Inhibitors of Cell Wall synthesis Flashcards
Cell wall synthesis inhibitors
B-lactams abs - Penicillins - Cephalosporins - Carbapenems - Monobactams Vancomycin Daptomycin Bacitracin Fosfomycin
require actively proliferating bactera (cell wall synthesis must be occuring)
Penicillin-binding proteins (PBP)-
bacterial enzymes involved in cell wall synthesis. Target site for B-lactam antibiotics.
Penicillin
MOA?
what king of organisms is it inactive against?
- Inhibits last step of peptidoglycan synthesis through binding to PBPs.
- Penicillins also activate autolysin (bacterial enzyme) to initiate cell death by lysis and inhibiton of cell wall assembly. - Inactive against organisms w/out peptidoglycan cell wall. eg. mycoplasma/ protozoa/ fungi/ viruses
Natural penicillins: Penicillin G
- what is it active against?
- What is t susceptible to?
Benzylpenicillin
- active against:
- Most gram positive cocci (NOT STAPH)
- Gram-postive rods (eg. Listeria/ C- perfringes)
- Gram negative cocci (eg. Neisseria)
- Most anaerobes (NOT BACTERIODES) - Susceptible to inactivation by B-lactamases
What is the DOC for:
Syphilis
Strep infections (especially in prevention of rheumatic fever)
Susceptible pneumococci
Penicillin G
- Benzathine penicillin G for syphilis and Rheumatic fever prophylaxis.
Repository Penicillins are used for:
Mode of transmission is through:
Prolonging Penicillin G by increasing t1/2.
- Penicllin G procain
- Penicillin G Benzathine
Intramuscular not IV (risk of procaine toxicity)
- seldom used (increased resistance
Natural penicillins: Penicillin V
Administration?
DOC?
less sensitive ti Gram -ve bacteria than G
More acid stable (Can be given orally)
DOC for Strep throat
- employed orally for mild-moderate infections eg. pharyngitis/ tonsilits/ skin infections (caused by strep throat)
‘Antistaphylococcal’ penicillins
special trait:
First line tx for:
Methilcillin Nafcillin (Naf for staph) Oxacillin Dicloxacillin - B-lactamase resistant - Inactive against MRSA
First line for staphylococci endocarditis in patients w/out artificial heart valves.
Extended-spectrum penicllins
Ampicillin
Amoxicllin
Similar to penicillin G (+ gram negative activity)
susceptible to B-lactamases
activity enhanced w/ B-lactamase inhibitor
Amoxicillin special because
Highest oral bioavailabilty than other penicillins
also common ab prescribed for children an pregnancy
Ampicillin and Amoxicillin clinical appllications
Acute otitis media
streptococcal pharyngitis
pneumonia
skin infections
UTIs
- widely used to treat upper respiratory infections (H. Influenzae and S. pneumoniae)
- Prophylaxis against endocarditis during dental and respiratory tract procedures.
Ampicillin + aminoglycoside are used to treat
Enterococci
Listerial infections
Antipseudomonal Penicillins
Active against what type of organisms?
Carbenicillin
Ticarcillin (+ clavulinate B-lactamase inhibitor)
Piperacillin (+ Tazobactam)
Effective against many gram -ve and +ve bacilli
Often combined w/ B-lactamase inhibitor
Active against P. aeruginosa
Carbenicillin
Ticarcillin
Piperacillin
Clinical applications:
- Pseudomonas aeruginosa treatment
- Main clinical use= as an injectable tx. of Gram -ve’s
Treatment of moderate to severe infections of susceptible organisms (eg. uncomplicated and complicated skin/ gynecologic and intra-abdominal infections/ febrile neutropenia)
Penicillin + aminoglycoside
DOC for?
Synergistic
Penicillins facilitate movement of aminoglycosides through cell wall
- Never place in the same infusion fluid (form inactive complex)
DOC: Effective emperic tx. for infective endocarditis
Penicillin PK
- Oral absorption?
- Nafcillin oral absorption?
distribution?
Impaired by food
t1/2=30-60 mins (except for repository penicillins)
Nafcillin = erratic (not suitable for oral admin)
Penicillin PK
distributiontion?
Excretion?
All achieve therapeutic levels in pleural pericardial pertioneal synovial fluids and urine
Naficillin ampicillin and piperacillin achieve high levels in bile
levels in prostate and eye = insufficient
CSF penetration = poor (except in meningitis)
Excreted mostly in Kidney
Nafcillin = exception as primarily excreted in bile*
Penicillin AE
Hypersensitivity*
- Penicillic acid = major antigenic determinant
Gi disturbances (eg. diarrhea)*
Pseudomembranous colitis (ampicillin)*
Maculopapular rash (ampicilln/ amoxicillin)*
Interstitial nehritis (methicillin)
Neurotoxicity (epileptics at risk)
Hematologic toxicities (ticarcillin)
Neutropenia (naficillin)
Hepatitis (oxacillin)
Secondary infections (eg. Vaginal candidiasis)
B-lactamase inhibitors
MOA?
