Overview of Antimicro- Waller Flashcards
Top 5 drugs:
Amoxicillin Azithromycin Amoxicillin-clavulanic acid Trimethoprim-sulfamethoxazole Ciprofloxacin
antibiotic Misuse may occur in a variety of ways:
Given when not needed
Continued when no longer necessary
Given at the wrong dose
Broad spectrum agents used for very susceptible bacteria
The wrong antibiotic given to treat infection
inappropriate prescribing
Over 50% of antibiotic prescribing may be inappropriate Most of this inappropriate use is for: Acute respiratory infections Pharyngitis Sinusitis Bronchitis
Antibiotics are a common cause of ADE-related ED visits, accounting for:
7 of top 15 drugs in pediatric patients ADE-ED visits
1 of 5 ADE-related visits to ED in adults
A 37 y/o female with poorly controlled type 1 diabetes and end-stage renal disease, on hemodialysis, presents to the ED with 3-day history of dyspnea, cough with purulent sputum production, and intermittent fever.
She recently completed a course of meropenem for catheter-associated blood-stream infection 2 weeks ago.
Physical and laboratory findings are consistent with pneumonia. She is admitted to the hospital.
Questions to ask yourself about anti-microbial therapyp
Ask yourself whether an antimicrobial agent is warranted:
Is an antimicrobial indicated based on clinical findings? yes
Have appropriate cultures been obtained?
What is the most likely causative organism?-
What must be done to prevent secondary exposure?- not likely to have a 2ndary exposure in this case,
Is there clinical evidence or established guidelines that have determined antimicrobial therapy provides a clinical benefit?- yes, esp. for pneumonia
A 37 y/o female with a history of end-stage renal disease, on dialysis, is admitted to the hospital with pneumonia. Antibiotics are initiated to cover the most likely pathogen(s).
Types & Goals of Therapy?
Empiric therapy; we suspect common organisms
A 68 y/o male presents for a total hip replacement. Prior to surgery, he is given one dose of cefazolin to prevent development of a surgical wound infection.
Types & Goals of Therapy?
Prophylaxis
A 37 y/o female with a history of end-stage renal disease, on dialysis, is admitted to the hospital with pneumonia. Cultures result with sensitive Pseudomonas, vancomycin (mostly for gram positive) discontinued.
Types & Goals of Therapy?
Definitive therapy
An 8 y/o male presents to the ED with a perforated appendix. Antibiotics are initiated pre-operatively to reduce risk of intra-abdominal abscess & wound infection.
Types & Goals of Therapy?
pre-emptive; this patient already has appendicitis
to prevent abdominal abscess
A 75 y/o male presents for follow-up of prosthetic hip joint infection. He receives continued, low dose antimicrobial therapy as hip prosthesis was unable to be removed.
Types & Goals of Therapy?
Suppressive
Most valuable, time tested method for immediate ID of bacteria =
gram stain
gram positive vs negative
neg- 2 cell membranes, LPS endotoxin
pos- thicker peptidoglycan layer, teichoic acid stabilizes peptidoglycan layer (rigid, provides structural shape)
beta lactamase
an important resistance mechanism against beta lactam antibiotics
Susceptibility Testing
Susceptible
- Likely to inhibit pathogenic microorganism
Intermediate
- May be effective at higher dosage, more frequent administration, or in specific body site
Resistant
- Not effective at inhibiting growth of microorganism
Types of Susceptibility Tests:
Dilution Tests
Disk Diffusion
Gradient Diffusion
Minimum inhibitory concentration (MIC)
lowest concentration of drug required to inhibit growth
Breakpoints established by Clinical and Laboratory Standards Institute (CLSI)
Antibacterial Spectrum
Narrow-spectrum
- Act on a single or a limited group of microorganisms
Extended-spectrum
