Pharmacology - Bacterial Cell Wall Synthesis Inhibitors Flashcards
What are the categories of bacterial cell wall synthesis inhibitors?
- Beta lactams (Penicillins, Cephalosporins, Carbapenems, Monobactams)
- Glycopeptides (Vancomycin)
What are the 4 subclasses of penicillins?
- Natural penicillins
- Penicillinase-resistant penicillins
- Aminopenicillins
- Anti-pseudomonal penicillins
What is the mechanism of action of the beta lactams?
Bind to the active site of transpeptidase enzyme (aka penicillin binding protein) which catalyses the cross-linking of the terminal peptide components of linear polymer chains
This inhibits with peptidoglycan synthesis to exert bactericidal effect, by weakening cell wall structure, to build up intracellular osmotic pressure, resulting in cell lysis
What is the route of admin for Penicillin G?
Potassium: IV
Procaine: IM
Benzathine: IM
What is the route of admin for Penicillin V?
PO
What is the spectrum of action of the natural penicillins?
Mostly Gram Positives: Streptococcus spp, Enterococcus fecalis, Finegoldia magna (may work against some strains of MSSA, use AST to determine)
Some Gram Negatives: Meningococci, Gonococci
Must be beta lactamase negative
Pen G Benzathine used for syphilis
Are the natural penicillins able to penetrate the CSF?
Acceptable
Penetration increases if meninges are inflammed
Pen G potassium reaches higher concentrations than procaine or benzathine
How are the natural penicillins excreted?
Renal, largely by tubular secretion, as unchanged parent drug
How can cloxacillin be administered?
IV/IM/PO
What is the spectrum of action of cloxacillin?
Cover most penicillinase producing staphylococci especially MSSA
Can also be used as empiric therapy of Streptococcus (except S. pneumoniae)
INEFFECTIVE against Gram negative
All are less effective against microorganisms susceptible to penicillin G
Can cloxacillin penetrate the CSF well?
No
How is cloxacillin excreted?
Renal
How are the aminopenicillins administered?
PO or IV
Which broad spectrum penicillin has better oral bioavailability?
Amoxicillin
What is the spectrum of action of the broad spectrum penicillins?
Good penetration for Gram negative
Indicatied for B-lactamase negative strains as monotherapy
Empiric use against Streptococcus spp (incl S. pneumoniae), Enterococcus fecalis and Finegoldia magna acceptable
No coverage of Pseudomonas or Klebsiella
(do not use for empiric Gram negative coverage)
Do the broad spectrum penicillins penetrate CSF well?
Yes, but only by IV
Penetration increases w inflamed meninges
How are the broad spectrum penicillins excreted?
Renal, as unchanged drug in urine
How is piperacillin administered?
IV
What is the spectrum of activity of piperacillin-tazobactam?
Greater activity than other penicillins against Gram negative - can use as empiric Tx for Bacteriodes fragilis, Hemophilus influenzae, E.coli, Klebsiella, P. mirabilis and Pseudomonas aeruginosa
Gram positives that can be treated empirically: MSSA, Streptococcus spp (incl S.pneumoniae), Enterococcus fecalis and Finegoldia magna
Increased anaerobic coverage
Is piperacillin able to penetrate the CSF?
Yes, if meninges are inflamed
How is piperacillin excreted?
Primarily renal - 70% excreted unchanged in urine
How do the beta lactamase inhibitors work?
Inactivate beta lactamases by binding to the beta lactamase to inactivate it
Clavulanic acid: binds covalently to restructure the beta lactamase to permanently inactivate
Sulbactam and Tazobactam: irreversibily bind to beta lactamase at or near its active site to protect the beta lactam antibiotics
What are the beta lactam and beta lactamase inhibitor pairings?
- Amoxicillin clavulanate
- Ampicillin Sulbactam
- Piperacillin Tazobactam
How are the beta lactam and beta lactamase inhibitor pairs administered?
- Amoxicillin clavulanate: PO/IV
- Ampicillin Sulbactam: IV
- Piperacillin Tazobactam: IV
What is the spectrum of action of amoxicillin clavulanate?
Effective against B-lactamase producing strains of staphylococci, H. influenzae, gonococci and E. coli
Empiric use acceptable: MSSA, Streptococcus spp (incl S. pneumoniae), Enterococcus fecalis, Finegoldia magna, Bacteriodes fragills, H. influenzae, E coli, Klebsiella, P. mirabilis
Used in skin, LRTI and UTI
Can amoxicillin clavulanate be used for CSF?
