CELL WALL SYNTHESIS INHIBITORS Flashcards
Why do CW synthesis inhibitors work?
-mammalian cells DO NOT have a cell well
–> these drugs require actively proliferating bacteria (CW synthesis must be occuring) in order for them to be effective
CELL WALL SYNTHESIS INHIBITORS
1) B-LACTAM ANTIBIOTICS = MP CC
–> PENICILLINS, CEPHALOSPORINS, CARBAPENEMS, MONOBACTAMS
MISCELLANEOS:
1) VANCOMYCIN
2) DAPTOMYCIN
3) BACITRACIN
4) FOSFOMYCIN
PENICILLINS: B-LACTAM
B-LACTAM
- is widely effective, has little toxicity, but there has been to shown to be increasing levels of resistance
- structure includes a B-lactam ring
MOA: is BACTERICIDAL: –> inhibit the lAST STEP in peptidoglycan synthesis through binding to PBPs
Note: is INACTIVE against organisms w/o peptidoglycan CW (eg mycoplasma, protozoa, fungi, viruses)
PENICILLIN MOA
What are autolysins?
-are BACTERICIDAL
–> inhibit last step in peptidoglycan synthesis through binding to PBPs
–> inactive against organisms w/o peptidoglycna CW
PBPs:
–> are bacterial enzymes that get inactivated by penicillins
–> includes transpeptidases
–> number varies with type of organism
–> RESISTANCE CAN DEVELOP WITH PBP MUTATIONS
–> AUTOLYSIN PRODUCTION: is produced by bacteria and mediates cell lysis –> penicillins activate autolysins to initiate cell death –> BACTERIA EVENTUALLY LYSE D/T ACTIVITY OF AUTOLYSINS + INHIBITION OF CW ASSEMBLY!!!
PENICILLIN G
IS AN IM DRUG!!! (T1/2 = 3-4 weeks)
-Benzylpenicillin
• Active against:
- most Gram-positive cocci (not staph)
- Gram-positive rods (eg, Listeria, C.perfringens) • Gram-negative cocci (eg, Neisseria sp)
- most anaerobes (not bacteroides)
DOC FOR
1) SYPHILLIS (benzathine penicllin G)
2) STREP INFECTIONS (especially in prevention of rheumatic fever)
3) SUSCEPTIBLE PNEUMOCOCCI
PENICILLIN G PROCAINE
REPOSITORY PENICILLIN
IM, not IV (risk of procaine toxicity)
–> t1/2 = 12-24 hours
-is SELDOM USED (increased resistance)
PENICILLIN G BENZATHINE
- IM
- t1/2 = 3-4 weeks
DOC FOR
1) SYPHILLUS
2) RHEUMATIC FEVER PROPHYLAXIS
PENICILLIN V
- similar antibacterial spectrum to Penicillin G (less active against Gram -ve bacteria)
- most are ACID STABLE than G (CAN GIVE ORALLY)
DOC: for STREP THROAT
“like swallowing a sharp KniVe” when have strep throat –> give penicillin V
–> employed mostly orally for mild-moderate infections eg) pharyngitis, tonsilitis, skin infectious (caused by Strep)
ANTISTAPHYLOCOCCAL PENICILLINS
“NOD” that you know what to do with the STaff” –> used for Staph endocarditis and patients with artificial valves
1) METHICILLIN –> only used in the lab now (not in humans)
2) NAFCILLIN
3) OXACILLIN
4) DICLOXACILLIN
they are ALL B-LACTAMASE RESISTANT (inactive against MRSA)
–> is restricted to treatment of B-lactamase-producing staphylocci
DOC for
1) STAPH ENDOCARDITIS
2) PTS WITH ARTIFICIAL HEART VALVES
EXTENDED SPECTRUM PENICILLINS
USE AMPS (blasting music, travels far) and AMO (can shoot far) for EXTENDED spectrum
1) AMPICILLIN:
2) AMOXICILLIN: has a HIGHER ORAL BIOAVAILABILITY than other penicillins (including ampicillin)
–> is a common antibiotic prescribed for children and in pregancy
- are both similar to penicilin G, but also ahve gram -ve activity
- susceptible to B-lactamases
- activity enhanced with B-lactamase inhibitor
USES:
1) ACUTE OTITIS MEDIA