Clavulanic Acid
Sulbactam
Tazobactam
MOA: Bind to and inactivate most B-lactamsases
- do not have significant anti bacterial activity.
Cepahalosporins are considered inactive against?
"CAMELL" Enterococci Listeria Legionella Chlamydia Mycoplasma Acinebacter
4th Gen. cephalosporins are similar to which other generations?
What similarities do they both share?
Similar to 1st gen. against gram +ve cocci and are also active against most gram -ve bacilli.
5th Gen. cephalosporins are similar to which other generations?
Whats unique about 5th gen?
Have similar spectrum to the 3rd gen.
They are unique in that they have activity against MRSA
Cephalosporin 1st generation:
what are they substitutes of?
What are they resistant to?
Activity against?
Cefazolin (FEZ), Cephalexin (FLEX)
- Penicillin G substitutes
- Resistant to staphylococcal penicillinase
- Activity against gram positive cocci and P. mirabilis, E. coli and Klebsiella pneumoniae (PEK)
- surgical prophylaxis
Cefalozin is the DOC for?
What infections are 1st gen. cephalosporins DOC for?
- Surgical prophylaxis
2. Rarely DOC for any infections
Cephalosporin 2nd generation:
what kind of bacterial coverage do they have?
Activity against?
weak against?
Cefaclor, cefoxitin (FOX), cefotetan (tea cup), cefamandole 1. Extended gram -ve coverage 2. Greater active against HENS* - H. Influenzae - Enterobacter aerogenes - Neisseria species - Serratia 3. Weak against gram -ve.
Cephalosporin 2nd generation:
Clinical applications?
- sinusitis, otitis and lower respiratory tract infections.
- Cefotetan and cefoxitin: used for abdominal and pelvic infections therapy and prophylaxis.
Cephalosporin 3rd generation:
High activity towards?***
DONOT cover?
Ceftriaxone*(axes), Cefoperazone, cefotaxime (axe), Ceftazidime(General TAZ) cefixime
- high activity towards, enterobacteriae, H. Influenzae and Neisseria!!!
- Enhanced activity towards gram -ve cocci.
- ceftriaxone and cefotaxime usually active against pneumococci
- DONOT COVER MRSA
3rd generation (ceftriaxone) DOC for:
DOC for gonorrhea(intramuscular)
DOC for meningitis due to ampicillin resistant H. Influenzae!!
prophylaxis of meningitis in exposed people.
Tx. for lyme disease (CNS or joint infection).
3rd generation (ceftazidine and cefaperazone)- clinical applications
Activity against Pseudomonas aeruginosa
CefTAZ covers pseudomonAZ
Cephalosporin 4th generation:
Cefipime (General prime)
- serious systemic infections with ab resistant organisms
- Parenteral admin. only
- wide antibacterial spectrum
- Gram +ve activity of 1st gen. and Gram -ve activity of 3rd gen.
eg. Enterobacter, Haemophilus, Neisseria, E. coli, Pneumococci, P. mirabilis and P. aeroginuosa
Cephalosporin 4th generation: clinical applications
Cefipime
Tx. of infections with susceptible organisms
eg. UTI’s, complicated intra-abdominal infections, febrile neutropenia
Cephalosporin 5th generation:
Unique*
Ceftaroline (General TARA)
- Parenteral admin. only
- ACTIVITY against MRSA!!*
- similar spectrum of activity to 3rd generation
Ceftaroline - 5th gen. cephaloporine clinical applications:
Skin and soft tissue infection due to MRSA particularly if gram -ve pathogens are co-infecting
- community-acquired pneumonia (when first-line agents are unsuccessful).
Cephalosporins PK
- administration?
- Most administered parenterally except cephalxin, cefaclor, cefixime.
- Only 3rd gen reach adequate levels in CSF
- Mainly eliminated via kidneys (exceptions= ceftriaxone and cefoperazone excreted in bile.
Cephalosporins:
AE
What do cefamandole and cefoperazone?
