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Sites and their fluids that are considered sterile

Bloodstream Blood
Subarachnoid space CSF
Pleural space Pleural fluid
Peritoneum Peritoneal fluid
Pericardium Pericardial fluid
Synovium Synovial fluid
Urinary tract Urine (directly from bladder)

anything that grows in these sites is a pathogen/infection



organism inadvertently introduced during specimen collection or processing

ex. Coag-neg staph in blood of patient



organism is present at body site but is not invading host tissue or inducing signs and symptoms of infection

ex. Pseudomonas aeruginosa in the sputum of a patient who is not displaying signs of pneumonia



pathogenic organism is damaging host tissue and eliciting signs and symptoms of infection

ex. Streptococcus pneumoniae in sputum of patient with fever, productive cough, and shortness of breath


Antibiotics may be chosen before results of the cultures are available based on what information

Site of infection and likely causative organism
Gram-stain result (does result correlate with most likely suspected organism?) (in the CSF gram stain may give an exact diagnosis)


empiric therapy vs. directed or targeted therapy

empiric therapy - Antibiotics are chosen that have activity against likely pathogens

direct therapy - Antibiotic regimen is modified once culture and susceptibility results are available


of Activity

Spectrum of activity is the general list of bacteria that are killed or inhibited by an antibiotic
- Established during early clinical trials of the antibiotic
- Recent local, regional and national susceptibility patterns of each bacteria should be continuously evaluated because antibiotic activity may change over time due to emergence of resistance


narrow vs broad spectrums of activity

Narrow Spectrum = antibiotic has activity against a limited group of bacteria

Broad Spectrum = antibiotic has activity against a wide variety of bacteria


Appropriate antimicrobial therapy depends on

knowledge of:
the potential site of infection;
the infecting pathogen(s);
the expected activity of the antibiotic(s) against the infecting pathogen(s);
and host characteristics.

Therefore, appropriate diagnosis is crucial.


Minimum Inhibitory Concentration or MIC

lowest concentration of an antibiotic that inhibits visible bacterial growth (unaided eye) of a bacteria after 18
to 24 hours of incubation


Minimum Bactericidal Concentration or MBC

the lowest concentration of an antibiotic that results in a decrease of > 99.9% of the bacterial inoculum


Susceptibility Breakpoints

based on the MIC of an antibiotic for a specific bacteria

Susceptible - organism will most likely be eradicated with normal doses of the antibiotic
Intermediate - treatment may be successful using maximal doses of the antibiotic
Resistant - MIC exceeds usual serum concentrations of the antibiotic, so less than optimal results are expected


Susceptibility Breakpoints are based on

• Pharmacokinetics of the drug - achievable serum and tissue concentrations
• General activity of the antibiotic
• Site of infection
• Data from clinical efficacy trials

In general, MIC values should not be compared between different antibiotics

Interpretive guidelines for S, I and R for each antibiotic and each bacteria are different


how is the MIC determined

Macrodilution, microdilution, Disk Diffusion – Kirby Bauer, E-Test®, and PCR



Macrodilution - two-fold serial dilutions of an antibiotic are incubated with a standard inoculum of the infecting bacteria in test tubes
• MIC = first tube without visible growth
• Results yield the EXACT MIC of the antibiotic against the infecting organism
• Not routinely performed because it is labor and resource intensive


MBC from macrodilution

(not routine) – extension of macrodilution test; MBC represents the antibiotic concentration that kills bacteria (no colonies are present on agar plates)



microtiter plates or cassettes with (already prepared) serial dilutions of several antibiotics tested at the same time
• Automated; most common method
• Due to size restraints of cassettes, not all concentrations of an antibiotic can be tested for susceptibility
• Result may be reported as an MIC range, such as ≤ 8 µg/ml Susceptible
• Vitek,Microscan


Disk Diffusion – Kirby Bauer

QUALITATIVE test of the in vitro activity of an antibiotic; MIC is not determined
• Filter paper disks impregnated with a fixed concentration of an antibiotic are placed on agar plates inoculated with a standard concentration of the infecting bacteria
• Clear zone of inhibition is observed around the disk - bacteria only grows where concentrations of the antibiotic are below those required to inhibit bacterial growth
• Zone diameters (in mm) correlate with S, I, R



Combines quantitative benefits of broth dilution with the ease of disk diffusion; yields an MIC
• Plastic strip impregnated with known, predefined concentration gradient of antibiotic is placed on agar plates • inoculated with standard concentration of infecting bacteria
• Clear elliptical zone of inhibition is observed around strip - bacteria only grow where concentrations are below those required to inhibit bacterial growth
• MIC = where ellipse crosses the strip


Hospital Antibiograms

- Susceptibility data for most common bacteria isolated in hospital annually
- Helps guide choice for empiric antibiotic therapy before bacteria has been identified


Empiric therapy

Antibiotics are administered that have activity against the predicted or most likely pathogens causing a patient’s infection based on the signs and symptoms of infection. The site of infection may or may not be known, and the culture results are pending, negative, or unobtainable.