2) STREP PHARYNGITIS
3) PNEUMONIA
4) SKIN INFECTIONS
5) UTIs, etc…
6) WIDELY USED TO TREAT UPPER RESP INFECTIONS (H. influenza + Strep pneumonia)
7) AMOXICILLIN = STANDARD FOR ENDOCARDITIS PROPHYLAXIS during DENTAL/RESP TRACT PROCEDURES
ENDOCARDITIS PROPHYLAXIS during DENTAL PROCEDURES
AMOXICILLIN
TX OF ENTEROCOCCI + LISTERIA INFECTIONS
- AMPICILLIN is used in COMBO with AMINOGLYCOSIDES to treat
1) ENTEROCOCCI
2) LISTERIA
ANTIPSEUDOMONAL PENICILLINS
she’s eating grapes, so those are CARBS, she has a pet TIGER (dalmation), and the PIPERACILLIN piper player on the left
1) CARBENICILLIN
2) TICARCILLIN
3) PIPERACILLIN
- is effective against MANY gram -ve and gram +ve BACILLI
- is often combined with a B-LACTAMASE INHIBITOR
- is active against Pseudomonas Aeruginosa
1) CARBENICILLIN
2) TICARCILLIN
3) PIPERACILLIN
- commonly used to treat PSUEDOMONAS AERUGINOSA
- main clincial use = an INJECTABLE TREATMENT of GRAM -VEs
- Treatment of moderate-severe infections of susceptible organisms (eg, uncomplicated & complicated skin, gynecologic and intra-abdominal infections, febrile neutropenia)
EFFECTIVE EMPIRIC TX FOR INFECTIVE ENDOCARDITIS
PENICILLIN + AMINOGLYCOSIDE
are SYNERGISTIC
-penicillins facilitate the movement of aminoglycosides through cell wall
–> should never be placed in same IV (form inactive complex)
–> is an EFFECTIVE EMPIRIC TX FOR INFECTIVE ENDOCARDITIS
PENICILLINS - RESISTANCE
- one of 4 general mechanisms (primary or acquired):
1) INACTIVATION by B-lactamase
2) MODIFICATION of TARGET PBPs
3) IMPAIRED PENETRATINO of drug to target PBPs
4) INCREASED EFFLUX
Note: MRSA –> have altered target PBPs (low affinity for B lactam antibiotics)
PENICILLIN HALF LIFE AND ABSORPTION
Half-life
• ~30-60 min (except repository penicillins)
Oral absorption
• Absorption impaired by food
-EXCEPTIONS: amoxicillin –> high oral bioavailability)
• Nafcillin = erratic (not suitable for oral admin.)
PENICILLINS = DISTRIBUTION
- All achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids & urine
- Nafcillin, ampicillin & piperacillin achieve high levels in bile, (PAN = high in the bile)
- Levels in _prostate & eye = insufficient***_
- CSF penetration = poor (except in meningitis)
PENICILLIN - ADVERSE EFFECTS:
1) HYPERSENSITIVITY: penicilloic acid = major antigenic determinant
–> ~5% of patients claim to have some reaction (maculopapular rash –> anaphylaxis)
–> • Cross-allergic reactions between B-lactam antibiotics can occur
2) GI disturbances (eg, diarrhea)
3) Pseudomembranous colitis (ampicillin)
4) Maculopapular rash (ampicillin, amoxicillin)
5) Interstitial nephritis (particularly methicillin)
6) Neurotoxicity (epileptic patients at risk)
7) Hematologic toxicities (ticarcillin)
8) Neutropenia (nafcillin)
9) Hepatitis (oxacillin)
10) Secondary infections (eg, vaginal candidiasis)
PENICILLIN - EXCRETION
-most excreted primarily via KIDNEY (beware of kidney failur)
NAFCILLIN = EXCEPTION –> is primarily excreted in the BILE
OXACILLIN + DICLOXACILLIN = renal + biliary excretion
CLAVULANIC ACID
SULBACTAM
TAZOBACTAM
B-LACTAMASE INHIBITORS
-contain B-lactam ring but do not have signif antimicrobial activity
–> bind to and inactivate most B-lactamases
–> available only in fixed combinations with specific penicillins
WHAT ARE THE 3 B-LACTAMASE INHIBITORS?
