Overview of Antimicrobial Agents Lecture Flashcards
1
Q
Drug Classes
A
Natural Penicillins
Anti-staphylococcal Penicillins
Aminopenicillins
Anti-pseudomonal Penicillins
First Generation Cephalosporins
Second Generation Cephalosporins
Third Generation Cephalosporins
Fourth Generation Cephalosporins
Carbapenems
Monobactams
B-lactamase Inhibitors
Glycopeptides
Lipopeptides
Fluoroquinolones
Aminoglycosides
Tetracyclines/Glycylcyclines
Macrolides/Ketolides
Lincosamides
Oxazolidinones
Metronidazole
Sulfonamides/Trimethoprim
2
Q
Natural Penicillins
A
Penicillin G (IV, IM)
Penicillin V (PO)
3
Q
Anti-staphylococcal Penicillins
A
Oxacillin (IV, IM)
Dicloxacillin (PO)
Nafcillin (IV, IM)
4
Q
Aminopenicillins
A
Ampicillin (PO, IV, IM)*
Amoxicillin (PO)*
5
Q
Anti-pseudomonal Penicillins
A
Piperacillin (IV)
6
Q
First Generation Cephalosporins
A
Cefazolin (IV, IM)
Cephalexin [Keflex] (PO)
7
Q
Second Generation Cephalosporins
A
Cefoxitin (IV)
Cefuroxime (PO, IV, IM)
8
Q
Third Generation Cephalosporins
A
Ceftriaxone [Rocephin] (IV, IM)*
Ceftazidime (IV, IM)*
9
Q
Fourth Generation Cephalosporins
A
Cefepime (IV, IM)*
10
Q
Carbapenems
A
Imipenem/cilastatin (IV)
Meropenem (IV)*
Ertapenem (IV, IM)*
11
Q
Monobactams
A
Aztreonam (IV, IM, INH)
12
Q
B-lactamase Inhibitors
A
Ampicillin-sulbactam (IV)*
Amoxicillin-clavulanic acid [Augmentin] (PO)*
Piperacillin-tazobactam (IV)*
13
Q
Glycopeptides
A
Vancomycin (PO, IV)*
14
Q
Lipopeptides
A
Daptomycin (IV)
15
Q
Fluoroquinolones
A
Ciprofloxacin [Cipro] (PO, IV, topical)
Levofloxacin (PO, IV, topical)*
Moxifloxacin (PO, IV, topical)
16
Q
Aminoglycosides
A
Tobramycin (IV, IM, INH, topical)
Gentamicin (IV, IM, topical)*
17
Q
Tetracyclines/Glycylcyclines
A
Minocycline (PO, IV)
Doxycycline (PO, IV) *
18
Q
Macrolides/Ketolides
A
Clarithromycin (PO)
Azithromycin [Zithromax, Z-pak] (PO, IV, topical)*
19
Q
Lincosamides
A
Clindamycin [Cleocin] (PO, IV, IM, topical)*
20
Q
Oxazolidinones
A
Linezolid (PO, IV)
21
Q
Metronidazole
A
Metronidazole [Flagyl] (PO, IV, topical)
22
Q
Sulfonamides/Trimethoprim
A
Sulfamethoxazole/trimethoprim (PO, IV)
23
Q
Introduction to anitmicrobials
A
265,500,000 courses of outpatient antibiotics prescribed in 2011
842 prescriptions per 1000 persons
Most common categories: penicillins and macrolides
Top 5 drugs:
Azithromycin
Amoxicillin
Amoxicillin-clavulanate
Ciprofloxacin
Cephalexin
24
Q
Microorganisms & Antimicrobials
A
Bacteria = Antibacterial
Virus = Antiviral
Fungus = Antifungal
Parasite = Antiparasitic
25
Appropriate Antimicrobial Therapy
Ask yourself whether an antimicrobial agent is warranted:
Is an antimicrobial indicated based on clinical
findings?
Have appropriate cultures been obtained?
What is the most likely causative organism?
What must be done to prevent secondary
exposure?
Is there clinical evidence or established guidelines
that have determined antimicrobial therapy
provides a clinical benefit?
