Beta lactams and cell wall synthesis inhibitors (Fitz) Flashcards
Because B-lactams resemble ___, they inhibit cross-linking enzyme(s)/Transpeptidases
D-ala-D-ala
Which enzyme is a target of Pencillins (and other B lactams)?
transpeptidase
These penicillins are narrow spectrum but potent and effective drugs against sensitive strains of gram + cocci, certain gram - cocci, certain gram + anaerobic species, spirochetes
Natural penicillins –> G and V
What gram + cocci and diseases are clinically indicated for use of natural penicillins?
S. pneumo –> pneuomococcal pneumonia (resistant)
S. pypgenes –> pharyngitis, scarlet fever
S viridans group –> endocarditis
What are routes of Penicillin G? Penicillin V?
G –> IV, IM, PO (low bioavailability); distributed into CNS with inflamed meninges
V–> PO, stable at gastric, acidic pH and has good oral bioavailability
What is a complication of natural penicillins?
Hypersensitivity –> includes life-threatening anaphylaxis
This enzyme produced by bacterial pathogens renders them penicillin resistant
B lactamase –> cleaves B lactam rings, inactivating penicillin G and conferring drug resistance
B lactamase enzymes efficiently degrades these natural penicillins:
Penicillin G and V
B lactamase enzymes efficiently degrades these extended spectrum abx:
ampicillin, amoxicillin
B lactamase enzymes efficiently degrades these anti-pseudomonals:
ticarcillin and piperacillin
Name the anti-staphylococcal penicillins:
Methicillin, Nafcillin, Oxacillin, Dicloxacillin
Methicillin, Nafcillin, Oxacillin, and Dicloxacillin are drugs of choice for ___
penicillin-resistant BUT methicillin-sensitive organisms S aureus (MSSA)
Methicillin is not used clinically d/t this toxicity:
interstitial nephritis
What is the route, clearance, and toxicity associated with Nafcillin/
IV
hepatic, biliary
Hypersensitivity, Increase P450 induction
Oxacillin and Dicloxacillin each are PO, Renal/biliary, and both cause hypersensitivity
Methicillin and related anti-staphylococcal penicillins bind to __ involved in cell wall synthesis in MSSA
penicillin binding proteins
Alteration of __ gene and __ in S. aureus confers high-level resistance to Methicillin, oxacillin and other anti-staph penicillins despite the fact that they are not substrates for B lactamase. This is known as MRSA
mec A
PBP2
MRSA is due to alteration of ___ and not caused by B lactamase enzymes
PBPs (PBP2)
what is the drug of choice for MRSA?
Vancomycin
what are vancomycin uses for Gram +?
MRSA (S aureus)
MRSE (S epidermidis)
Enterococci (E faecalis, E faecium) –> avoid overuse to avoid vancomycin resistance
Special use to treat C difficile –> oral admin for topical effect in bowel (if metronidazole failed)
what activity does vancomycin have against gram - aerobes or anaerobes
no activity
Vancomycin binds to D-ala-D-ala blocking ___ elongation and cross-linking
peptidoglycan
list some vancomycin adverse effects:
Vanc-induced erythroderma or shock
Neprhotoxicity and ototoxicity
Dermatologic-rash
Phlebitis at injection site
These penicillins enter via porins, bind to PBPs in periplasm and disrupt cell wall integrity
extended spectrum Aminopenicillins –> Ampicillin and Amoxicillin
What gram + cocci and diseases are clinically indicated for extended spectrum aminopenicillins?
Gram + cocci: S pneumo, S pyogenes, S viridans, Enterococci
Respiratory infx –> CAP, sinusitis, bronchitis, pharyngitis. Amoxicillin is active against penicillin sensitive S pneumonia and often used for pharyngitis in children because of “taste”
what gram - org and diseases are clinically indicated for extended spectrum aminopenicillins?
H influenza: bronchitis in COPD
what would you add to ampicillin if there is resistance d/t B lactamase?
Sulbactam –> irreversibly inactivates enzyme; depletes B lactamase activity; spares ampicillin; Sulbactam has no inrinsic Abx effect
Ampicillin plus sulbactam - IV
what would you add to amoxicillin if there is resistance d/t B lactamase?
Clavulanic acid
Amoxicillin plus clavulanic acid - PO
List the antipseudomonal penicillins:
Ticarcillin
Piperacillin
What populations are at risk for Pseudomonas aeruginosa infx?
Burn pts
CF pts
Injection drug users
immunosuppressed
Ticarcillin and Piperacillin cover these orgs in addition to pseudomonas aeruginosa
Gram - rods
Enterobacter spp., E coli, proteus mirabilis, H influenza
which anti-pseudomonal is most potent?
piperacillin
what are some resistance mechanisms employed by pseudomonas aeruginosa?
altered PBPs
porin deficit- multi-drug resistance (MDR)
In what clinical scenarios would you use ticarcillin and piperacillin together with a B lactamase inhibitor?
Severe pneumonia in hospitalized pt with structural lung disease (COPD)
Neutropenic fever-sepsis
Aspiration pneumonia in hospitalized pt, or stroke victim
For empirical therapy of serious infx
Which B lactamase inhibitor can you add to Ticarcillin? Pipericillin?
