Intro to antibiotics

Question 1

What is required for appropriate antimicrobial therapy for an infectious disease?

Answer 1

1) knowledge of the potential site of infection
2) knowledge of the infecting pathogens
3) expected activity of the antibiotics against the infecting pathogens
4) Host characteristics

appropriate diagnosis is crucial

Question 2

When does normal flora bacteria becoem pathogenic?

Answer 2

when host defenses are impaired

when they are transloacated to normally sterile body sites during trauma, IV insertion, or surgery.

Question 3

Hospital fora tend to be

Answer 3

gram negative aerobes

Question 4

Normal flora of the skin

Answer 4

Diptheroids (Corynebacterium spp.)

• Propionibacteriaceae*
• Bacillus spp.*
• Staphylococci (esp. coagulase-negative)*
• Streptococci*

Question 5

Normal bacterial flora of the upper respiratory tract

Answer 5

• Bacteroides spp.*
• Haemophilus spp.*
• Neisseria spp.*
• Streptococc*i (anaerobic)

Question 6

Normal bacterial flora of the GI tract

Answer 6

• Bacteroides spp.*
• Clostridium spp.*
• Enterobacteriaceae (E. coli, Klebsiella spp.) Streptococci (anaerobic)*
• Enterococcus spp.*
• Fusobacterium spp.*

Question 7

Nornal bacterial flora of the genitourinary tract

Answer 7

• Lactobacillus spp.*
• Corynebacterium spp.*

Enterobacteriaceae – especially E.coli

Staphylococci (S. saprophyticus)

Streptococci

Question 8

Body fluids/sites that are sterile

Answer 8

blood stream

cerebrospinal fluid

pleural fluid

peritoneal fluid

pericardial fluid

synovial fluid

Bone

Urine (take directly from bladder)

Question 9

contamination

Answer 9

an organism is introduced into the specimine during the sample acquisition process

Example: isolation of coagulase negative staphylococci in the blood of a patient where the blood was drawn via a peripheral stick and the patient does not have signs of infection (normal skin flora bacteria contaminated blood culture)

Question 10

Colonization

Answer 10

an organism is present at a body site but is not invading host tissue, or causing a host response

Example: isolation of Pseudomonas aeruginosa from a sputum culture in a patient without fever, cough, or infiltrate on chest x-ray (pathogenic bacteria in patient without clinical/radiologic signs of pneumonia).

Question 11

Infection

Answer 11

A pathogenic organism is present at a body site and is damaging host tissues, illiciting a host response, and symptoms consistent with infection.

Example: isolation of Streptococcus pneumoniae in the cerebrospinal fluid of a patient with fever, headache, photophobia, and neck stiffness.

Question 12

Clinical signs of localized infection

Answer 12

pain, inflammation, swelling, erythema, purulent discharge, sputum production, cough, abnormal discharge

Question 13

Clinical signs of systemic infection

Answer 13

fever, chills, rigors, tachycardia, tachypnea, malaise, hypotension, mental status changes

Question 14

Laboratory signs if infection

Answer 14

elevated white blood cell count. (peripheral {leukocytosis} and/or at site of infection) with a “left shift”

Positive gram stain and culture

elevated erythrocyte sedimentation rate (ESR)

elevated C-reactive protein (CSR)

hypoxemia (pO2)

positive antigen or antibody titers

Question 15

Radiographic signs of infection

Answer 15

infiltrate on chest x-ray in pts with pneumonia

periosteal elevation, and bony destruction on a bone x-ray in a patient with osteomyelitis

Question 16

Assessment of severity of an infection

Answer 16

Severity of a patient’s infection is based on the degree of abnormality in the lab and radiology analysis.

significant alteration in cardiac, respiratory, CNS, may signify life threatening infection.

The severity of infection may influence the choice, route of administration, and dose of antibiotics used.

Question 17

Organisms that typicaly infect the mouth

Answer 17

Peptococcus

Peptostreptococcus

Actinomyces israelii

Treponema pallidum

Question 18

Narrow spectrum antibiotic

Answer 18

has activity against a limited group of bacteria

ex: penicillin has activity against some gram-positive and gramnegative cocci, but not gram-negative bacilli

Question 19

Broad spectrum antibiotic

Answer 19

has activity agaisnt a wide variety of bacteria such as gram positive and gram negative.

ex: imipenem has activity against gram-positive and gram-negative aerobes and anaerobes

Question 20

Minimun inhibitory concentration (MIC)

Answer 20

The lowest concentration of antibiotic that prevents visible growth (to the unaided eye) of a bacteria after 18-24 hours of incubation

MIC cannot be comparted between antibiotics

MIC is less than or equal to MBC

Question 21

Minimum bacterial concentration (MBC)

Answer 21

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

MBC is only determined in limited circumstances such as in the treatment of certain infections where bactericidal activity may be more predictive of a favorable outcome (meningitis, endocarditis).