- Allergic reactions (cross-sensitivity w/ penicillins can occur)
- However, minor penicillin allergic patients often treated successfully w/ a cephalosporin
- Pain at infection site (IM), Thrombophlebitis (IV)
Superinfections (eg. c. difficile)
Cefamandole, cefoperazone and cefotetan contain methyl-thiotetrazole group, all can cause:
- hypoprothrombinemia (Vit K1 admin can prevent)
- disulfiram-like reactions (avoid alcohol)
Carbapepenems
Imipenem, Meropenem
- Synthetic B-lactam antibiotics
Carbapenems:-clincal applications
DOC for:
- enterobacter infections
- extended spectrum B-lactamase producing Gram-negatives.
Carbapenems- Antibacterial spectrum
- Resist hydrolysis by most B-lactamases
- Very broad spectrum of activity**
- Active against penicillinase-producing Gram-positive and negative organisms; aerobes and anaerobes; P. aeroginosa
- Not active against Carbapenemase producing organisms* eg, carbapenem resistant enterobacteriaceae, carbapenem resistant Klebsiella.
- Not active against MRSA**
Carbapenems- PK
- IV
- Imipenem forms potentially nephrotoxic metabolite. Combining w/ enzyme inhibitor Cilastin (“keep it lasting with cilastin”) prevents metabolism thus prevent toxicity and increases availability.
Carbapenems- AE
Allergic reactions* (partial cross reactivity with penicillin’s)
HIGH levels of impenem can cause seizures
GI distress (nausea, vomitin , diarrhea)
MONOBACTAMs
Aztreonam (AZ-3M)
- Aerobic (bellows) Gram-negative rods ONLY (including pseudomonas)
- No activity against Gram-positive bacteria or anaerobes*
- Resistant to action of B-lactamases (plasmid encode)
Monobactam clinical applications
UTI's Lower Resp. tract infections Septicemia Skin/structure infections Intraabdominal infections Gynecological infections caused by susceptible Gram -ve bacteria
Monobactam PK
Mainly IV or IM
can be given by inhalation in CF patients
Penetrates CSF when inflamed
Excreted primarily via urine
Monobactam AE
Little cross-hypersensitivity w/ other B-lactam abs*
Phlebitis or thrombophlebitis reported w/ IV use
Vancomycin (VAN)
Bacterial glycoprotein (D-ALA D-ALA)
Bactericicdal
Acts against Gram +ve bacteria ONLY
*Effective against multi-drug resistant organisms (eg, MRSA, enterococci, PRSP)
Vancomycin MOA
Binds to D-ALa-D-Ala terminus of nascent peptidoglycan pentapeptide.
- Inhibits bacterial cell wall synthesis and peptidoglycan polymerization.
Vancomycin resistance
Plasmid mediated changes in drug permeabiltity
- Modification of the D-Ala-D-Ala binding site (D-Ala replaced by D-lactate)
Vancomycin clinical applications
- Tx serious infections caused by B-lactam resistant gram +ve organisms eg MRSA
- Tx of Gram +ve infections in patiens severely allergic to B-lactams
- In combination with an aminoglycoside for emperical treatment of Infective endocarditis
- In combination w/ an aminoglycoside for treatment of enterococcal endocarditis of PRSP.
- Given ORALLY for the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis (take a VAN to the METRO (metronidazole) when treating c. diff.)
Vancomycin PK
Requires slow IV infusion (60-90 min)
poor oral absorption
Penetrates the CSF when inflamed
90-100% excreted by kidney
Vancomycin AE
- ‘Red man’ or ‘Red neck’ syndrome (infusion related flushing over face and upper torso)
- Ototoxicity (drug accumulation)
- Nephrotoxicity (drug accumulatio)
Daptomycin (police dept)
Bactericidal
- Effective against gram resistant Gram-postive organisms ( eg MRSA (ORSA), enterococci, VRE and VRSA)
- Inactive against Gram -ve bacteria
- Not effective in treatment of pneumonia, deactivated by pulmonary surfactant.
- Depolarization
Daptomycin MOA
Novel mechanim
- Binds cell membrane via calcium-dependent insertion of lipid tail
- results in depolarization of cell membrane with K+ efflux–> cell death
Daptomycin clincal applications
AE
- recommended for tx of severe infections caused by MRSA or VRE
- Tx of complicated skin/structure infections caused by susceptible S. aureus
- IV only
- can accumulate in renal insufficiency
AE:
Constipation, Nausea, headache, insomnia
Elevated creatnine phosphokinases (recommended to discontinue coadmin. of statins)
Bacitracin MOA
Unique mechanisms–>no cross resistance
Interferes in late stage cell wall synthesis
Effective against Gram-positive organisms
Marked nephrotoxicity–> mainly topical use*
Fosfomycin
used or treatment of uncomplicated lower UTI’s