1) CLAVULANIC ACID
2) SULBACTAM
3) TAZOBACTAM
CEPHALOSPORINS
• B-lactam antibiotics
• Bactericidal
• Same MOA as penicillin’s
• Affected by similar resistance mechanisms
• Classified into generations
1ST GEN = “LIN is EXIN” us up
CEFAZOLIN
CEPHALEXIN
2ND GEN = DOLE… TIN OR TAN?
1) CEFOXITIN
2) CEFACLOR
3) CEFOTETAN
4) CEFAMANDOLE
3RD GEN: “DIME ZONE XIME” with the TRI-AX-ONE dude
1) CEFTRIAXONE
2) CEFOPERAZONE
3) CEFTAZIDIME
4) CEFIXIME
4) 4th GEN: “4th line rides the PINE”
1) CEFEPIME
CEPHALOSPORIN ACTIBACTERIAL SPECTRUM
1st, 2nd, 3rd, 4th, and 5th generations based on:
- 1) Order of introduction into clinical use
- 2) Spectrum of activity
CLASS 1 —————–> CLASS 3
GRAM +VE <————–> GRAM -VE
In general, Gram positive activity diminishes while Gram- negative activity increases moving from the first-to third generations
- 4th generation demonstrate similar activity to first- generation agents against Gram-positive cocci and are also active against most Gram-negative bacilli. = BROAD SPECTRUM –> ie we should probably save this drug so we can use it when we have no damn clue what kind of bacteria is causing the illness
- 5th generation have a similar spectrum to the 3rd generation. They are unique in that they have activity against MRSA.
NOTE:
-All 1st-4th generation cephalosporins are considered inactive against MRSA,
• All cephalosporins are considered inactive against enterococci, Listeria, Legionella, Chlamydia, mycoplasma, and acinetobacter species.
PENICILLIN used when kidney problems?
NAFCILLIN
(b/c is excreted via BILE, not by kidney)
ALL CEPHALOSPORINS ARE CONSIDERED INACTIVE AGAINST WHICH BACTERIA?
“LA MEAL”
L= Legionella
A = actinomyces
M = MRSA
E = Enterococci
A = atypical bact (Chlamydia, Mycoplasma)
L = Listeria
Class notes: also include Legionella + Actinetobacter
CEFAZOLIN
CEPHALEXIN
1ST GENERATOIN CEPHALOSPORIN
are penicillin G substitutes
-are resistant to staphylococcal penicillinase
–> activity against gram +ve COCCI + P. mirabilis, E. coli, and K. pneumoniae
-is RARELY DOC FOR ANY INFECTIONS
CEFAZOLIN = DOC FOR SURGICAL PROPHYLAXIS
DRUG FOR SURGICAL PROPHYLAXIS AGINAST GRAM +VE INFECTION
CEFAZOLIN
CEFACLOR
CEFOXITIN
CEFOTETAN
CEFAMANDOLE
2nd GENERATION CEPHALOSPORINS
- extended gram -ve coverage
- greater activity against H. Influenze, Enterobacter aerogens, and some Neisseria species
“HEN PEcKS”
Haemophilus influenzae, Enterobacter aerogenes, Neisseria spp., Proteus mirabilis, E. coli, Klebsiella pneumoniae, Serratia marcescens.
