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MICABI - Exam 1

Lecture 4

these proteins are important for gram-negative susceptibility to b-lactam drugs porin proteins
general mechanism of action of beta-lactam drugs inhibition of cell wall synthesis (bactericidal)
three mechanisms of resistance to beta-lactam drugs 1) beta-lactamases2) altered PBP structure3) failure to penetrate the cell (gram-negatives, can be due to porin changes)
beta-lactamase inhibitors (3) Clavulanate; Sulbactam; Tazobactam
an example of altered PBP structure resistance to beta-lactams MRSA: PBP2’ in Staphylococci – resistant to ALL Beta-lactams
absolute contraindications to beta-lactams (3) Steven's johnsons; exfolative dermatitis; toxic epidermatitis necrolysis (TEN)
cross-reactivity between penicillins and cephalosporins Small risk (5-10%), and highest with 1st generation. If patient is skin test +, should probably not receive cephalosporins unless the benefit > risk.
cross-reactivity between penicillins and carbapenems Appreciable cross-reactivity
cross-reactivity between penicillins and monobactams Negligible cross-reactivity (acceptible to prescribe if penicllin hypersensitivity)
indications where you would use desensitization Syphilis in pregnancy, Neurosyphilis, Listeria, Enterococcal Endocaditis (cases where penicillin is the gold standard and ptn is allergic)
beta-lactam drug toxicities Hypersensitivity, GI upset, Neurotoxicity
characteristics of beta-lactam neurotoxicity associated with high-dose, esp. high-dose penicillin IV to treat serious infections; common sign is seizure (esp in young children)
these patients require dose monitoring and adjustment with beta-lactams patiens with renal or hepatic insufficiencies
most staph and neisseria produce this beta-lactamases
members of class I penicillin; narrow-spectrum, penicillinase-sensitive (4) penicillin G, procaine PG, benzathine PG, penicillin V
class I penicillin spectrum narrow-spectrum, penicillinase sensitive; Gram-positive (most of streptococci) plus Neisseria, many anaerobes, and spirochetes; Good CNS penetration
class I pencillin typically administered IV (Pen V can be oral; the PGs have parenteral)
class I penicillins - metabolism renally excreted
class I penicillins - common uses meningitis, Strep, and syphillis (Jarisch-Herxheimer Reaction)
class I penicillins - primary SE allergy
class II penicillins spectrum Narrow spectrum, penicillinase-resistant (Same spectrum but not as potent as penicillin G to nonpenicillinase-producing strains of staphylcocci); Gram-positive (most of streptococci) plus Neisseria, many anaerobes, and spirochetes
class II penicillins - common uses Staphylococcus aureus infection
class II penicillins (5) Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin
isoxazolyl penicillins [class II], (3) Oxacillin, Cloxacillin, Dicloxacillin
class II penicillins - administration isoxazolyl penicillins - oral or IV; methicillin and Nafcillin - IV only
methicillin toxicity nephrotoxicity (not used that much anymore, class II)
nafcillin metabolism Excreted in bile - eliminated mostly thru the liver (no need to adjust dose in renal impairment).
class III penicillins (aminopenicillins) spectrum broader spectrum - Gram positive, plus some gram negative bacilli (H. influenzae, E. coli, Proteus mirabilis) and gram negative cocci (Neisseria) and entercocci
class III penicillins - administration oral and IV
gram-positive cocci that are resistant to many antibiotics enterococcus
class III penicillins - primary SEs GI upset and rash
class III penicillins - uses UTI, URI, pneumonia, STDs, meningitis
class III penicillins; Gram positive, plus some gram negative bacilli (2) Ampicillin, Amoxicillin
class III penicillin combined with clavulante amoxicillin (better absorbed than ampicillin)
class IV penicillins spectrum broader spectrum - Gram positive, expanded gram-negative bacilli activity including anti-pseudomonas (which is notoriously resistant)
class IV penicillins (5) Carbenicillin, Mezlocillin, Piperacillin, Ticarcillin, Carbenicillin indanyl
Carbenicillin Beta-lactamase sensitive; Di-sodium, (conjugated with 2 sodiums, used for severe infections); Class IV
Carbenicillin indanyl indanyl ester, oral for UTIs; Bleeding side effect (alpha-carboxy); Class IV
Ticarcillin Like carbenicillin but more active; lower doses; Combined with clavulanate(Timentin); Class IV
Mezlocillin & Piperacillin Uriedo penicillins. Expanded gram negative spectra, including Psuedomonas; Beta-lactamase sensitive; i.v. only; renally excreted; Class IV/V
Class IV penicillin uses serious gram-negative infections; IN COMBINATION with aminoglycosides
First generation Cephalosporins - spectrum Most gram-positive aerobes, limited gram-negative aerobes, including Staph; E. coli, Klebsiella, Proteus mirabilis; NOT active against Strep. Faecalis (enterococcus), Neisseria, H. influenza; Penicillinase resistant but destroyed by gram-negative beta-la
First generation Cephalosporins - excretion, penetration, and cross-reactivity Renally excreted; Little CSF penetration; 10% cross-sensitivity with penicillins (rashes mostly)
First generation Cephalosporins - uses gram positive infections (Pneumococci, strep, staph), some UTIs
First generation Cephalosporins (5) Cephalothin, Cefazolin, Cephalexin, Cefadroxil, Cephradine
Cephalothin - admin & major SEs (1st gen ceph) i.v. only; pain and thrombophlebitis
Cefazolin - admin & major SEs (1st gen ceph) i.v. only; no pain/Thrombophlebitis; longer half-life (t.i.d.)
