Cell Wall Inhibitors

Question 1

There are 4 generations of Cephalosporins, list what antibiotics fall under each generation

Answer 1

1st Generation: cephalexin, cefazolin, cefadroxil

2nd Generation: cefaclor, cefproxzil, cefoxitin, cefuroxime

3rd Generation: cefdinir, cefixime, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone

4th Generation: cefepine

Question 2

For maximal effect of cell wall inhibitors, what is required? What are the major members of the cell wall inhibitor class?

Answer 2

Maximum effect requires actively proliferating microorganisms
*They are generally bactericidal, so shouldn’t combine with bacteriostatic since may be less effective

Major members: Beta-lactam, Vancomycin, Daptomycin, and Bacitracin

Question 3

List the subclasses that are beta-lactam compounds

Answer 3

Penicillins
Cephalosporins
Carbapenems
Monobactams
Beta lactamase inhibitors

Work by undergoing acylation to covalently bind to trans-peptidase

Defined by their beta-lactam rings which are unstable to pH and beta-lactamases (i.e. from bacteria)

Subclasses are defined by their beta-lactam ring modifications (substituting side chains can result in alteration to antimicrobial spectrum, absorption, characteristics, and lactamase deactivation resistance)

Question 4

What is penicillin mechanism of action and how do bacteria become resistant to its effects?

Answer 4

Mechanism: binds/inhibits transpeptidases (aka penicillin binding proteins) which are responsible for catalyzing cross-linking of peptidogylcans (last step in cell wall synthesis) = unstable membrane ruptures
Does NOT work against organisms with no cell wall

Resistance:
Beta-lactamase inactivation (MOST COMMON)
PBP modification so PCN can’t bind (i.e. MRSA and PCN-resistant pneumococci, can overcome by increasing dose)
Impaired drug penetration (gram negative rods change porins or downregulation)

Question 5

What are the classes of penicillins?

Answer 5

Natural PCN
Aminopenicillins
Penicillinase-Resistant PCN
Antipseudomonal PCN

Question 6

Which PCN are the natural PCN and what do they target?

Answer 6

Penicillin G or Penicillin V
(PCN G is acid labile so can only given IV, PCN V can be taken orally)

PCN G and V are narrow spectrum and penicillinase sensitive
BEST against sensitive strains of gram positive cocci but NOT staphylococcus (i.e. Streptococcus, Enterococcus faecalis, Listeria monocytogenes)…also anaerobes like Bacteroides and Fusobacterium… as well as some gram negative (i.e. E.coli, H. influenzae, N. gonnorhoeae, Treponema pallidium and susceptible Pseudamonas)

Treats upper and lower respiratory tract, throat, skin and GU tract infections

Prophylaxis for rheumatic fever, dental procedures for high risk endocarditis, gonorrhea or syphilis exposure

*NOT active against gram negative or enterococci but DOES have activity against anaerobes above the diaphragm

Question 7

Give 2 PCNs classified as Aminopenicillins and how they are different from natural PCN

Answer 7

Ampicillin and Amoxicillin

Activity of PCN G but with added coverage of gram-negative cocci and Enterobacteriaceae
*Not active against Treponema sp. or Actinomyces sp.

Used for URI, uncomplicated UTI, meningitis, salmonella (but therapeutic uses depends on resistance patterns in the area)

Resistance led to combining these with beta-lactamase inhibitors = Augmentin (amoxicillin with clavulanic acid), Unasyn (ampicillin with sulbactam)
*These combos offer better coverage of H.influenzae and Klebsiella sp.