• Therapy chosen based on DOC for most likely organism and regional susceptibility patterns
• Given until culture and susceptibility results for infecting bacteria are available


Directed or targeted therapy

antibiotics are selected to treat documented/established infections
• Antibiotic selected based on results of susceptibility studies → change to a more narrow spectrum agent
• Given for predefined duration of therapy


Prophylactic therapy

antibiotics given to prevent the development of infection
• Therapy chosen based on DOC for most likely organism and regional susceptibility patterns
• Administered for as long as patient is at risk

examples: antibiotics given during surgery or dental procedures,


Combination therapy

Broaden bacterial coverage to cover all organisms causing infection
Decrease the emergence of resistance
Take advantage of synergy when antibiotics are used together


drug Synergy

activity of the antimicrobial combination is greater than expected from the additive activity of the individual antibiotics

(A + B) > A + B



activity of the combination is no greater than the sum of the effects of each individual agent
(A + B) = A + B



activity of the combination is less than expected from the additive activity of the individual agents
(A + B)



antibiotic that inhibits bacterial growth; killing depends on host defense mechanisms
• Disadvantages: in setting of inadequate host defenses, any partially inhibited organisms may survive, replicate, and produce recurrent infection when the antibiotic is discontinued (or serum concentrations fall below MIC)
• Examples include macrolides, ketolides, tetracyclines, glycylcyclines, sulfonamides, clindamycin, Synercid, linezolid



antibiotic kills bacteria; less dependent on host defense mechanisms
• Preferable if the host immune system is compromised or does not function well (e.g. neutropenic, immunosuppressed)
• Required for the treatment of meningitis, endocarditis, osteomyelitis, febrile neutropenia
• Examples: penicillins, cephalosporins, carbapenems, aztreonam, fluoroquinolones, aminoglycosides, vancomycin, daptomycin, Bactrim®, metronidazole


Cell wall synthesis inhibitors are bactericidal or bacteriostatic



Protein synthesis inhibitors are bactericidal or bacteriostatic


except aminoglycosides- bacteriocidal


nucleic acid synthesis inhibitors are bactericidal or bacteriostatic



metabolic inhibitors are bactericidal or bacteriostatic



Pharmacodynamics (PD)

is the study of the time course or rate of bacterial killing relative to serum concentrations. The study of pharmacodynamic provides a rational basis for optimizing dosing regimens by describing the relationship between drug, host, and antimicrobial effect by integrating both pharmacokinetic and MIC data.



the higher the serum concentration of the antibiotic, the more rapid and extensive the degree of bacterial killing.
• Concentration-dependent agents also appear to have prolonged persistent effects (post antibiotic effects or PAE) that allow for infrequent dosing.


Post-Antibiotic Effect

PAE is the time it takes for a bacteria to regrow once serum concentrations of the antibiotic have dropped below the MIC
• Duration of PAE is drug and organism specific
• Agents with long PAEs can be dosed to allow serum concentrations to fall below the MIC
• Gram-positive bacteria - all antibiotics have some PAE; 2 hours for β-lactams
• Gram-negative bacteria - prolonged PAEs with protein or nucleic acid synthesis inhibitors such as aminoglycosides and fluoroquinolones


Time Dependent Killing

Killing depends on time of exposure above the MIC (Not higher serum concentrations)

must give the next dose right away when it is predicted that the concentration will fall below MIC


Renal and hepatic function

diminished function may lead to drug accumulation and undue toxicity - adjust doses!
• Antibiotics primarily eliminated by kidneys include most β-lactams, vancomycin, the aminoglycosides, some FQs, Bactrim, daptomycin, tetracycline
• Antibiotics primarily eliminated by the liver include the macrolides, Synercid, linezolid, clindamycin, metronidazole, some FQs, Bactrim, doxycycline, tigecycline