

-Aztreonam mainly covers gram – bugs

-Given IM/IV

-Relatively non-toxic, but can cause phlebitis, rash and elevated LFTs

-Safe drug used for those allergic to PCN, Cephalosporins, Carbapenems

-Renal dosage

-Aztreonam= PROTOTYPE

-Mainly used in:
-Treating serious Gram-negative infections, especially in patients allergic to penicillins or cephalosporins.

Question 29

ß-Lactamase Inhibitors

Answer 29

-Hydrolysis of the ß-lactam ring—destroys the antimicrobial effect

-ß-lactamase inhibitors, such as Clavulanic acid, Sulbactam and Tazobactam contain a ß-lactam
ring, but alone have no antimicrobial effects or cause any SE

-ß-lactamase inhibitors function by inactivating ßlactamases, and protect the antibiotics that are normal substrates for these enzymes

-ß-lactamase inhibitors are combined with ß-lactamasesensitive antibiotics, such as Amoxicillin, Ampicillin and
Piperacillin

-Mainly used in:
-Are essential in broad-spectrum therapy, particularly when Pseudomonas, ESBL, or anaerobes are concerns.

Question 30

Cephalosporin + ß-lactamase Inhibitor Combinations

Answer 30

-Ceftolozane + Tazobactam:
IV medication used to treat resistant multi-drug resistant P. aeruginosa

-Ceftazidime + Avibactam:
-IV medication with broad gram –
-Adding Avibactam allows the drug to resist hydrolysis against broad spectrum ß-lactamases

-Both of these drugs are used to treat
INTRA-ABDOMINAL INFECTIONS [with
Metronidazole] and for management
of COMPLICATED UTIs

-Are reserved for the
treatment of infections due to
multiple-drug resistant pathogens

Question 31

Carbapenem + ß-lactamase Inhibitor Combinations

Answer 31

-Meropenem + Vaborbactam:
-Approved for the treatment of complicated UTIs including PYELONEPHRITIS

Question 32

Vancomycin

Answer 32

-Tricyclic glycopeptide (bactricidal)

-Active against: gram + pathogens—MRSA, MRSE, Enterococcus, C. Diff

-Used in SKIN/SOFT TISSUE INFECTIONS, ENDOCARDITIS, PNA

-Dosing frequency depends on GFR—
monitoring creatinine clearance is needed to optimize exposure while minimizing toxicity

-Best cure rates occur when trough is 10-20 mcg/mL (Initial trough levels are drawn before the 4th or 5th dose to ensure proper dosing)

-ADEs: nephrotoxicity, infusion related reactions [“Red-Man”
Syndrome and phlebitis], ototoxicity

-Because resistance is now being seen—prudent use of the drug should take place

Question 33

Lipoglycopeptides

Answer 33

-“Vancin’s”

-Bactericidal concentration-dependent lipoglycopeptide drugs
active against gram + pathogens

-Spectrum is similar to Vancomycin—
staphylococcus, streptococcus and
enterococcus

-Are MORE potent than Vanco and may cover VR isolates

-Telavancin is an alternative to Vancomycin for acute bacterial skin
infections, hospital acquired pneumonia from resistant gram + organisms, including MRSA

-Use of Telavancin may be limited by ADEs: nephrotoxicity, risk of fetal harm, interactions with drugs that prolong the QTc, renal function and
pregnancy test must the evaluated before prescribing this drug, infusion reaction

-Ex. Telavancin, Oritavancin,
Dalbavancin

Question 34

Daptomycin

Answer 34

-Bactericidal concentration-dependent lipopeptide antibiotic
that is an alternative to other agents,(Vancomycin or Linezolid) to treat infections caused by resistant gram + organisms (MRSA and VRE)

-Used to treat complicated SSSIs/ BACTEREMIA/ RIGHT SIDED ENDOCARDITIS

-This drug is inactivated by pulmonary surfactants—so it cannot be used to treat pneumonia EVER

-Given IV once a day

-NOTE* Dapto is the only lipopeptide abx whos MOA is depolorization of cell membrane, inhibiting DNA/RNA synthesis as opposed to just inhibits bacterial wall synthesis*

Question 35

Fosfomycin

Answer 35

-Is a synthetic derivative of phosphonic acid that blocks cell wall synthesis

-Used for UTIs from E. coli or E. faecalis—is considered 1st line
for ACUTE CYSITIS

-Rapidly absorbed after oral ingestion

-Excreted in active form in urine and maintains high levels for days—
allowing for one time dosing

-ADEs: diarrhea, vaginitis, nausea and headache

Question 36

Polymyxins

Answer 36

-Are cation polypeptides that bind to phospholipids on bacterias cell membranes on gram - bugs

-Detergent like effects that disrupt cell membrane and cause cell death

-Concentration dependent bactericidal agents

-Polymyxin B= PROTOTYPE

-Use of these drugs is limited
due to renal and neurotoxicity
[when used systemically]

-With increasing gram – resistance, these agents are now used as
SALVAGE AGENTS for multi-drug
resistant infections (last ditch efforts)