- Active against gram-positive bacteria but also against significant number of gram-negative bacteria
Broad-spectrum
- Act on a wide variety of bacterial species, including both gram-positive and gram-negative
Bacteriostatic vs. Bactericidal
Bacteriostatic: arrests growth and replication of bacteria (limits spread of infection)
Bactericidal: kills bacterial
- Concentration-dependent killing: rate and extent of killing increase with increasing drug concentrations
- Time-dependent killing: activity continues as long as serum concentration above minimum bactericidal concentration
This concept is relative
Certain drugs are –cidal against specific bacteria while –static against others
Drug-drug enhancement or synergism
Gentamicin – ineffective against enterococci in the absence of a cell-wall inhibitor
Combining penicillin with gentamicin leads to bactericidal activity
Antimicrobial Classification
Antimicrobials classified based on:
Class and spectrum of microorganisms it kills
Biochemical pathway it interferes with
Chemical structure
Sites of Antibacterial Action
Cell wall synthesis Cell membrane synthesis Protein synthesis Nucleic acid metabolism Function of topoisomerases Folate synthesis
β-Lactams- MOA, list, resistance
cell wall inhibitors
Penicillins
Cephalosporins
Monobactam
Carbapenems
Time-dependent; structural analogs of D-Ala-D-Ala; covalently bind penicillin-binding proteins (PBPs), inhibit the last transpeptidation step in cell wall synthesis
Structural difference in PBPs
Decreased PBP affinity
Inability for drug to reach site of action (i.e. gram-negative organisms)
Active efflux pumps
Drug destruction/inactivation by B-lactamases
β-Lactamase Inhibitors
Amoxicillin + clavulanic acid,
ticarcillin + clavulanic acid,
ampicillin + sulbactam,
piperacillin + tazobactam
MOA: prevent destruction of B-lactam antibiotics
Fluoroquinolone Mechanism of Action
Concentration-dependent, targets bacterial DNA gyrase & topoisomerase IV. Prevents relaxation of positive supercoils
Inhibitors of Protein Synthesis- areas of action
Formation of initiation complex
Amino-acid incorporation
Formation of peptide bond
Translocation
Aminoglycosides MOA
blocks initiation of protein synthesis
blocks further translation and elicits premature termination
incorporation of incorrect amino acid
Bind 30S subunit
Tetracyclines MOA
Bind 30S subunit
Macrolides MOA
Bind 50S subunit
Sulfonamides and Trimethoprim
Inhibit folic acid synthesis; block sequential steps in pathway.
Natural Penicillins spectrum, use
Penicillin G (IV, IM), penicillin V (PO)
Spectrum: highly effective against gram-positive cocci (GPC) but easily hydrolyzed by penicillinase
Therapeutic Use: narrow-spectrum, Streptococcus pneumoniae pneumonia and meningitis. Penicillin V for Streptococcus pyogenes pharyngitis, toxic shock, viridians streptococci endocarditis if susceptible, syphilis
Anti-Staphylococcal Penicillins spectrum, therapeutic use
Oxacillin (IV, IM), dicloxacillin (PO), nafcillin (IV, IM)
Spectrum: penicillinase resistant; agents of first choice for Staphylococcus aureus (MSSA) and Staphylococcus epidermidis (MSSE) that are not methicillin-resistant
Therapeutic Use: restricted to infections with known Staphylococcus sensitivity
Aminopenicillins
extended spectrum
Ampicillin (PO, IV, IM), amoxicillin (PO)
Spectrum: extended-spectrum; extends beyond gram-positive to gram-negative (Haemophilus influenzae, Escherichia coli, Proteus mirabilis), Listeria monocytogenes, susceptible meningococci, enterococci
Therapeutic Use: upper respiratory tract infections (S. pyogenes, S. pneumoniae, H. influenzae), sinusitis, otitis media, enterococcal infections
Antipseudomonal Penicillins
piperacillin (IV)- use with tazobactam
Spectrum: extends spectrum to Pseudomonas aeruginosa, Enterobacter, and Proteus spp.
