Cell Wall Inhibitors Flashcards
There are 4 generations of Cephalosporins, list what antibiotics fall under each generation
1st Generation: cephalexin, cefazolin, cefadroxil
2nd Generation: cefaclor, cefproxzil, cefoxitin, cefuroxime
3rd Generation: cefdinir, cefixime, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone
4th Generation: cefepine
For maximal effect of cell wall inhibitors, what is required? What are the major members of the cell wall inhibitor class?
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
List the subclasses that are beta-lactam compounds
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)
What is penicillin mechanism of action and how do bacteria become resistant to its effects?
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)
What are the classes of penicillins?
Natural PCN
Aminopenicillins
Penicillinase-Resistant PCN
Antipseudomonal PCN
Which PCN are the natural PCN and what do they target?
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
Give 2 PCNs classified as Aminopenicillins and how they are different from natural PCN
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.
When are Penicillinase-Resistant PCN indicated for use? Name them
(aka “Antistaphylococcal PCN)
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
What do Antipseudomonal Penicillins cover? Give examples
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.
How do beta-lactamase inhibitors work? Name the combo antibiotics using beta-lactamase inhibitors
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)
Which PCN drugs are restricted in terms of route they are allowed to be administered?
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
What are the pharmacokinetics of PCNs and how does it factor into delivery route?
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
What are the ADRs of using PCN?
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)
What is the general guideline on PCN when concerned about drug interactions?
Any other PCN drug interactions?
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
Compare and contrast Cephalosporins with Penicillins
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
How does resistance develop against cephalosporins in comparison to PCN?
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)
Name 1st Generation Cephalosporins and their uses
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)
What are the two classes under 2nd Generation Cephalosporins?
- 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)
- 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)
How do 1st Generation and 2nd Generation Cephalosporins compare?
1st generation is somewhat better than 2nd for gram positive
2nd generation is SIGNIFICANTLY better than 1st generation for gram negative
What is the main new feature when you move onto 3rd Generation Cephalosporins?
3rd generation expands gram-negative coverage and now allows BBB penetration (3rd-5th can penetrate BBB)
What are the 3rd Generation Cephalosporins categorized based on route/administration?
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
How are 3rd Generation Cephalosporins used clinically? How does it compare to 1st and 2nd generation?
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
What do 4th Generation Cephalosporins further add in terms of coverage? Give example
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
Give 2 examples of the 5th Generation Cephalosporin
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