MIC is less than or equal to MBC

Question 22

Susceptible (S)

Answer 22

organism will most likely be erradicated during treatment of infection using normal doses of the specific antibiotic; concentrations of the antibiotic by the MIC are easily achieved in patient’s serum with usual doses.

Question 23

Intermediate (I)

Answer 23

results are considered equivocal or intermediate. MICs are higher, treatment may be successful when maximum doses are used at the site of infection.

Question 24

Resistant (R)

Answer 24

Less than optimal results are anticipated if the particular antibiotic is used. MIC exceeds usualy serum concentrations (even if maximal doses ar used)

Question 25

Broth dilution

Answer 25

quantitative determination of the invitro activity of an antibiotic since the exact MIC or MIC range can be detemrined. (macrodilution with test tubes, micro dilution with automated microtiter plates of cassettes)

Dilutions of an antibiotic (based on achievable serum concentrations after usual doses) are placed in broth with a standard inocculum of the infecting bacteria, they are incubated for 18-24 hours

Question 26

Macrodilution testing

Answer 26

employs two-fold serial dilutions of an antibiotic (based on achievable serum concentrations after usual doses) incubated in test tubes with a standard inoculum of the patient’s infecting bacteria; the exact MIC of the antibiotic is the first tube without visible growth; labor and resource intensive.

Test tubes without visible growth are cultured on agar plates. After incubation colonies counted - MBC is the concentration that reduced the original inoculum by 99.9% after 24 hours of incubation.

Question 27

Disk Diffusion (Kirby Bauer Method)

Answer 27

a qualitative determination of the in vitro activity of an antibiotic a. Filter paper disks impregnated with a fixed concentration of an antibiotic are placed on agar plates inoculated with a standardized inoculum of the patient’s infecting bacteria. b. Bacteria multiply on the plate while antibiotic diffuses out of the disk; bacterial growth occurs only in areas where drug concentrations are below those required to cause inhibition of bacterial growth. c. A clear zone of inhibition is then observed around the disk - the larger the diameter, the more active the drug against the bacteria. Zone diameters in millimeters (mm) for each drug have been correlated to susceptible and resistant interpretations; however, exact MICs cannot be determined.

Question 28

E-Test (Epsilometer Test)

Answer 28

combines the quantitative benefits of microdilution with the ease of agar dilution

a. A plastic strip impregnated with a known, prefixed concentration gradient of antibiotic is placed on an agar plate with a standardized inoculum of the patient’s infecting bacteria.

b. Bacteria multiply on the agar plate while antibiotic diffuses out of the strip according to the concentration gradient; bacterial growth occurs only in areas where drug concentrations are below those required to cause inhibition of bacterial growth.

c. An elliptical zone of inhibition is then formed, and the MIC is measured where the ellipse crosses the antibiotic strip. An exact MIC can be determined.

Question 29

Susceptibility Reports

Answer 29

For each patient’s infecting bacteria, a susceptibility report will be generated that lists the antibiotics that were tested for activity against the organism, the exact MIC or zone size (or MIC range if automated systems are used) and CLSI interpretation (S, I, and R). b. This information is utilized with other clinical and patient-specific parameters (to be discussed later) to select an antibiotic regimen for the treatment of the patient’s infection.

Question 30

Hospital Antibiograms

Answer 30

Susceptibility data from organisms cultured from patients (inpatients and/or outpatients) are compiled in an annual report called an Antibiogram. b. The susceptibility data in an antibiogram is typically used to help guide the choice of empiric antibiotic therapy before the infecting organism has been identified in the lab. Clinicians use the antibiogram to determine the most active antibiotic against specific organisms at that specific institution.

Question 31

How is the treatment of infectious diseases different than other disease states requiring drug therapy?