26
Organism Identification
Most valuable, time tested method for immediate ID of bacteria = gram stain
27
Gram-Positive vs. Gram-Negative
28
Peptidoglycan
29
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
30
Susceptibility Testing
Minimum inhibitory concentration (MIC):
Minimum inhibitory concentration (MIC): lowest concentration of drug required to inhibit growth
Breakpoints established by Clinical and Laboratory
Standards Institute (CLSI)
Types of Susceptibility Tests
Dilution Tests
Disk Diffusion
Optical Diffusion
31
Susceptibility Testing
Dilution Tests
32
Susceptibility Testing
Disk Diffusion
33
Susceptibility Testing
Clinical and Laboratory Standards Institute (CLSI) Breakpoints
Clinical and Laboratory Standards Institute (CLSI) Breakpoints
Example: antibiotic X
34
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
35
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
36
Concentration-Dependent
37
Time-Dependent
38
Bacteriostatic vs. Bactericidal
This concept is relative
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
39
Bacteriostatic vs. Bactericidal
Graphically
40
Antimicrobial Selective Toxicity
41
Antimicrobial Classification
Antimicrobials classified based on:
Class and spectrum of microorganisms it kills
Biochemical pathway it interferes with
Chemical structure
42
Site of Antibacterial Action
* Cell wall synthesis
* Cell membrane synthesis
* Protein synthesis
* Nucleic acid metabolism
* Function of topoisomerases
* Folate synthesis
43
Cell Wall Inhibitors
44
β-Lactams
Penicillins
Cephalosporins
Monobactam
Carbapenems
45
β-Lactam Mechanism of Action
Time-dependent; structural analogs of D-Ala-D-Ala; covalently bind penicillin-binding proteins (PBPs), inhibit the last transpeptidation step in cell wall synthesis
46
β-Lactamase Inhibitors
Amoxicillin + clavulanic acid, ticarcillin + clavulanic acid, ampicillin + sulbactam, piperacillin + tazobactam
MOA: prevent destruction of B-lactam antibiotics
47
Inhibition of Cell Wall Synthesis
48
Fluoroquinolone Mechanism of Action
Concentration-dependent, targets bacterial DNA gyrase & topoisomerase IV. Prevents relaxation of positive supercoils
49
Inhibitors of Protein Synthesis
Formation of initiation complex
Amino-acid incorporation
Formation of peptide bond
Translocation
50
Aminoglycosides
51
Tetracyclines
52
Macrolides
53
Sulfonamides and Trimethoprim
Inhibit folic acid synthesis; block sequential steps in pathway
54
Β-Lactams
MOA: structural analogs of D-Ala-D-Ala; covalently bind penicillin-binding proteins (PBPs), inhibit transpeptidation
Resistance:
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
55
Natural Penicillins
* 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
56
Anti-Staphylococcal Penicillins
* 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
57
Aminopenicillins
_**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
58
Anti-Pseudomonal Penicillins
Ticarcillin (IV), _**piperacillin\***_ (IV)
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
59
Penicillins
Adverse effects:
Adverse effects:
Allergic reactions (0.7-10%)
Anaphylaxis (0.004-0.04%)
Nausea, vomiting, mild to severe diarrhea
Pseudomembranous colitis
60
1st-Generation Cephalosporins
* 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
61
2nd-Generation Cephalosporins
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)
62
3rd-Generation Cephalosporins
* **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
63
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
64
Cephalosporins
Adverse Effects:
Adverse effects:
* 1% risk of cross-reactivity to penicillins
* Diarrhea
65
Carbapenems
Imipenem/cilastatin (IV), 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
Adverse effects:
Nausea/vomiting (1-20%), seizures (1.5%), hypersensitivity
66
Monobactam
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 à effective for gram-negative infections which would usually be treated with B-lactam
67
Glycopeptides
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
68
Glycopeptides
Spectrum:
Therapeutic use:
Adverse effects:
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
Adverse effects:
Macular skin rash, chills, fever, rash
Red-man syndrome (histamine release): extreme flushing, tachycardia, hypotension
Ototoxicity, nephrotoxicity (33% with initial trough \> 20 mcg/mL)
69
Fluoroquinolones
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
70
Fluoroquinolones
Adverse Effects:
Adverse effects:
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)
71
Aminoglycosides
Tobramycin (IV, IM, INH, topical), _**gentamicin\***_ (IV, IM, topical)
MOA: concentration-dependent; 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
72
Aminoglycosides
Adverse Effects:
Adverse effects:
* Ototoxicity (may be as high as 25%)
* Nephrotoxicity (8-26%)
* Neuromuscular block and apnea
73
Tetracyclines/Glycylcyclines
Minocycline (PO, IV), _**doxycycline\***_ (PO, IV), tigecycline (IV)
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; effective for: Rickettsia, Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia spp, Legionella, atypical mycobacterium, Plasmodium, Borrelia burgdorferi (Lyme’s disease), Treponema pallidum (syphilis)
74
Tetracyclines/Glycylcyclines
## Footnote
Therapeutic use:
Adverse effects:
Therapeutic use: CAP, atypical CAP coverage, community acquired SSTIs, community acquired MRSA, acne, Rickettsial infections (Rocky Mountain Spotted Fever), Q fever, anthrax
Adverse effects:
* GI (epigastric burning, nausea, vomiting, diarrhea)
* Superinfections of C. difficile
* Photosensitivity
* Teeth discoloration
* Thrombophlebitis
75
Macrolides/Ketolides
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
76
Macrolides/Ketolides
## Footnote
Adverse effects:
Drug interactions:
Adverse effects:
* GI (epigastric distress)
* Hepatotoxicity
* Arrhythmia
* QT prolongation
Drug interactions: CYP3A4 inhibition – prolongs effects of digoxin, warfarin
77
Lincosamides
* **_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
78
Lincosamides
Adverse Effects:
Adverse effects:
* GI diarrhea (2-20%)
* Pseudomembranous colitis (0.01-10%)
* -Due to C. difficile
* Skin rashes (10%)
* Reversible increase in aminotransferase activity
* May potentiate neuromuscular blockade
79
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)
80
Oxazolidinones
## Footnote
Therapeutic use:
Adverse effects:
Drug interactions:
Therapeutic use: VRE faecium (SSTI, UTI, bacteremia), nosocomial pneumonia caused by MSSA and MRSA, CAP, complicated/uncomplicated SSTI infections
Adverse effects:
* Myelosuppression [thrombocytopenia
* (2.4%),anemia, leukopenia]
* Headache
* Rash
Drug interactions: weak, nonspecific inhibitor of monoamine oxidase