Ticarcillin plus clavulanic acid
Pipericillin plus tazobactam
All Gen 1-3 cephalosporins are ineffective and lack activity against:
- Listeria monocytogenes
- Legionella spp
- Atypical mycoplasma
- MRSA
- Enterococci
what are the 1st generation cephalosporins?
Cefazolin (parenteral, IV, IM) –> penetrates well into bone
CEPHALEXIN (PO) –> 2x daily for pharyngitis
Cephradrine (Parenteral and PO)
1st generation cephalosporins have a useful spectrum of activity against:
gram + cocci, streptococci and staph aureus
NOT active against: MRSA, MRSE, enterococci
what are clinical uses of 1st generation cephalosporins?
Surgical prophylaxis if skin flora are likely pathogens; soft tissue and skin infx d/t S aureus, S pyogenes
what are the 2nd generation cephalosporins?
Cefoxitin (IV, IM)–> active vs anaerobes, eg, B fragilis
Cefotetan (IV, IM) –> same as above
CEFACLOR (PO) –> serum sickness in peds
CEFUROXIME AXETIL (PO) –> poor substrate for B lactamase
2nd generation cephalosporins have a useful spectrum of activity against
Enhanced activity against Gram - orgs, i.e., E coli, Klebsiella, H influenza; Moraxella cattharalis, proteus spp
what are clinical uses of 2nd generation cephalosporins?
If facultative gram - bacteria and anaerobes are likely pathogens, i.e., intra-abdominal and gynecological sepsis, surgical prophylaxis for intra-abdominal & colorectal surgery
List the 3rd generation cephalosporins:
Ceftriaxone –> Long t1/2 ~8 hrs, 1x daily; Penetrates CSF and bone; Activate vs N gonorrhea; Biliary clearance
Cefotaxime –> Enters CSF; useful for meningitis d/t H influenza, S pneumonia, N meningitidis
Cetazidime –> active vs pseudomonas aeruginosa
Cefaperzone –> Disulfiram like alcohol intolerance
3rd generation cephalosporins have a useful spectrum of activity against:
comparable to 1st generation vs S aureus, S pneumo, S pyogenes. Enhanced activity vs Gram - rods, enteric orgs
This 3rd gen cephalosporin is given IV, IM with a t1/2 ~8 hrs, recommended for therapy of penicillin-resistant gonorrhea, Lyme disease involving the CNS or joints, meningitis d/t ampicillin-resistant H influenza and meningitis in children
Ceftriaxone
Biliary excretion
This 3rd gen cephalosporin is given IV, IM, penetrates well in CNS and is useful for bacterial meningitis from covered orgs such as H influenza, S pneumo, N meningitis, and Gram - enteric bacteria
Cefotaxime
renal elimination tubular secretion
This 3rd gen cephalosporin is particularly active against P aeruginosa and is an effective therapy for serious infx d/t P aeruginosa when the org is resistant to anti-pseudomonal penicillins or the pt is penicillin allergic.
Ceftazidime
Ceftazidime should generally be given in combo with __ for tx of serious P aeruginosa
aminoglycoside (Tobramycin)
What is a 4th generation cephalosporin?
Cefepime (IV, IM) –> activity greater than or equal to cefotaxime vs Gram - bacteria, H influenza, N gonorrhea, N meningitidis; Excellent penetration into CSF; Its activity is about = to Ceftazidime vs pseudomonas aeruginosa
What is Cefepime (4th gen cephalosporin) insensitive to?
many B lactamases
why is Cefepime able to better penetrate through outer membrane of gram - bacteria?
+charged quaternary ammonium
What are adverse effects of cephalosporins?
Hypersensitivity (immediate=anaphylaxis, bronchospasm, urticaria; DTH=rash)
Disulfiram-like rxn: nausea, flushing, headache; Disulfirm inhibits aldehyde dehydrogenase
Cefotetan and Cefaperazone should be used with caution in these pts:
pts taking warfarin or with coagulation abnormalities –> MTT side chain causes reduction in vitamin K-producing bacteria in GI tract - Hypoprothrombinemia and bleeding
Name a Monobactam:
Aztreonam
Aztreonam binds to __ of gram - rods
PBP3
What is the activity spectrum (which Gram - rods) of Aztreonam and when are they taken?
Gram - rods: Klebsiella, Pseudomonas, Serratia, etc
Substitute for extended spectrum penicillin or gen 3,4 cephalosporins if these are contraindicated b/c of hypersensitivity
what are your options for empirical therapy covering serious gram - infections if the pt has a severe allergy to penicillins?
Aztreonam (IV, IM; it is a monobactam)
inactive vs Gram + spp and anaerobes
Name Carbapenems:
Imipenem/Cilastatin (not a carbepanem but given alongside to avoid nephrotoxicity)
This type of abx is the broadest spectrum of abx available and cover gram + (including Enterococcus faecalis and listeria); gram - orgs (including H influenza, N gonorrhea, Enterobacteriaceae and P aeruginosa); anaerobes, including B fragilis
Carbapenems
not degraded by B lactamases
This carbapenem is metabolized by the kidney to a nephrotoxic metabolite
Imipenem
what are adverse effects of Carbapenems?
Hypersensitivity and rash
CNS toxicity-seizures, confusion
Nephrotoxicity-Imipenem. Always used with cilastatin
This drug is used in combo with Imipenem and inhibits the dipeptidase enzyme in the proximal tubule to minimize nephrotoxicity of Imipenem
Cilastatin