Question 8

When are Penicillinase-Resistant PCN indicated for use? Name them
(aka “Antistaphylococcal PCN)

Answer 8

Nafcillin, Oxacillin, Dicloxacillin
(Methicillin and Cloxacillin no longer available in US… since resistance to i.e. methicillin lead to MRSA)

These are narrow spectrum and for treatment of staphylococcal infections with high-beta lactamase production (i.e. in cellulitis or endocarditis)
*Does NOT work against gram negative or anaerobic organisms

Question 9

What do Antipseudomonal Penicillins cover? Give examples

Answer 9

Piperacillin, Ticarcillin, Carbenicillin

Activity of PCN G with more gram-negative coverage that includes pseudomonas, H. influenzae and Klebsiella sp.
(preferred choice if target is pseudomonas)

Treats gram-negative infection in combo with aminoglycosides (i.e. bacteremia, pneumonias, resistant UTI, burn infections)

Paired with beta-lactamase inhibitors to deal with resistance i.e. Zosyn (piperacillin and tazobactam), Timentin (ticarcillin and clavulanic acid)

*Like the aminopenicillins, not active against Treponema palladium or Actinomyces sp.

Question 10

How do beta-lactamase inhibitors work? Name the combo antibiotics using beta-lactamase inhibitors

Answer 10

Beta-lactamase inhibitors = clavulanic acid, sulbactam, tazobactum

Suicide inhibitors by irreversibly binding to many lacatamases, with a spectrum that extends that of the antibiotic it is combined with

i. e. Aminopenicillin combos (Augmentin and Unasyn)
i. e. Antipseudomonal combos (Timentin and Zosyn)

Adding this increases coverage of H. influenzae, staph, Moraxella catarrhalis
Variable coverage against gram-negative due to resistance against the beta-lactamase inhibitor itself (pseudomonas, enterobacter, E.coli, Klebsiella, Serratia)

Question 11

Which PCN drugs are restricted in terms of route they are allowed to be administered?

Answer 11

Oral only = PCN V, and Amoxicillin with/without clavulanic acid

Oral and IV = Nafcillin and Ampicillin

IV only = Antipseudomonal PCN i.e. piperacillin with/without tazobactam

Depot (IM) = procaine and benzathine PCN G

Question 12

What are the pharmacokinetics of PCNs and how does it factor into delivery route?

Answer 12

Most can not be absorbed orally and food can decrease absorption of available oral PCN (IV can bypass this and is preferred for serious infections)

Widely distributed with tissues and to serum
Only penetrates CNS when meninges inflamed
Poor penetration of eye, CNS and prostate

Kidneys are main route of elimination since most PCN not metabolized (10% filtered and 90% actively secreted into urine, active secretion can be blocked by Probenecid)
Therefore need to adjust dose in renal insufficiency

*Anti-pseudomonal PCN and Nafcillin removed via biliary excretion

Question 13

What are the ADRs of using PCN?

Answer 13

Overall safe and well-tolerated

Risk of HYPERSENSITIVITY i.e. cross-reactivity (allergy in response to beta-lactam ring and derivatives), anaphylactic shock (rare), serum sickness (urticaria, rash, fever, angioedema), interstitial nephritis and hemolytic anemia

Can try using desensitization protocols

Other ADRs: GI upset for oral (very common), diarrhea, secondary infections like candida, reactions specific to a particular agent (hepatitis from Oxacillin, neutropenia from Nafcillin, abnormal platelet aggregation with Ticarcillin and Carbenicillin)

Question 14

What is the general guideline on PCN when concerned about drug interactions?
Any other PCN drug interactions?

Answer 14

Do not give PCN (generally bacteriacidal) with a TCN (tetrocycline) or other bacteriostatic agent

Anti-pseudomonal PCN affects warfarin metabolism, will need to increase warfarin dose

Question 15

Compare and contrast Cephalosporins with Penicillins

Answer 15

Both are: similar chemically, in toxicity, and in mechanism… inhibit cell-wall synthesis

In contrast: PCN has beta-lactam ring, while cephalosporins have a dihydrothiazine ring that’s connected to the beta-lactam ring… cephalosporins are more resistant to beta-lactamases and have broader spectrum

*Category B in pregnancy

Question 16

How does resistance develop against cephalosporins in comparison to PCN?

