PHPR 6440: INFECTIOUS DISEASES MODULE
Antibiotic Selection Factors
Madhavi Manduru, Pharm.D.
Fall Semester 1997
OBJECTIVES
Upon completion of the class discussion, the student should be able to:
1. Discuss the role of fever in the diagnosis of infection.
2. Describe changes in the white blood count indicative of infection.
3. List common predisposing factors to infection.
4. Discuss the role of stains, serological tests, and cultures in the diagnosis of an infection.
5. List the drug-specific factors one considers in antibiotic selection.
6. Describe methods utilized to assess the clinical response of an infected patient.
7. Discuss factors that should be assessed when a patient fails to respond clinically to antimicrobial therapy.
REQUIRED READINGS:
Pharmacotherapy, A Pathophysiologic Approach. 3rd edition. Dipiro JT, Talbert RL, Yee GC. Et al, eds. Chapter 97 and 98.
PHPR 6440: INFECTIOUS DISEASES MODULE
Antibiotic Selection Factors
Madhavi Manduru, Pharm.D.
Fall Semester 1997
I. BACTERIOLOGY
A. AEROBES
Gram positive cocci Gram negative cocci
Staphylococci Moraxella catarrhalis
Coagulase +: S. aureus Neisseria gonorrhoeae
Coagulase -: S. epidermidis Neisseria meningitidis
S. saprophyticus
S. hominis
Streptococci
S. pneumoniae
S. pyogenes (Grp A, ß-hemolytic)
S. agalactiae (Grp B)
S. bovis (Grp D)
S. equinis (Grp D)
Viridans Group
S. sanguis
S. mitior
S. mutans
S. milleri
Enterococcal spp. (Grp D. streptococci)
E. rafinosus
E. faecalis
E. durans
E. faecium
Gram positive bacilli Gram negative bacilli
Bacillus cereus Enterobacteriaceae
Bacillus anthracis Citrobacter sp.
Diptheroids Enterobacter sp.
Cornybacterium diptheriae Escherichia coli
JK Cornyebacterium Klebsiella sp.
Listeria monocytogenes Serratia sp.
Morganella sp.
Proteus mirabilis (indole +)
Proteus vulgaris (indole -)
Providencia sp.
Salmonella sp.
Serratia sp.
Shigella sp.
Pseudomonas sp.
P. aeruginosa
P. cepacia
Xanthomonas maltophilia
Haemophilus influenzae
Legionella pneumophila
B. ANAEROBES
Gram positive cocci Gram negative bacilli
Peptostreptococcus Bacteroides fragilis
Peptococcus Bacteroides sp.
Gram positive bacilli
Clostridium sp.
C. difficile
C. perfringens
C. tetani
C. ACID FAST BACILLI
Mycobacterium avium-intracellulare complex
Mycobacterium bovis
Mycobacterium fortuitum
Mycobacterium tuberculosis
D. FUNGI
Yeasts
Candida sp. ( C. albicans, C. krusei, C. tropicalis)
Cryptococcus neoformans
Aspergillus sp.
Aspergillus fumigatus
II. NORMAL FLORA
A. An organism may be considered normal flora at one area of the body, but pathogenic when found in another part of the body or even at the same site were it is normally found.
B. Normal flora plays an important role in the host defenses
C. Normal flora
1. Skin
2. Gastrointestinal tract
3. Upper respiratory tract
4. Genital tract
III. HOST DEFENSES
A. External Defense Mechanisms
1. Skin:
2. Respiratory Tract
3. Alimentary Tract
4. Genitourinary Tract
5. Eye
B. Nonspecific immunologic Defenses
C. Specific Immunologic Defense Mechanisms
1. Antibodies
a. IgG
b. IgA
c. IgM
d. IgD
e. IgE
IV. CONFIRMATION OF INFECTION
A. Fever
1. significant if oral temp > 99.5-100.5° F (37.5-38.0° C)
2. non-infectious causes (tumor, drug fever)
3. absence in presence of other signs and symptoms of infection (antipyretics, antimicrobial therapy)
4. pattern of fever (spiking vs. continuous)
B. Signs and Symptoms
1. White blood cell count
a. leukocytosis (normal WBC 4,000-10,000/mm3)
-bacterial infections - associated with elevated granulocytes (neutrophils, basophils) and immature neutrophils (bands)
-may be elevated due to non-infectious diseases (e.g. leukemia) or drug therapy (e.g. steroids, lithium).