Cephalexin - admin (1st gen ceph) Orally absorbed, q.i.d.
Cefadroxil - admin (1st gen ceph) Orally absorbed, long T1/2
Cephradine - admin (1st gen ceph) IV & oral
only first generation cephalosporin available both IV and oral Cephradine
2nd generation cephalosporins - spectrum Spectrum is expanded with activity against a greater number of gram-negative organisms, including resistance to some beta-lactamase hydrolysis; somewhat higher MICs for gram-positives; no CSF penetration
two groups of 2nd generation cephalosporins (based on spectrum) Cefamandole-like & Cefoxitin-like
spectrum of Cefoxitin-like cephalosporins (2nd gen) Excellent activity against Bacteroides (gram neg-anaerobes); use for pelvic infection
spectrum of Cefamandole-like cephalosporins (2nd gen) Good activity against Hemophilus influenzae, including beta-lactamase-producing strains; also expanded activity against E. coli, etc
Cefamandole-like 2nd gen cephalosporins (3) Cefamandole, Cefuroxime, Cefaclor
Cefamandole specifics (2nd gen ceph) i.v. only; no CSF penetration; Renally excreted; Methythiotetrazole (MTT) side chain is related to bleeding, disulfiram reaction
Cefaclor specifics (2nd gen ceph) orally absorbed, widely used for URI in children
Cefuroxime specifics (2nd gen ceph) like cephamandole, longer T1/2 ; some CNS penetration (but not good enough for therapuetic use)
Cefuroxime axetil Cefuroxime prodrug (2nd gen ceph)
Cefoxitin specifics (2nd gen ceph) i.v. only, no CSF penetration
Cefotetan specifics (2nd gen ceph) like cefoxitin, has MTT side chain
Cefmetazole specifics (2nd gen ceph) like cefoxitin
3rd generation cephalosporins spectrum gram positive, Expanded gram-negative spectrum, increased beta-lactamase stability; Less activity against gram-positive organisms; NO activity against Strep faecalis (enterococcus); Most are not active against Pseudomonas; most have CSF penetration so the
3rd generation ceph uses mostly reserved for gram-negative infections
cefotaxime specifics (3rd gen ceph) CSF penetration. Some gm + activity, iv., renally excreted
ceftizoxime specifics (3rd gen ceph) Deacetylated Cefotaxime
ceftriaxone specifics (3rd gen ceph) Important addition, im. iv. long half-life, good CSF levels; good for gonorrhea in 3rd world countries where ptns may only get one dose
Ceftazidime specifics (3rd gen ceph) Antipseudomonal, iv. (v. important because most cephs don't have anti-pseudomonas activity)
Cefoperazone specifics (3rd gen ceph) Some biliary excretion; Bleeding side effect
Cefixime specifics (3rd gen ceph) Oral absorption; long T1/2; Used for H. influenzae URIs
Cefpodoxime proxetil specifics (3rd gen ceph) Prodrug; like cefixime
3rd generation cephalosporins (7) cefotaxime, ceftizoxime, ceftriaxone, Ceftazidime, Cefoperazone, Cefixime, Cefpodoxime proxetil
4th generation cephalosporin (1) Cefepime
Cefepime (4th gen ceph) - spectrum spectrum is more extensive than 3rd gen cephs, has cefotaxime's gram-pos spec and ceftazidime's in gram neg spec; Cefepime has better resistance to beta-lactamases; NOT good for MRSA or enterococcus
Cefepime (4th gen ceph) - penetration and excretion Excellent penetration to CSF, almost 100% renally excreted
Cefepime (4th gen ceph) - use should be reserved for treatment of serious infections, especially to those in immunocopromised patients and polymicrobial infections
Imipenem spectrum (beta-lactam) Very broad spectrum; active against gram-positives, including Enterococus (maybe); and gram-negatives, including most Pseudomonads and Bacteroides; NO MRSA; some anaerobes; and some pseudomonads; resistant to beta-lactamase
Imipenem (b-lac, carbapenem) - admin/penetration Not orally absorbed; penetrates into CSF (not recc in menigitis b/c of SEs though)