Use is discouraged, penetration is only moderate
How is amoxicillin clavulanate excreted?
Renal, as unchanged drug in urine
What is the spectrum of action of ampicillin sulbactam?
Effective against B-lactamase procuding strains of S. aureus, Gram negative aerobes, and anaerobes
Used in skin, intra-abdominal and gynecologic infections
Can ampicillin sulbactam be used for CSF?
Only when there is meningeal inflammation
How is ampicillin sulbactam excreted?
Renal, as unchanged drug in urine
Can piperacillin tazobactam be used for CSF?
Use is discouraged, penetration is modest only
How is piperacillin tazobactam excreted?
Renally
Piperacillin as unchanged drug, Tazobactam as both parent drug and metabolites in urine
Do the penicillins need to be dose adjusted?
Yes, for renal function
What are the adverse reactions of the penicillins?
- Allergy/Hypersensitivity
- contraindicated for previous anaphylactic reactions or serious skin reactions - GI Sx - N/V, CDAD
- Neurotoxicity - convulsions, coma at v high doses due to renal failure
What generation of cephalosporin does cefazolin belong to?
1st
How is cefazolin administered?
IM/IV/Eye drop
What generation of cephalosporins does cephalexin belong to?
1st
How is cephalexin administered?
PO
Which generations of cephalosporins are administered orally and parenterally respectively?
PO: 1st and 2nd gen
IV/IM: 3rd, 4th, 5th
What are the advantages of the 3rd, 4th and 5th generation cephalosporins as compared to the 1st and 2nd generations?
- Higher CSF penetration
- Higher Gram Negative coverage
- Greater resistance against beta lactamase producing strains
What is the spectrum of coverage of the 1st gen cephalosporins?
V active against Gram positives - Streptococci (Except penicillin resistant strains eg S. pneumoniae), S. aureus (Except MRSA)
Poor coverage against Gram negatives and B-lactamase positive bacteria
Also acceptable as empiric therapy for Finegoldia magna, Hemophilus influenzae, E coli, Klebsiella and P mirabilis
What are the microbes that 1st and 2nd generation cephalosporins are ineffective against?
- Pseudomonas aeruginosa AND
LAME
Listeria monocytogenes
Atypicals (Mycoplasma, Chlamydia, Legionella)
MRSA
Enterococcus spp
What generation of cephalosporins does cefuroxime belong to?
2nd
What is the spectrum of action of cefuroxime?
Less active than 1st generation against Gram positive, but slightly more active against Gram negatives
Empiric use acceptable: MSSA, Streptococcus spp (incl S. pneumoniae), Finegoldia magna, Hemophilus influenzae, E coli, Klebsiella, P mirabella
What generation of cephalosporins does ceftriaxone belong to?
3rd
What generation of cephalosporins does ceftazidime belong to?
3rd
What is the spectrum of action of ceftriaxone?
MSSA, Streptococcus spp (incl S. pneumoniae), Finegoldia magna, Hemophilus influenzae, E coli, Klebsiella, P mirabilis
Do not cover LAME
What is the spectrum of action of ceftazidime?
Finegoldia magna, E coli, Klebsiella, P mirabilis, Pseudomonas aeruginosa
Do not cover LAME
What generation of cephalosporins does cefepime belong to?
4th
What is the spectrum of action of cefepime?
MSSA, Streptococcus spp (incl S. pneumoniae), Finegoldia magna, Hemophilus influenzae, E. coli, klebsiella , P. mirabilis, Pseudomonas aeruginosa
What generation of cephalosporins does ceftaroline belong to?
5th
What is the spectrum of action of ceftaroline?
MRSA, VRSA, MSSA, Streptococcus spp (incl S. pneumoniae), Finegoldia magna, Hemophilus influenzae, E coli, Klebsiella, P. mirabilis, Moraxella catarhalis
How are the cephalosporins cleared?
Renally, except for ceftriaxone that is cleared hepatically
Which cephalosporins do not cover LAME?
1st, 2nd, 3rd, 4th generations
Which cephalosporins cover Pseudomonas aeruginosa?
Ceftazidime, Cefepime
What are the adverse effects of the cephalosporins?