–> Weaker activity against Gram + ve organisms than 1st gen
CLINICAL APPLICATIONS:
1) Primarily used to treat sinusitis, otitis & LOWER respiratory tract infections
2) Cefotetan & cefoxitin = prophylaxis & therapy of abdominal and pelvic cavity infections
CEFTRIAXONE
CEFOPERAZONE
CEFOTAXIME
CEFTAZIDIME
CEFIXIME
3RD GENERATION CEPHALOSPORINS
- Enhanced activity against Gram-negative cocci
- Highly active against enterobacteriacae, Neisseria, &
H.influenzae
- Less active against most Gram-positive organisms
- Cefotaxime & ceftriaxone = usually active against pneumococci
CEFTRIAXONE DOC
3rd GENERATION CEPHALOSPORIN
1) DOC FOR GONORRHEA
2) DOC FOR MENINGITIS d/t AMPICILLIN RESISTANT H. INFLUENZA
3) PROPHYLAXIS OF MENINGITIS IN EXPOSED INDIVIDUALS
4) TREATMENT OF LYME’S DISEASE (CNS or Joint infection)
CEFAPERAZONE
CEFTAZIDIME
3RD GENERATION CEPHALOSPORIN
-Has activity against Pseudomonas aeruginosa
CEFIPIME
4TH GENERATION CEPHALOSPORIN
• Parenteral admin. Only (ie NOT orally)
- Wide antibacterial spectrum
- Gram +ve activity of 1st generation + Gram -ve activity of 3rd generation
- eg, enterobacter, Haemophilis, Neisseria, E.coli, pneumococci, P.mirabilis & P.aeruginosa
CEFIPIME CLINICAL APPLICATIONS:
4th generation cephalosporin
-Treatment of infections with susceptible organisms
eg, UTI’s, complicated intra-abdominal infections, febrile neutropenia
CEFTAROLINE
5TH GENERATION CEPHALOSPORIN
-PARENTERAL ADMIN. ONLY
-HAS ACTIVITY AGAINST MRSA
-similar to spectrum of actiivty of 3rd generation
CLINICAL APPLICATIONS:
1) Skin and soft tissue infection due to MRSA, particularly if gram-negative pathogens are coinfecting
2) Community-acquired pneumonia (when first-line agents are unsuccessful)
PHARMACOKINETICS OF CEPHALOSPORINS
-most administered PARENTERALLY
–> exceptions = cephalexin, cefaclor, cefixime
ONLY 3RD GENERATIONS reach adequate levels in CSF
-mainly eliminated via KIDNEYS
–> exceptions = CEFTRIAXONE + CEFOPERAZONE (excreted in bile)
CEPHALOSPORIN ADVERSE EFFECTS
• Allergic reactions (cross-sensitivity with penicillins can occur)
_However, minor***** penicillin allergic patients often treated successfully with a cephalosporin_
- Pain at infection site (IM), thrombophlebitis (IV)
- Superinfections (eg, C.difficile)
- Cefamandole, cefoperazone & cefotetan contain methyl-thiotetrazole group, all can cause:
1) hypoprothrombinemia (Vit. K1 admin can prevent) &
2) disulfiram-like reactions (avoid alcohol)
IMIPENEM
MEROPENEM
CARBAPENEMS
-Resist hydrolysis by most B-lactamases
• Very broad spectrum of activity
• Active against penicillinase-producing Gram-positive &
negative organisms; aerobes & anaerobes; P.aeruginosa
• Not active against carbapenemase producing organisms
eg, carbapenem-resistant enterobacteriaceae, carbapenem-resistant klebsiella
• Not active against MRSA
CARBAPENEM CLINICAL APPLICATIONS
DOC FOR:
1) ENTEROBACTER INFECTIONS
2) EXTENDED-SPECTRUM B-LACTAMASE PRODUCING GRAM -VES
CARBAPENEM PHARMACOKINETICS + ADVERSE EFFECTS
-administered via IV
“imiPEN” IN ME –> produces SEIZURES, can be potentially NEPHROTOXIC, combine with CIALstatin (like cialsis is good right?) and this makes things better
Imipenem forms potentially nephrotoxic metabolite. Combining with enzyme inhibitor Cilastatin prevents metabolism thus prevents toxicity & increases availability.
