Antibacterials - Cell Wall Synthesis Inhibitors Flashcards
Define bacteriostatic
reversible inhibition of growth
Define bactericidal
irreversible inhibition of growth
Define Minimal Inhibitory Concentration (MIC)
Lowest concentration of antibiotic that prevents visible growth
Define Minimal Bacterialcidial Concentration (MBC)
Lowest concentration of antibiotic that results in a 99.9% decline in colony count after overnight borth dilution incubations
What are the 6 considerations to select the right agent?
- Organism’s identity and susceptibility to an agent
- Necessity of empiric therapy
- Site of infection
- Pharmacology
- Patient factors
- Cost of therapy
What are the three major mechanisms of antibiotic resistance?
- Altered uptake of antibiotic
- Altered target
- Drug inactivation
What is the difference between primary resistance and aquired drug resistance?
- Primary resistance - structural absence of target for drug to act on
- Acquired resistance - spontaneous mutation of DNA, DNA transfer, or altered expression of proteins in drug-resistant organisms
Transfer of genetic information can occur due to?
- Conjugation (F+ plasmid for sex pilus)
- Transposons (mobile genetic elements)
- Transduction (bacteriophage)
- Transformation (DNA uptake)
What are 3 complications of antibiotic therapy?
- Hypersensitivity
- Direct toxicity
- Superinfection
What are the 4 MOA for antibacterials?
- Cell wall synthesis inhibitors
- Protein synthesis inhibitors
- Drugs that affect nucleic acid synthesis
- Miscellaneous and urinary antiseptics
What are the mechanisms of synergism?
- Sequential blockade
- Blockade of drug-inactivating enzymes
- Enhanced drug uptake
What are the cell wall synthesis inhibitors?
- B-lactam (penicillins, cephalosporins, carbapenems, monobactams)
- Vancomycin
- Daptomycin
- Bacitracin
- Fosfomycin
Beta-lactams MOA?
MOA: bactericidal that inhibits the last step in peptidoglycan synthesis by binding to PBPs and activate autolytic enzymes to initiate cell death
What is the mechanism of Beta-Lactamases?
bacterial enzymes (pinicillinases, cephalosporinases) that hydrolyze the Beta-lactam ring to inactivate it
What are the 3 beta-lactamase inhibitors and what is their MOA?
- Clavulanic Acid
- Sulbactam
- Tazobactam
MOA: have beta-lactam ring with no antibacterial activity that will bind and inactivate beta-lactamses
What determines penicillins ability to reach PBPs?
- Size
- Charge
- Hydrophobicity
What is the antibacterial spectrum for penicillins and why?
- Gram-positive: cell wall easily crossed
- Gram-negative: porins to permit transmembrane entry
What is a synergistic combination for penicillin and why?
Penicillin + Aminoglycoside: penicillin facilitate movement of aminoglycosides through cell wall, need different infusions because will form inactive complex, and is an effective emperic treatment for infective endocarditis
What are the 4 general mechanisms of penicilin resistance?
- Inactivation by B-lactamase
- Modification of target PBPs
- Impaired penetration of drug to target PBPs
- Increased efflux
What are the clinical applications Penicillin G?
- Mostly used for Gram + organisms
- Syphilis (benzathine penicillin G)
- Strep Infections
- Susceptible pneumococci
What are the 2 repository penicillins and what are their purpose?
- Penicillin G Procaine (12-24hr) and Penicillin G Benzathine (3-4wks)
- Developed to prolong during of Penicillin G
What are the clinical application of Penicillin G Benzathine?
- syphilis
- Rheumatic fever prophylaxis
What is the importance that differentiates Penicillin V?
More acide stable that G so can be given orally
What is the clinical application of Penicillin V?
Mild to moderate:
- Pharyngitis
- Tonsilitis
- Skin infections (caused by Strep)
What are the 4 antistaphylococcal Pencillins and what differentiates them from the other penicillins?
Beta-lactamase resistant used to treat B-lactamase producing staphylococci
- Methicillin
- Nafcillin
- Oxacillin
- Dicloxacillin
What are the extended spectrum Penicillins?
- Ampicillin
- Amoxicillin
What are the clinical application of Amoxicillin?
- Acute otitis media
- Streptococcal pharyngitis
- PNA
- Skin infections
- UTIs
Amoxicillin + Clavulanic Acid is prophylactic treatments for dog, cat, and human bites
What are the clinical applications of Ampicillin?
- Acute otitis media
- Streptococcal pharyngitis
- PNA
- Skin infections
- UTIs
Ampicillin + Sulbactam for dog, cat, and human bites
What are the Antipseudomonal Penicillins and what differentates them?
- Carbenicillin
- Ticarcillin
- Piperacillin
Effective against many gram negative and gram positive bacilli (P. aeruginosa)
What are the clinical applications of antipseudomonal Penicillins?
- Pseudomonas auruginosa
- Injectable treatment of Gram negative
- Treatment of moderate-severe infections of suceptible organisms (skin, gynelogical, intra-abdominal, febrile neutropenia)
What are the pharmokinetic effects of distribution and excretion of Penicillins?
Distribution: therapeutic levels in pleural, pericardial, peritoneal, synovial fluids, urine, and CSF (meningitis) but insufficient in prostate and eye
Excretion: primarily via kidney except for Naficillin is primarily excreted in bile
What are 4 adverse effects of Penicillin?