Answer 16

Much of the same way, it is harder to destroy cephalosporins but not impossible

Mutations for resistance;
Or plasmids carrying resistance factors (mutations in PBP, beta-lactamase production, porin alterations in gram-negative)

Question 17

Name 1st Generation Cephalosporins and their uses

Answer 17

Cefazolin (IV)
Cephalexin and Cefadroxil (PO)
Similar to antistaph and aminopenicillins

Good for aerobic gram positive, anaerobes above the diaphragm, and community-acquired gram negative organism
-Stable against penicillinase produced by staph

Use for septic arthritis, skin infection, acute otitis media, pharyngitis, prophylaxis for surgery, UTI, and patients with gram positive infections but can’t take penicillins
(but does not work against Listeria, enterococci or MRSA)

Question 18

What are the two classes under 2nd Generation Cephalosporins?

Answer 18

1. Added gram-negative coverage: IV and PO for Cefuroxime, Cefaclor, Cefprozil against i.e. Moraxella, Neisseria, Salmonella, Shigella, H. influenzae… can treat sinusitis, otitis, bronchitis, CAP, skin infection, UTI)
2. Added anaerobic coverage: Cefotetan and Cefoxitin (IV) against i.e. particularly B. Fragilis… can treat abdominal and gynecologic infections (since in these cases it’s more of an issue with anaerobes)
   * (does not work against Listeria, enterococci, MRSA)

Question 19

How do 1st Generation and 2nd Generation Cephalosporins compare?

Answer 19

1st generation is somewhat better than 2nd for gram positive

2nd generation is SIGNIFICANTLY better than 1st generation for gram negative

Question 20

What is the main new feature when you move onto 3rd Generation Cephalosporins?

Answer 20

3rd generation expands gram-negative coverage and now allows BBB penetration (3rd-5th can penetrate BBB)

Question 21

What are the 3rd Generation Cephalosporins categorized based on route/administration?

Answer 21

Oral: Cefpodoxime, Cefdinir, Cefixime, Cefditoren, Cefibuten
(note: oral agents can’t penetrate CSF)

IV/IM: Cefotaxime, Ceftriaxone (long half life)

IV: Ceftazidime (has increased anti-pseudomonal coverage)…approved to be combined with Avibactam (beta-lactamase inhibitor) and called Avycav as the combo

Question 22

How are 3rd Generation Cephalosporins used clinically? How does it compare to 1st and 2nd generation?

Answer 22

Variety of serious infections that may be resistant to other agents both empirically and in combination (also for PCN-resistant pneumococcus)

FIRST CHOICE drug for meningitis, also used for pneumonia, sepsis, peritonitis, UTI, skin infection, osteomyelitis, and Neisseria gonorrhea infections

Ist Generation is still better than 2nd and 3rd for gram-positive

3rd and 2nd generation are equally better than 1st generation for gram-negative

Question 23

What do 4th Generation Cephalosporins further add in terms of coverage? Give example

Answer 23

Good against both gram-positive and gram-negative along with adding more anaerobic coverage
i.e. P aeruginosa, H influenzae, N meningitidis, N gonorrhoaea, and enterobacteriaceae (which are resistant to the other cephalosporins)

Treat intra-abdominal infections, respiratory tract infections, skin infections

i.e. Cefepime IM/IV (no oral option available)

4th generation better than 2nd or 3rd against gram-positive
4th generation is equal or better than 2nd and 3rd against gram-negative

Question 24

Give 2 examples of the 5th Generation Cephalosporin

Answer 24

Ceftaroline fosamil: used to treat complicated skin and skin infections like against MRSA, and CAP… works by inhibiting PBP needed for cell wall synthesis and stable against being hydrolyzed by many gram-positive beta-lactamases
(tolerated well, positive Coombs test without hemolysis)

Ceftolozane plus tazobactam (Zerbaxa): used to treat complicated UTI including pyelonephritis and complicated intra-abdominal infections (when combined with metronidazole)

*5th generation are available in IV only

Question 25

What are the pharmacokinetics for Cephalosporins?