NOTE: Meropenem is not metabolized by same enzyme (no need
for Cilastatin)
ADVERSE EFFECTS:
- GI distress (nausea, vomiting, diarrhea)
- High levels of imipenem can provoke seizures
- Allergic reactions (partial cross-reactivity with penicillin’s)
AZTREONAM
MONOBACTAM
- used for AEROBIC GRAM -VE RODS ONLY!!! (including pseudomonas)
- has NO activity vs gram +ve bacteria or anaerobes
- is resistant to action of B-lactamases
CLINICAL APPLICATIONS: –> look out for CF (Pseudomonas aeruginosa)
UTI’s, lower respiratory tract infections, septicemia, skin/structure infections, intraabdominal infections, gynecological infections caused by susceptible Gram- negative bacteri
AZTREONAM PK AND AE
MONOBACTAM
- Mainly IV or IM
- Can be given by inhalation in CF patients
- Penetrates CSF when inflamed
- Excreted primarily via urine
AE:
- Relatively nontoxic
- Little cross-hypersensitivity with other B-lactam antibiotics –> can be used in patients with penicillin anaphylaxis
- Occasional skin rashes / elevation of serum aminotransferases
- GI upset, vertigo, headache
- Phlebitis or thrombophlebitis reported with IV use
VANCOMYCIN
MOA + resistance
If you have a VAN you know you’re always +1 (having kids) D-ALA-D-ALA (looks like the windows of the long van)
Bacterial glycoprotein
- Bactericidal
- Active against Gram-positive bacteria only
- Virtually all Gram-negative organisms are intrinsically resistant
- Effective against multi-drug resistant organisms (eg, MRSA, enterococci, PRSP)
MOA: Binds to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide–> INHIBITIS CELL WALL SYNTHESIS and PEPTIDOGLYCAN POLYMERIZATION
Resistance:
- Plasmid-mediated changes in drug permeability
- Modification of the D-Ala-D-Ala binding site (D-Ala replaced by D-lactate)
VANCOMYCIN
CLINICAL APPLICATIONS
1) Treatment of serious infections caused by B-lactam resistant Gram +ve organisms eg, MRSA
2) Treatment of Gram +ve infections in patients severely allergic to B-lactams
3) In combination with an aminoglycoside for empirical treatment of infective endocarditis
4) In combination with an aminoglycoside for treatment of enterococcal endocarditis or PRSP
5) Given orally for the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis (C.difficile)
VANCOMYCIN PK + AE
PK
- Poor oral absorption
- Requires slow IV infusion (60-90 min)
- Penetrates CSF when inflamed
- 90-100% excreted via kidneys
AEs: KNOW THESE
- Mostly minor eg, fever, chills, phlebitis at infusion site
- ‘Red man’ or ‘red neck’ syndrome (infusion-related
flushing over face and upper torso)
- Ototoxicity (drug accumulation)
- Nephrotoxicity (drug accumulation)
DAPTOMYCIN
DAPTOMYCIN “DEPOLARIZES” –> K+ depolarization of bacteria leads to death
- Bactericidal
- Effective against resistant Gram-positive organisms (eg,
MRSA (ORSA), enterococci, VRE & VRSA) • Inactive against Gram-negative bacteria
• Not effective in treatment of pneumonia
MOA:
- Novel mechanism of action –> useful against multi-drug resistant bacteria
- Binds to cell membrane via calcium-dependent insertion of lipid tail
- Results in depolarization of cell membrane with K+ efflux
–> cell death
DAPTOMYCIN
CLINICAL APPLICATIONS, PK, AE
_1) Recommended for treatment of severe infections caused by MRSA*** or VRE***_
2) Treatment of complicated skin/structure infections caused by susceptible S.aureus
PK: IV ONLY!!! can accumulate in renal insufficiency
AE:
- Constipation, nausea, headache, insomnia
- Elevated creatine phosphokinases (recommended to discontinue coadmin. of statins)
BACITRACIN
-Unique mechanisms –> no cross resistance
- Interferes in late stage cell wall synthesis
- Effective against Gram-positive organisms
- Marked nephrotoxicity –> mainly topical use
FOSFOMYCIN
- Inhibits cytoplasmic enzyme enolpyruvate transferase in early stage of cell wall synthesis
- Active against Gram-positive and negative organisms
- Oral
- Used for treatment of uncomplicated lower UTI’s, but is NOT first line