b. Normal differential count in adults
Cell Type % neutrophils (PMNs) 50-70 immature neutrophils 3-5 metamyelocytes 0-1 lymphocytes 20-40 monocytes 0-7 esosinophils 0-5 basophils 0-1
c. lymphocytosis - associated with viral or fungal infections
d. monocytosis - associated with more chronic infections (e.g. TB)
e. eosinophilia - associated with parasitic infections
2. Pain and inflammation
a. easily detected in a superficial infection
b. deep-seated infections - tissues must be examined (e.g. sputum, CSF, urine)
c. may be absent in neutropenic hosts
C. Non-specific lab tests
1. erythrocyte (sedimentation rate (ESR)
2. complement (may be reduced in infection)
3. C-reactive protein (usually elevated in infection)
D. Predisposing factors
1. Alterations in normal flora
a. broad-spectrum antibiotics
b. hospitalization
2. Disruption of natural barriers
a. Skin/mucous membranes
- burns, trauma, IV sites
b. Respiratory cilia
- smoking
- viral infections
c. pH/motility of the GI tract
d. Urine/tears
- flow
- enzymes
3. Immunosuppression due to:
a. malnutrition
b. underlying disease
c. hormonal changes
d. drugs (e.g. cytotoxic chemotherapy)
4. Age
V. IDENTIFICATION OF THE PATHOGEN
A. Collection of infected material
1. must be as rapid as possible to avoid false-negative cultures
2. aspiration of infected fluids (abscesses)
3. contamination must be avoided
4. colonization vs. infection
a. quantitative cultures
B. Identification of organisms
- radiolabeled CO2
- slides containing differential growth media
- resin bottles (adsorb antimicrobials)
C. Direct examination
1. Gram stain
a. staining characteristics (positive, negative)
b. morphological appearance (coccus, bacillus)
2. Other stains
3. Fluorescent antibody
D. Serologies
1. detection of antibodies
- immunodiffusion
- immunofluorescence
- immunoassay (e.g. ELISA)
2. detection of antigens
- agglutination
- immunoelectrophoresis
- immunoassay
VI. MICROBIOLOGIC TEST TO ASSESS ANTIMICROBIAL ACTIVITY
A. Minimum inhibitory concentration (MIC), Minimum bactericidal concentration (MBC),
Time-Kill testing
1. Methods
a. Broth dilution (macrodilution vs. microdilution)
(More expensive, technically more difficult, better quantifies the MIC/MBC)
MIC
![[First Graphic]](sel-1.gif)
(1) Inoculum Effect
- increase in the MIC/MBC noted when a larger than standard inoculum is used (105 CFU/ml is the standard inoculum for most microbiological tests)
- may affect different classes of antimicrobials, but is most pronounced with beta-lactams
(2) Breakpoints testing
- utilizes fewer concentrations of the antibiotic (usually only 2) than full MIC testing
- See following figure
Interpretation of breakpoint testing
- changes in interpretative guidelines (breakpoints) may cause profound changes in reported susceptibility patterns
BP 2,4 µg/ml BP 4,8 µg/ml 0.5 0.5 1.0 S = 30% 1.0 2.0 2.0 4.0 4.0 S = 60% 4.0 I= 30% 4.0 4.0 4.0 8.0 8.0 8.0 R = 40% 8.0 I = 30% 8.0 8.0 16.0 16.0 R = 10%
b. Agar dilution
- usually three concentrations of the antibiotic are tested against the organism
- the antibiotic is incorporated into the agar plate
- used more often for research than clinical susc. testing
c. Disc diffusion (Kirby-Bauer)
(Simpler methodology, requires less technical expertise, approximates MIC)
(1) relationship between zone diameter and MIC of the organism
d. Etest- combines principles of disk diffusion with quantitative value of broth MIC
2. MBC lowest concentration of antibiotic that results in 99.9% reduction in initial bacterial density ( See broth dilution MIC figure)
a. Tolerance: MBC > 32 x MIC
3. Time kill curves- unlike MIC tests, the time-kill study evaluates antimicrobial over 24 hours. Thus, can assess rate and extent of bactericidal activity
4. Post antibiotic effect persistent effect of an antimicrobial on bacterial growth following brief exposure of an organism to a drug
B. Synergy Testing- assessing antimicrobial combinations
1. Methods
a. Checkerboard
(1) FIC Index
b. Time-kill curves
c. Disc Diffusion
2. Definitions
Synergy: effect of 2 drugs greater than when used alone
Indifference/Additive: insignificant increase effect when 2 drugd are used in combination
Antagonism: decrease in effect when 2 drugs are used in combination
C. Serum inhibitory/bactericidal testing (Schlichter's test, SIT/SBT, SBA)
1. Methods
SBT
a. Technical factors which affect results
inoculum size, phase of growth, pH, cation conc., osmolarity, media (diluent), bactericidal endpoint, methodology (macro vs. micro)
2. Clinical Use
a. Endocarditis
(i) Recommended peak titer ³ 1:64
Recommended trough titer ³ 1:32
- Ann Intern Med 1985;78:262-269
b. Osteomyelitis
Acute Chronic
(i) Recommended peak No value ³ 1:16
Recommended trough ³ 1:2 ³ 1:4
- Ann Intern Med. 1987;83:218-222.