- Hypersensitivity
- GI disturbances
- Pseudomembranous colitis (ampicillin)
- Maculopapular rash (ampicillin, amoxicillin)
What is cephalosporins MOA and distinguishing feature from penicillin?
MOA: beta-lactam antibiotic same as penicillins
Affected by similar resistance mechamisms but less susceptible to beta-lactamases
What are the generations of cephalosporins based on their classifications?
Based on:
- Order of introduction into clinical use
- Spectrum of activity
1-3rd: Gram positive activity diminished while Gram negative activity increased from first to third
4th: Gram positive cocci and Gram negative bacilli
5th: similar to thirds with activity against MRSA
What are all cephalosporings inactive against?
LAME
- Listeria
- Atypical (Chlamydia, Mycoplasma)
- MRSA
- Enterococci
What is the major mechanisms of cephalosporin resistance?
- Modification of target PBPs
What are the 1st generation cephalosporins and their clinical applications?
Cefazolin and Cephalexin
- Rarely DOC for any infection
- Cefazolin = DOC for surgical prophylaxis
What are the 2nd generation cephalosporins and their clinical applications?
Cefaclor, Cefoxitin, Cefotetan, Cefamandole
- Sinusitis, otitis, and lower respiratory tract infections
- Cefotetan & Cefoxitin = prophylaxis and therapy of abdominal/pelvic infections
What are the 3rd generation Cephalosporins and their clinical applications?
Ceftiaxone, Cefoperazone, Cefotaxime, Ceftazidime, Cefixime
- Highly active against enterobacteriacae, Neisseria, and H. influenzae
- DOC for gonorrhea (Ceftriaxone)
- DOC for empiric treatment of meningitis (Ceftriaxone
- Prophylaxis of meningitis (Ceftriaxone)
- Treatment of disseminated Lyme disease (Ceftriaxone)
- Activity against P. aeruginosa (Cefoperazone and Ceftazidime)
What is the 4th generation cephalosporin and its clinical application?
Cefipime
- Wide antibacterial spectrum
- Treatment of mixed infection with susceptible organisms
- Complication UTIs, complicatied intra-abdominal infections, febrile neutropenia
What is the pharmokinetic factors of cephalosporins?
- Most administered paraenterally (exceptions = cephalexin, cefaclor, cefixime)
- Only 3rd generation reach adequate levels in CSF
- Mainly eliminated by kidneys (exceptions = ceftriaxone & cefoperazone excreted in bile)
What is the 5th generation cephalosporins and its clinical applications?
Ceftaroline
- Activity against MRSA
- Skin and soft tissue infection from MRSA, particulary if Gram-negative pathogens are co-infecting
What are the adverse effect of Cephalosporins?
- Allergic reactions (minor penicillin allergic pts treated with cephalosporin)
- Superinfection from C. difficile
- Cefamandole, cefoperazone, and cefotetan have methyl-thiotetrazole group that can cause:
- Hypoprothrombinemia
- Disulfiram-like reactions
What is the MOA of carbopenems and what differentiates them from penicillin?
MOA: synthetic beta-lactam antibiotics
- Resist hydrolysis by most beta-lactamases
What are the carbapenems and their clinical applications?
Doripenem, Ertapenem, Imipenem, Meropenem
- Use limited to life-threatening infecitons commonly extended spectrum beta-lactamase producing Gram-negatives
What the pharmokinetics of carbapenems?
- IV
- Imipenem forms nephrotoxic metabolite so but combine with Cilastatin (dehydropeptidase I inhibitor)
What are the adverse effects of Carbapenems?
- Allergic reactions (partial cross-sensitivity with penicillin’s)
- GI distress
- High levels of imipenem can cause CNS toxicity
What is the monobactam and was differentiates it from penicillin?
Aztreonam
- Active against gram negative rods only (pseudomonas)
- resistent to beta-lactamases
What are the clinical applications of Monobactram?
- Treatment of Gram-negative infections in patients allergic to penicillin
What are the adverse effects of Monobactam?
- Little cross-hypersensitivy with other beta-lactam antibiotics
- Occasional skin rash and GI upset
What is the MOA, CA, AE of Vancomycin?
MOA: bacterial glycoprotein the binds D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide to inhibit bacterial cell wall synthesis
CA: serious infections caused by B-lactam resistent Gram positive organisms (MRSA) and gram positive infections in patients severly allergic to B-lactams
PK: requires slow IV, renal excretion
AE: Red man/neck syndrome, ototoxicity, nephrotoxicity
What is the MOA of Daptomycin?
MOA: binds cell membrane via calcium-dependednt insertion of lipid tail > depolarization of cell membrane with K+ efflux > cell death
- Novel mechanism of action useful against multi-drug resistant bacteria
What are the clinical applications of Daptomycin?
- treatment of severe infections caused by MRSA or VRE
- treatment of complicated skin/structure infections cause by susceptible S. aureus
What is the pharmokinetics and adverse effects of daptomycin?
- Only given by IV
- Elevated creatine phosphokinases (so stop statins)
- Constipation, nausea, headache, insomnia
What is the MOA, clinical application, and pharmokinetics of Bacitracin?
MOA: interferes in late stage wall synthesis in unique mechanisms so no cross resistance
- Effective against Gram positive organisms
- Marked nephrotoxicit to mainly topical use
What is the MOA, clinical applications, and pharmacokinetics of Fosfomycin?
MOA: inhibits cytoplasmic enzyme enolpyruvate transferase in early stage cell wall synthesis
- Treatment of uncomplicated lower UTI’s
- Given orally