Therapeutic Use: serious gram-negative infections, hospital acquired pneumonia (HAP), immunocompromised patients, bacteremia, burn infections, UTI
Penicillins ADRs
Allergic reactions
Anaphylaxis
Nausea, vomiting, mild to severe diarrhea
Pseudomembranous colitis
1st-Generation Cephalosporins spectrum and therapeutic uses
Cefazolin (IV, IM), cephalexin (PO)
Spectrum: good gram-positive coverage, modest gram-negative (covers Moraxella, E. coli, Klebsiella pneumoniae, P. mirabilis), orally active anaerobes
Therapeutic Use: skin and soft tissue infections (SSTIs), surgical prophylaxis
2nd-Generation Cephalosporins spectrum and use
Cefoxitin (IV), cefuroxime (PO, IV, IM)
Spectrum: somewhat increased activity against gram-negative, but less active than 3rd-generation. Subset active against Bacteroides fragilis
Therapeutic Use: used in gram-negative mixed anaerobic (intra-abdominal infections, pelvic inflammatory disease, diabetic foot infections)
3rd-Generation Cephalosporins MOA and uses
Ceftriaxone (IV, IM), ceftazidime (IV, IM)
Spectrum: less active against gram-positive, more active against Enterobacteriaceae (although resistance increasing due to B-lactamase producing strains)
Therapeutic Use: serious gram-negative infections (Klebsiella, Proteus, Providencia, Serratia, Haemophilus), ceftriaxone DOC for all forms of gonorrhea & severe Lyme’s disease; meningitis. Ceftazidime covers Pseudomonas
4th-Generation Cephalosporin
Cefepime (IV, IM)
Spectrum: extends beyond 3rd-generation, useful in serious infections in hospitalized patients. Effective against Pseudomonas
Therapeutic Use: empirical treatment of nosocomial infections
Cephalosporins ADRs
1% risk of cross-reactivity to penicillins
Diarrhea
Carbapenems spectrum, use, ADRs
), meropenem (IV), ertapenem (IV, IM)
Spectrum: aerobes & anaerobes; gram-positive, Enterobacteriaceae, Pseudomonas, Acinetobacter. Stenotrophomonas maltophilia is resistant.
Therapeutic Use: UTI, lower respiratory tract infection (LRTI), intra-abdominal, gynecological, SSTI, bone and joint infections
ADRs:
Nausea/vomiting (1-20%), seizures (1.5%), hypersensitivity
Monobactam spectrum, therapeutic use
Aztreonam (IV, IM, INH)
Spectrum: activity against gram-negative (Enterobacteriaceae, Pseudomonas, H. influenzae, gonococci), no activity against GPC or anaerobes
Therapeutic Use: patients who are allergic to B-lactams appear not to react to aztreonam effective for gram-negative infections which would usually be treated with B-lactam
Glycopeptides MOA, resistance, spectrum, ADRs
Vancomycin (PO, IV)
MOA: inhibits cell wall synthesis binding with high affinity to D-Ala-D-Ala terminal of cell wall precursor units.
Resistance: alteration of D-Ala-D-Ala target to D-alanyl-D-lactate or D-alanyl-D-serine which binds glycopeptides poorly. Intermediate resistance may also occur
Spectrum: broad gram-positive coverage – S. aureus (including MRSA), S. epidermidis (including MRSE), Streptococci, Bacillus, Corynebacterium spp., Actinomyces, Clostridium
Therapeutic Use: osteomyelitis, endocarditis, MRSA, Streptococcus, enterococci, CNS infections, bacteremia, orally for C. difficile
ADRs:
Macular skin rash, chills, fever, rash
Red-man syndrome (histamine release): extreme flushing, tachycardia, hypotension
Ototoxicity, nephrotoxicity - watch out with renal patients!
Fluoroquinolones MOA, spectrum, therapeutic use, ADRs
MOA: concentration-dependent; targets bacterial DNA gyrase & topoisomerase IV.
Spectrum: E. coli, Salmonella, Shigella, Enterobacter, Campylobacter, Neisseria, Pseudomonas aeruginosa, S. aureus (not MRSA), limited coverage of Streptococcus spp.
Levofloxacin, moxifloxacin, “respiratory fluoroquinolones” cover Streptococcus spp.