c. Bacteremia
d. Other diseases/other body fluids
(e.g. urine, CSF)
3. Comparison of antibiotics
- used as a research tool to assess activity of single agents or combinations of antimicrobials
VII. ANTIMICROBIAL FACTORS
A. Empiric vs. specific therapy
1. site of infection
2. knowledge of normal flora
3. knowledge of local susceptibility patterns
B. In vitro microbiological activity
1. Susceptibility Tests
a. MIC/MBC
b. Breakpoint tests
c. Disc diffusion
2. Synergy
a. Checkerboard
b. Time-kill curves
3. Resistance
a. altered receptors
b. decreased entry of drug into bacteria
c. destruction of the drug (e.g. beta-lactamases)
4. Post-antibiotic effects
5. Serum inhibitory/bactericidal titers
C. PHARMACOKINETICS
1. Absorption
a. dose-limited
b. impaired due to disease state, surgery, drug therapy
2. Distribution
a. Achievable serum concentration
b. Protein binding
(1) Type of binding proteins
(2) Concentration-dependent binding
c. Tissue distribution
(1) intracellular vs. extracellular concentrations
3. Metabolism
a. active/toxic metabolites
b. high vs. low intrinsic clearance
4. Elimination
a. Biliary
(1) advantages/disadvantages
b. Renal
(1) Mechanisms
- glomerular filtration
- secretion
(2) Concentrations
- achievable concentrations in urine
c. Other routes of elimination
D. PHARMACODYNAMICS
1. In vitro effects
a. concentration vs. time-dependent bactericidal activity
2. In vivo effects
3. effect of altered dosing regimens on clinical outcome
E. ADVERSE EFFECTS
1. Risk/benefit assessment
2. Problems with pre-marketing data
a. sample size vs. incidence
b. lack of comparative data
c. literature from other countries
F. DRUG INTERACTIONS
1. Reported in published literature
2. Suspected, based on known effects of the drug
a. effects of protein binding
b. enzyme inducers/inhibitors
G. HOST-SPECIFIC FACTORS
1. Alteration in normal host defenses (AIDS, neutropenia)
2. Known allergies
3. Renal/hepatic dysfunction
4. Metabolic abnormalities (e.g. G6PD, slow acetylators)
5. Age (effects on pharmacokinetics, types of pathogens)
6. Pregnancy (effects on pharmacokinetics, teratogenicity concerns)
7. Concomitant diseases (e.g. diabetes)
H. CLINICAL EFFICACY
1. FDA-approved indications
2. Problems with pre-marketing data
a. lack of comparative trials
b. exclusion of patients that are extremely ill
I. COSTS
1. Acquisition cost
a. institutional vs. national emphasis
2. Administrative
a. Supplies
b. Personnel
c. Inventory
3. Monitoring Costs
a. therapeutic drug monitoring
b. additional lab tests (e.g. creatinine, P.T.)
4. Costs of toxicity
a. extended length of stay
b. treatment costs
c. ? legal costs
5. Costs of poor clinical results
VIII. MONITORING CLINICAL RESPONSE
A. Clinical assessment
1. physical examination
2. non-invasive techniques (auscultation/percussion, x-rays, scans)
B. Laboratory tests
1. Serology
2. Cultures
3. Serum bactericidal activity
4. Therapeutic drug monitoring
C. Assessment of clinical failures
1. Due to antimicrobial selection
a. inappropriate dose
b. inappropriate route of administration
c. enhanced drug clearance
d. poor tissue penetration
e. drug interactions
f. drug inactivation
2. Due to host factors
a. immunosuppression (e.g. neutropenic patients)
b. foreign bodies (e.g. orthopedic hardware)
3. Due to microorganisms
a. development of resistance (e.g. beta-lactamase production)
b. mixed infections
4. Due to laboratory errors
a. identification of a pathogen
b. errors in susceptibility testing