Imipenem (b-lac, carbapenem) - metabolism metabolized by dihydropeptidase in proximal renal tubule; need to combine with cilastatin (dihydropeptidase inhibitor) = Primaxin to get therapeutic levels
Imipenem (b-lac, carbapenem) - SEs cross reactive allergy with penecillins (10%-20% not anaphylactic);seizures
Imipenem (b-lac, carbapenem) - uses Serious gram-negative infections
Meropenem (b-lac, carbapenem) - advantages over imipenem More active against Enterobacteriaciae, Pseudomonas; Less potential to induce seizure; Stable against degradation by renal dehydropeptidase (don't have to give in combo)
Aztreonam (monobactam) - spectrum Gram-negative activity (does not bind to PBPs of gram-positives; binds to PBP3 of Enterobacteriaceae); includes most pseudomonas; Aerobes only; Bactericidal; Good Beta-lactamase stability
Aztreonam (monobactam) - admin/excretion i.v., i.m. only; urinary excretion
Aztreonam (monobactam) - penetration Good CSF levels; good for CNS infections
only beta-lactam w/o penicllin cross sensitivity aztreonam (monobactam)
Aztreonam (monobactam) - uses serious gram-negative infections (doesn't work for gram-positives; also doesn't work against enterobacter or bacteroides b/c they are anaerobes)
which of these beta-lactamase inhibitors has the strongest activity - sulbactam, clavulanic acid, tazobactam tazobactam
polypeptide antibiotics (5) vancomycin, polymixins, mupirocin, spectinomycin, daptomycin
vancomycin (polypeptide) mechanism of action Inhibitor of cell wall synthesis
vancomycin (polypeptide) spectrum Gram-positive bacteria including staphylococci, streptococci, enterococci (anaerobe), and clostridium species; some gram-negative cocci (neisseria); DOES NOT work on gram-negative bacilli and mycobacteria (resistant)
vancomycin (polypeptide) PK NOT orally absorbed; must give i.v. painful for i.m. Administration. Excreted in urine; must adjust dose in renal dysfunction (keep around 30 ug/ml peak). Not concentrated in bile; therapeutic CSF levels achieved in some patients with meningitis, but var
vancomycin (polypeptide) major SE if given too fast "Red neck” or “Red man” syndrome (Flushing and hypotension), including muscle spasms in chest and rarely cardiac arrest, if administered in too fast i.v. infusion; GIVE SLOWLY 
vancomycin (polypeptide) major SEs if combined with aminoglycosides nephrotoxicity and ototoxicity (dose dependent, rarer with newer preps)
vancomycin (polypeptide) uses MRSA; Other gram-positive infections including Strep. faecalis in pen-allergic pts.; orally for C. difficile enterocolitis (not absorbed - stays and cleans out GI)
Bacitracin (polypeptide) specifics inhibits cell wall synth (bactericidal) in gram-positives, very little resistance, high nephrotoxicity if administered orally; topical use only
Polymixins (polypeptides) specifics Polymixin B and Polymixin E (mixture); Disrupts cell membranes; Gram-negative bacilli, incl. Pseudomonas; not absorbed orally or through the skin; VERY nephrotoxic and neurotoxic if given systemically; used topically for gram-neg infections
Mupirocin (polypeptide) specifics [a.k.a. pseudomonic acid] binds tRNA screwing up protein synth; covers Staphylococci and streptococci (some resistance w/longterm use); little cross resistance w/other antibiotics; used topically for impetigo (Staph or strep) - RX only
Spectinomycin specifics structurally related to aminoglycosides; single i.m. dose for uncomplicated gonorrhea; (not for other STDs); little toxicity
Daptomycin spectrum Gram-positive organisms only; activity against enterococci (including glycopeptide-resistant Enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci and corynebacteria
Created by: Krafty