Answer 25

Oral cephalosporin is absorbed rapidly i.e. active transport from GI for Cephalexin, Cefaclor, Cefixime… passive absorption into SI cells to be hydrolyzed and excreted into blood for Cefuroxime and Cefpodoxime

Food may increase, decrease, or not affect absorption

Cephalosporin extensively distributes but most don’t cross into CSF (except Cefuroxime, Cefotaxime, Ceftriaxone, and Cefepime)

Elimination is mostly via kidneys

Question 26

What are the toxicities/ADRs of Cephalosporins?

Answer 26

Hypersensitivity: same spectrum covered as PCN but structure is different enough from PCN to allow use in PCN-allergic patients (5-10% cross-sensitivity)…but for high risk reactions like anaphylaxis or angioedema to PCN should not risk using cephalosporin

Increased serum level if taken with Probenecid

Increases effects of Warfarin (if Cefotetan, Cefazolin, Cefoxitin, Ceftriaxone)

ADR: well tolerated but there is GI upset (N/V/D) and 1-3% allergic reaction (rash, fever, urticaria, eosinophilia)…Ceftriaxone can lead to cholelithiasis due to preciptation…possible blood dyscrasias (eosinophilia, thrombocytopenia, leukopenia which should result with d/c)… Cefoperazone and Cefotetan have methylthiotetrazole side chains can result in hypoprothrombinemia from interfering with vitaminK-dependent clotting factor synthesis and can react with alcohol leading to Disulfiram-like reaction

Superinfection: resistant organism and fungi may proliferate

Question 27

Which class is the most broad spectrum of the beta-lactum class of antibiotics? Give examples

Answer 27

Carbapenems (covers gram positive and negative) and similar to aminoglycosides

The following are IV only

i. e. Ertapenem and Imipenem-Cilastin: covers gram-negative bacilli/P.aeruginosa, gram-positive bacteria/MRSA or Enterococcus, and anaerobes/Bacteriodes… these two carbapenems can treat UTI, pneumonia, intra-abdominal infections, skin and soft tissue infections
* Imipenem given with Cilastin in order to decrease its renal metabolism (protective function for drug itself, inhibits renal dehydropeptidase I that breaks beta-lactam ring to inactivate Imipenem, but not Meropenem or Ertapenem)… also is DOC for enterobacter (but no effect against enterococcus, C.diff, MRSA, former pseudomonads cepacia and maltophilia)

i.e. Meropenem: greater activity against gram-negative…treats intra-abdominal infections and meningitis for kids younger than 3 months

Question 28

What are the metabolic difference among some of the Carbapenems? Toxicities?

Answer 28

All must be given parenterally (IV) because they are unstable in the stomach

Well-tolerated but possible N/V, phlebitis at infusin site, leukopenia, elevated LFTs (seizures with renal failure patients)
*Cross-sensitivity with PCN (HIGH)

Well distributed in the body (i.e. Meropenem into CSF)

Renally excreted
(Renal) Dehydropeptidase I inactivates Imipenem (but not Meropenem or Ertapenem)

Question 29

What are the possible drug interactions from using Carbapenems?

Answer 29

Ertapenem needs to be given in a separate line (possible clumping) i.e. do NOT infuse with dextrose or other meds

Meropenem reduces Valproic Acid levels

Pregnancy Categories:
Category B (no risk) = Meropenem and Ertapenem
Category C (risk not ruled out) = Imipenem/Cilastin

Question 30

Name and discuss the only Monobactam available in the U.S.

Answer 30

Aztreonam (Azactam)

Indications: Gram-negative rods ONLY (narrow spectrum) i.e. to treat pneumonia, soft tissue infection, UTI, intra-abdominal and pelvic infections

Mechanism: Binds to PBP to inhibit mucopeptide synthesis in cell wall
Resistant to most beta-lactamases, acid labile, widely distributed that includes inflamed meninges, excreted UNCHANGED in urine

ADR: No major toxicity and is Category B and safe in kids older than 9 months
No reported drug interactions
Possible rash, N/D, elevated LFT, transient eosinophilia

Question 31

If a patient is allergic to both PCN and cephalosporin, what is another option?