Therapeutic Use: UTI, prostatitis, STI (chlamydia, Neisseria gonorrhoeae), traveler’s diarrhea, shigellosis, bone, joint, SSTI infections, diabetic foot infections
ADRs:
GI 3-17% (mild nausea, vomiting, abdominal discomfort)
CNS 0.9-11% (mild headache, dizziness, delirium, rare hallucinations)
Rash, photosensitivity, Achilles tendon rupture (CI in children)
Aminoglycosides MOA, spectrum, therapeutic uses, ADRs
gentamicin (IV, IM, topical)
MOA: concentration-dependent (one high dose can do the trick); binds 30S ribosomal subunit, disrupts normal cycle of ribosomal function
Spectrum: aerobic gram-negative bacteria, limited action against gram-positive, synergistic bactericidal effects in gram-positive with cell wall active agent
Therapeutic Use: UTI (not uncomplicated), used if resistance to other agents, seriously ill patients, pneumonia (infective against S. pneumoniae and anaerobes), HAP, peritonitis, synergy in bacterial endocarditis, tobramycin inhalation in CF
ADRs:
Ototoxicity (may be as high as 25%)
Nephrotoxicity (8-26%)
Neuromuscular block and apnea
Tetracyclines/Glycylcyclines MOA, spectrum,
doxycycline
MOA: bacteriostatic; binds 30S bacterial ribosome. Prevents access of aminoacyl tRNA to acceptor (A) site on mRNA ribosome complex
Spectrum: wide range of aerobic/anaerobic gram-positive and -negative activity; useful for atypical presentations and/or in outpatient setting
Therapeutic Use: CAP, atypical CAP coverage, community acquired SSTIs, community acquired MRSA, acne, Rickettsial infections (Rocky Mountain Spotted Fever), Q fever, anthrax
ADRs:
GI (epigastric burning, nausea, vomiting, diarrhea)
Superinfections of C. difficile
Photosensitivity
Teeth discoloration (it chelates calcium)
Thrombophlebitis
Macrolides/Ketolides MOA, uses, etc.
Clarithromycin (PO), azithromycin (PO, IV, topical)
MOA: bacteriostatic; binds reversibly to 50S ribosomal subunit, inhibits translocation
Therapeutic Use: respiratory tract infections (spectrum S. pneumoniae, H. influenzae, and atypicals: Mycoplasma, Chalmydophilia, Legionella), alternative for otitis media, sinusitis, bronchitis, and SSTIs. Pertussis, gastroenteritis, H. pylori, Mycobacterial infections
ADRs: GI (epigastric distress) Hepatotoxicity Arrhythmia * QT prolongation
DDIs: CYP3A4 inhibition – prolongs effects of digoxin, warfarin….
Lincosamides MOA, spectrum, uses
Clindamycin (PO, IV, IM, topical)
MOA: binds 50S subunit of bacterial ribosome, suppresses protein synthesis
Spectrum: pneumococci, S. pyogenes, viridans Streptococci, MSSA, *** anaerobes (B. fragilis)
Therapeutic Use: SSTIs, necrotizing SSTIs, lung abscesses, anaerobic lung and pleural space infections, topically for acne vulgaris
ADRs:
GI diarrhea
*** Pseudomembranous colitis Due to C. difficile
Skin rashes
Reversible increase in aminotransferase activity
May potentiate neuromuscular blockade
Oxazolidinones
Linezolid (PO, IV)
MOA: inhibits protein synthesis binding P site of 50S ribosomal subunit, prevents formation of initiation complexes
Spectrum: gram-positive Staphylococcus (MSSA, MRSA, VRSA), Streptococcus (penicillin resistant S. pneumoniae), enterococci (VRE), gram-positive anaerobic cocci, gram-positive rods (Corynebacterium, L. monocytogenes)
Therapeutic Use: VRE faecium (SSTI, UTI, bacteremia), nosocomial pneumonia caused by MSSA and MRSA, CAP, complicated/uncomplicated SSTI infections
ADRs:
Myelosuppression [thrombocytopenia (2.4%),anemia, leukopenia]
Headache
Rash
DDIs: weak, nonspecific inhibitor of monoamine oxidase