Answer 31

Antibiotics can be used to treat a suspected or documented infection, or can be used to prevent an infection from occurring in high-risk patients. 2. Additionally, anti-infective therapy is typically given for a finite duration of therapy or a particular number of days based on previous clinical data for that infection type and/or infecting organism. Occasionally, some patients may receive anti-infective therapy for an infinite duration (such as that given for diabetes, CHF, or hypertension)

Question 32

Empiric Therapy

Answer 32

ntibiotics 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.

The initial antibiotic therapy is selected based on the known or probable site of infection, the most likely causative organism(s), the drug of choice for that particular organism and infection, and the local (hospital antibiogram) or regional susceptibility patterns of the suspected bacterial pathogens. Empiric antibiotic therapy usually covers a wide variety of bacteria (broad-spectrum). 3. Empiric therapy is usually administered until the culture and susceptibility results are available. If an organism is not isolated, empiric therapy may be continued until the finite duration of antibiotic therapy has been completed for that infection type, assuming the patient is improving.

Question 33

Directed or targeted therapy

Answer 33

antibiotics are used to treat an established infection where the site of infection, causative pathogen, and antibiotic susceptibilities are known.

Example – a patient has bacteremia with methicillin-susceptible Staphylococcus aureus and is receiving intravenous nafcillin therapy. 2. Antibiotic therapy is selected based upon the susceptibility results of the infecting pathogen, and is typically changed from the empiric antibiotic originally chosen to a more narrow-spectrum agent directed toward the infecting organism. 3. Antibiotics are given for the finite duration of therapy as determined by the infection type. All effective antibiotics that have been administered for the infection count toward the effective days of therapy (empiric and directed).

Question 34

Prophylactic Therapy

Answer 34

antibiotics are given to prevent the development of infection during a procedure or immunocompromised state when there is a considerable risk of infection

Examples – a patient with a prosthetic heart valve is given amoxicillin to prevent endocarditis at the time of a bacteremia-inducing dental procedure; an AIDS patient is given Bactrim to prevent Pneumocystis carinii pneumonia when the CD4 count is less than 200 cells/mm3 ; antibiotics are given prior to surgical procedures to prevent surgical site infections

Antibiotic therapy is selected based on the local and regional susceptibility patterns of the most likely infecting bacteria. 3. Prophylaxis is administered for as long as the patient is at risk, such as single dose antibiotic therapy for surgical/dental prophylaxis or longer durations of antibiotic therapy during immunosuppressive states.

Question 35

Combination Therapy

Answer 35

Combination therapy may be selected in a limited number of circumstances for the treatment of infection

a. To provide coverage against all organisms in a mixed, polymicrobial infection where a single antibiotic does not cover all of the infecting organisms – used to broaden bacterial coverage. b. To take advantage of synergistic properties when the antibiotics are used together. c. To decrease the emergence of resistance – only for tuberculosis.

Question 36

Synergy

Answer 36

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

ampicillin and gentamicin are administered together in the treatment of Enterococcal endocarditis in order to produce bactericidal activity and achieve successful eradication of the infection (alone each agent is bacteriostatic against Enterococcus)

Question 37

Additive

Answer 37

the activity of the antimicrobial combination is no greater than the sum of the effects of each individual component (no greater and no worse)

Question 38

Antagonism

Answer 38

the activity of the antimicrobial combination is less than that expected from the additive activity of the individual antimicrobials

azole antifungals and amphotericin B

Question 39

Bacteriostatic

Answer 39

antimicrobial agents that inhibit the growth of susceptible bacteria and rely on host defenses to help kill the bacteria and subsequently eradicate the infection

a. Typically, normal host defenses are required for clinical success of bacteriostatic agents, so they should be used with caution in patients who are immunocompromised. b. Examples: macrolides, ketolides, streptogramins, oxazolidinones, tetracyclines, glycylcyclines, sulfonamides (alone), and clindamycin

Question 40

Bactericidal

Answer 40

antimicrobial agents that kill susceptible bacteria in the absence of host defenses a. Bactericidal activity is considered essential in the treatment of infections located in sites where host defenses are not adequate including the meninges (meningitis), heart valves (endocarditis), and bone (osteomyelitis); as well as in patients with impaired host defenses (febrile neutropenia).

Examples: beta-lactams, aminoglycosides, vancomycin, daptomycin, fluoroquinolones, metronidazole, and trimethoprim-sulfamethoxazole

Question 41

Pharmacodynamics (PD)

Answer 41

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.