Answer 31

Use a monobactam
(no cross-reactivity)

But narrow spectrum (gram-negative rods only) so only start if confirmed pathogen with a culture

Question 32

Cycloserine is what kind of antibiotic?

Answer 32

Cell wall inhibitor

Indication: ONLY used as a secondary anti-tubercular drug

Mechanism: Competitive inhibition of 2 enzymes for peptidoglycan synthesis

ADR: VERY TOXIC that is worse with renal impairment, has CNS toxicity that is reversible with pyridoxine
(also Cyclosporine is highly susceptible to resistance)

Question 33

Vancomycin is what kind of antibiotic?

Answer 33

Cell wall inhibitor, but acts on a different binding site than beta-lactams (is bactericidal)

Indications: Gram-positive organisms ONLY (even those that produce beta-lactamase)
MAIN indication for IV Vanco is for MRSA or Staph Epi…but also covers endocarditis, sepsis, osteomyelitis, wound infection, PCN-resistant pneumococcus in pneumonia
*Reserved for patients allergic to beta-lactams and for serious gram-positive infections, for MRSA, and for superinfection (i.e. antibiotic-associated enterocolitis particularly C.Diff… this would be the only case to give Vancomycin orally since most normal GI flora is gram-negative and it is not well-absorbed in GI)

Issues with Resistance: especially with E. faecium and some MRSA strains… resistance development may be from plasmid born/acquired (VanA phenotypes in which peptidoglycan component is modified to prevent Vanco binding), or innate resistance like with most gram-negatives that have outer membrane penetration resistance

Question 34

How is Vancomycin administered and how does it distribute in the body? ADRs?

Answer 34

Bad oral absorption, not given orally unless to treat C.diff-induced colitis

Use IV to keep levels in therapeutic range and avoid toxicity (after reaching steady-state, monitor with trough levels)

Widely distributed including CNS when meninges are inflammed

90% renally excreted (not metabolized) so half-life depends on CrCl (so may be prolonged depending on renal insufficiency, then need to adjust dose)

ADR: local and IRRs (Red Man Syndrome), phlebitis, ototoxicity (irreversible), nephrotoxicity

Question 35

Oritavancin

Answer 35

Indications: Gram-positive including MRSA, approved for skin infections

Mechanism: Concentration-dependent bactericidal by inhibiting wall synthesis

Metabolism: Given IVPB, 85% protein bound with half-life of 245 hours, renally excreted unchanged over 2 weeks after admin

ADR: Nausea, headache

Question 36

Daptomycin

Answer 36

Indications: Gram-positive ONLY including the ones producing beta-lactamase and includes complicated skin infections, bacteremia, osteomyelitis
*Reserved for beta-lactam allergic patients that have gram-positive infections i.e. MRSA or Enterococcus spp.

Mechanism: Give IV, highly protein bound, need to adjust dose with CrCl less than 30 mL/min

Question 37

Dalbavacin

Answer 37

Indication: For Gram-positive, bactericidal against Staphylococcus aureus and Streptococcus pyogenes…indicated in skin infection and IVPB is the only option

Mechanism: Dalbavacin is a lipoglycopeptide that prevents cross-liking in cell wall synthesis

Metabolism: 93% protein/albumin bound, 33% renally excreted unchanged, 12% as hydroxy metabolite, and 20% as feces unchanged

ADR: N/V/D and headache

Question 38

Bacitracin

Answer 38

Indication: Most gram-positive cocci and bacilli (often combined with neomycin and/or polymyxin i.e. for Missouri irrigation solution)
*Limited to topical use because toxic

Mechanism: Polypeptide compound that interferes with recycling steps of phospholipid carrier of peptidoglycan synthesis (membrane lipid target means it is not very specific, hence its toxicity)