- Hypersensitivity - low frequency of cross reactions with penicillins, but avoid if pt has Hx of serious hypersensitivity reactions with penicillin eg anaphylaxis, serious skin reactions
- GI Sx - V/D, colitis/CDAD
What is cilastatin?
DHP1 inhibitor
Used with Imipenem as imipenem is hydrolysed rapidly by DHP1
What do carbapenems mainly cover
Extended Spectrum B Lactamase (ESBL) producing bacteria
How are the carbapenems administered?
IV
List the names of the 3 carbapenems.
Imipenem
Meropenem
Ertapenem
Which carbapenem can penetrate the CSF?
Meropenem
What is the spectrum of action of imipenem?
Active against Streptococci (incl penicillin-resistant S. pneumoniae), Enterococci (excl E. faecium), staphylococci (incl penicillinase-producing strains), most strains of Pseudomonas, Finegoldia magna and anaerobes incl Bacteriodes fragilis
CTeng: Also can use as empiric Tx for Haemophilus influenzae. E. coli, Klebsiella, Enterobacter (Amp-C producign GNR)
What is the spectrum of action of meropenem?
Activity similar to imipenem, w activity against some imipenem-resistant P. aeruginosa strains, but less activity against Gram positive cocci
Can use in children w meningitis >3months old
CTeng: Also can use as empiric Tx for Haemophilus influenzae. E. coli, Klebsiella, Enterobacter (Amp-C producign GNR)
What is the spectrum of action of ertapenem?
Similar activity to imipenem except it lacks activity agains P. aeruginosa and Enterococcus species
How are the carbapenems excreted?
Renal
Imipenem as metabolite (which can be nephrotoxic)
Meropenem and Ertapenem excreted mostly unchanged
What are the adverse effects of the carbapenems?
- Hypersensitivity - cross allergy to penicillins possible but suggested to be potentially low, avoid w Hx of anaphylaxis or serious skin reactions to penicillins
- GI Sx - V/D, possible CDAD
- Neurotoxicity - seizures with high blood concentrations of carbapenems, resulting from high doses and renal impairments
How is aztreonam administered?
IM/IV
What is the spectrum of activity of aztreonam?
ONLY AGAINST GRAM NEGATIVES
NO ACTIVITY AGAINST GRAM POSITIVE AND ANAEROBES
Useful against many B-lactamase positive gram negative bacteria
Is aztreonam able to penetrate the CSF?
Yes, if the patient has inflammed meninges
How is aztreonam excreted?
Renal, unchanged in urine
What are the adverse reactions of aztreonam?
Generally well tolerated but can cause occasional skin rashes and transaminasemia
Which of the beta lactams exhibit cross reactivity with penicillin?
Cephalosporins, carbapenems
How is vancomycin administered?
IV
PO only for problems in GIT, eg CDAD - v poor PO bioavailability
What is the spectrum of activity of vancomycin?
Primarily acts on Gram positives - MSSA, MRSA, Streptococci (incl penicillin resistant & sensitive strains), Bacillus species, Clostridium species, Enterococcus
Not active against all Gram negatives - molecule too large to enter cell
Commonly used for osteomyelitis, endocarditis, pts w serious infections but allergic to penicillins, prophylaxis where MRSA is expected, CDAD (via PO, 1st line)
How is vancomycin excreted?
Renally, mostly as unchanged drug
What are the adverse reactions for vancomycin?
- Thrombophlebitis w fever, chills (swelling at admin site)
- Red man syndrome - rash above nipple line, can be accompanied by hypotension, infuse over longer time of 1-2h to avoid
- Nephrotoxicity and ototoxicity - rare but risk increaed when used w other nephro/ototoxic agents
What is the mechanissm of resistance underlying MRSA?
Altered penicillin binding protein, which most of the beta lactams do not have a good affinity for
What is the mechanism of action of vancomycin?
Inhibits cell wall peptidoglycan synthesis by acting against NAM-NAG transglyccosylation
What are the mechanisms of resistance to penicillin?
- Altered PBP w reduced affinity for penicillins
- Production of beta lactamases
- Decreased ability of antibiotic to reach PBP when bacteria decreases porin production
- Efflux pumps
What are the mechanisms of resistance to vancomycin?
expression of enzymes that modify bacterial cell wall precursors