PD studies have demonstrated marked differences in the time course of bacterial killing among different antibiotics, described by examining the relationship between pharmacokinetic parameters and the MIC.

Question 42

What are the two major groups of antibiotcs based on bactericidal activity

Answer 42

concentration dependent

concentration independent (time dependent)

Question 43

Concentration-dependent

Answer 43

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

Examples of concentration-dependent antibiotics include the aminoglycosides, the fluoroquinolones, daptomycin, and metronidazole

The major PD parameters that correlate with clinical and microbiologic outcome (efficacy) of concentration-dependent antibiotics are the Peak/MIC ratio and the AUC/MIC ratio.

Goal of dosing - infrequent dosing of large doses to maximize drug concentrations or magnitude of exposure for optimal bacterial killing.

Question 44

name some concentration dependant antibiotics

Answer 44

aminoglycosides, the fluoroquinolones, daptomycin, and metronidazole

Question 45

Concentration-independent (time-dependent)

Answer 45

higher serum concentrations of the antimicrobial do not produce enhanced bacterial killing. The extent of bacterial killing is largely dependent on the time of exposure. These agents are not rapidly bactericidal, and typically have a short or nonexistent PAE.

Examples include the beta-lactams, clindamycin, macrolides, ketolides, vancomycin, tetracyclines, linezolid, Synercid.

Goal of dosing - optimize the duration of exposure (Time>MIC). Maintain the serum concentrations of the antibiotic above the MIC for the infecting pathogen for at least 40-70% of the dosing interval, depending on the organism.

Question 46

Post-Antibiotic Effect (PAE)

Answer 46

the time it takes for a bacteria to recover after exposure to an antibiotic, or the time it takes for bacteria to recover and begin regrowth after an antibiotic has been removed

The exact duration of the PAE is drug and organism specific.

Agents with appreciable PAEs may be dosed to allow serum concentrations to fall below the MIC of the infecting bacteria since regrowth will not occur for a finite period (for as long as the antibiotic’s PAE).

All antibiotics produce some PAE against gram-positive bacteria; the PAE for beta-lactams is approximately 2 hours.

For gram-negative bacteria, prolonged PAEs are observed after exposure to protein synthesis inhibitors or nucleic acid synthesis inhibitors (fluoroquinolones and aminoglycosides); beta-lactams have short or nonexistent PAE.

Question 47

Infection-Specific Factors when selecting an antibiotic

Answer 47

Severity of infection (mild. moderate, severe, life-threatening) – influences the route of administration, dose, number of antibiotics Oral – for infections that are mild, or for those that are significantly improved and can be treated on an outpatient basis IV – used for infections that are serious or life-threatening, or for antibiotics with insufficient absorption from the GI tract.

Site of infection – influences the antibiotic and dose, since adequate concentrations of the drug must reach the site of infection for efficacy. Special considerations must be made for the treatment of meningitis (cross blood-brain barrier), endocarditis, prostatitis, etc.

Infecting organism – site of acquisition of the infection (community versus hospital, nursing home); exposure to ill family members, pets; employment; recent travel; known or anticipated susceptibility patterns; empiric versus directed therapy; drug of choice for particular organism/infection; need for combination therapy

Question 48

Host Factors when choosing an antibiotic

Answer 48

Allergies

Age

Pregnancy and nursing

Renal and Hepatic function

concomitent drug therapy (vancomycin and gentamicin → nephrotoxicity; ganciclovir and zidovudine → neutropenia). PD of another drug can be altered, may change ADME. (divalent cations decrease the absorption of fluoro-quinolones and tetracyclines. decreased concentrations and treatment failure.

underlying disease states

drug factors-

Question 49

Premature neonates and and sulfonamides

Answer 49

Premature neonates develop kernicterus from sulfonamides due to displacement of bilirubin from albumin

Question 50

Liver dysfunction alters the metabolism of which drugs

Answer 50

chloramphenicol, clindamycin, metronidazole, nafcillin/oxacillin, linezolid, Synercid, erythromycin, azithromycin, doxycycline, tigecycline, and Bactrim

Question 51

Gram-positive cocci in clusters

Answer 51

Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus haemolyticus

Staphylococcus hominis

Staphylococcus capitis

Staphylococcus saccharolyticus

Question 52

Gram-positive cocci in pairs

Answer 52

Streptococcus pneumoniae