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256 Cards in this Set
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MIC =
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Lowest concentration of antibiotic required to inhibit bacterial growth
Determined in vitro by several different techniques Used as a measure of antibiotic potency, i.e. the lower the MIC the more potent the antibiotic Commonly used for comparison of activities of various antibiotics |
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MBC=
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minimum bactericidal concentration
Lowest concentration of antibiotic required to kill bacteria |
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what MIC is most potent and what one is most pharmacologically active?
MIC= 0.12, 1, 0.25, 2 |
0.12 is the most potent, but it may not be the most effective so cannot determine what one is the most pharmacologically active
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Gatifloxacin vs. Standard Therapy or Levofloxacin for Community-Acquired Pneumonia
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916 patients in three separate trials randomized to receive one of four antimicrobial regimens
Studies included either outpatient or inpatient treatment x 7-14 days Gatifloxacin 400 mg QD IV/PO - 427 / 446 (96%) Clarithromycin 500 mg PO BID - 175 / 188 (93%) Ceftriaxone 1-2 g IV QD + ECN or Clarithromycin - 95 / 106 (90%) Levofloxacin 500 mg IV/PO QD - 165 / 176 (94%) there is no clinical of statistical difference between cure rates |
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Factors Influencing Clinical Outcome and antibiotices
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BUG: Virulence factors
Intrinsic susceptibility Resistance mechanisms DRUG: MOA In vitro MICs PK properties HOST: Genetic determinants Underlying illnesses - Altered PK/PD |
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Antimicrobial Pharmacodynamics
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Correlates the drug concentration with the clinical effect (i.e., bacterial killing) (or inhibition)
Uses surrogate markers such as minimum inhibitory concentration (MIC) Indexes serum concentration (PD property) (pharmacokinetic profile) to MIC to predict clinical outcomes The pharmacodynamic relationship is different for different antimicrobial classes what the drug is doing to the bacteria which is related to drug concentration |
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Optimizing Antimicrobial Therapy
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antibiotic--->(PK properties)---> concentration at site of infection and Pathogen MIC/MBC--->(PD properties) host factors/bacterial killing all determine clinical cure
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what property of a drug is more important to determine the concentration of the drug at the site of infection PK or PD
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PK
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what property governes what a drug does in the patient PK or PD
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PK
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what a graph looks like for an antibiotic that is time dependent
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woman, ninja (n.)
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مُنَقَبَة
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list of time dependent antibiotics
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penicillins
cephalosporins monobactams carbapenems macrolides clindamycin oxazolidiones azithromycin vancomycin |
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list of concentration dependent antibiotics
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aminoglycosides
fluoroquinolones metronidazole ketolides daptomycin telavancin |
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with time dependent antibiotics what is influencing the efficacy
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time>MIC
how long the drug concentration is above the MIC |
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with concentration dependent antibiotics what is influencing the efficacy
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Peak/MIC
cmax |
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PD Parameters Predictive of Outcome (time dependent examples and therapeutic goal)
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b-lactams
Macrolides Vancomycin Optimise duration of exposure |
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PD Parameters Predictive of Outcome (concentraion dependent examples and therapeutic goal)
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Cmax/MIC
Quinolones Aminoglycosides Optimise magnitude of exposure (side not quinolones are also dependent on the AUC/MIC not just cmax and MIC) |
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If the total daily dose of a drug is 4 Gm/day, what is the best way to administer the drug in order to optimize dosing from a pharmacodynamic perspective?
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If the drug is concentration-dependent, administer as a 4 Gm QD regimen
If the drug is time-dependent, administer as a 1 Gm QID regimen |
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Effect of Changing Dose or Dosing Interval on Pharmacodynamic Parameters
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Effect of Changing Dose or Dosing Interval on Pharmacodynamic Parameters
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Effect of Changing Dose or Dosing Interval on Pharmacodynamic Parameters
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Optimizing Pharmacodynamics of Antimicrobials
Concentration-Dependent Drugs: |
Give relatively large doses less frequently to maximize Cmax and/or AUC
relative to MIC |
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Optimizing Pharmacodynamics of Antimicrobials
Time-Dependent Drugs |
Give smaller doses more frequently to maintain higher Css, ave
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Time-dependent bactericidal activity
e.g., b-lactams and Macrolides |
Rate and extent of bacterial killing does not increase with increasing drug concentration
Clinical Goal: Maximize drug duration, i.e., time serum level remains above the MIC (Time > MIC) Time above MIC is expressed as a percentage relative to the dosing interval (τ) 6 hrs above MIC with τ = 8 hrs Time > MIC = 75% |
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what is time above MIC expressed in
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Time above MIC is expressed as a percentage relative to the dosing interval (τ)
6 hrs above MIC with τ = 8 hrs Time > MIC = 75% |
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what will a continuous infusion result in
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100% T>MIC
which is not necessarily better, clinical benefits tend to peak at 50% T>MIC |
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when a antibiotic is time dependent and the MIC50 and cmax perameters are given can you determine what drug is best
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nope because it is time dependent
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The “In vitro – in vivo Paradox of antibiotics
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Patients infected with “resistant” pathogens may often be effectively treated despite the apparently poor in vitro activity of the drug being used
this is due to the fact that tissue concentrations are different and the patient may have good immune funtion which are not taken into account in vitro |
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are antibiotic breakpoints based on plasma or tissue concentrations
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plasma because done in vitro, so if the site of infection is in the tissues the effectiveness of the drug is hard to determine
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Fluoroquinolone Pharmacodynamics Cmax/MIC ratio
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> 10-12 correlated with favorable clinical & microbiological response
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Fluoroquinolone Pharmacodynamics AUC/MIC ratio against gram - infections
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> 125-250 associated with increased likelihood of clinical efficacy and decreased resistance in Gram-negative infections
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Fluoroquinolone Pharmacodynamics AUC/MIC ratio against gram + infections
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AUC/MIC > 30-50 associated with optimal in vitro activity and decreased resistance in Gram-positive infections
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goal of fluoroquinolones with gram + and - infections
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Goal:
AUC:MIC > 125 gram – organisms AUC:MIC > 30-50 gram + organisms |
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if you have a choice of cipro, levo, gati or moxi whos AUC ratios are all will above the MIC except cipro to treat MSSA does it matter which one you choose
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the only one that would not be efficacios is cipro all the others would work equally as well
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why are none of the fluoroquinolones used againts MRSA
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because none of their AUC ratios are above the AUC/MIC point where they are effective
MRSA is resistant |
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what 3 fluoroquinolones are effective against s. peumoniae and why
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gati, levo and moxi because the ration of AUC.MIC is well above the point to be efficacious
whereas cipro is not |
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Fluoroquinolone Pharmacodynamics AUC/MIC ratio against gram + infections
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AUC/MIC > 30-50 associated with optimal in vitro activity and decreased resistance in Gram-positive infections
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Fluoroquinolone Pharmacodynamics AUC/MIC ratio against gram + infections
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AUC/MIC > 30-50 associated with optimal in vitro activity and decreased resistance in Gram-positive infections
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goal of fluoroquinolones with gram + and - infections
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Goal:
AUC:MIC > 125 gram – organisms AUC:MIC > 30-50 gram + organisms |
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goal of fluoroquinolones with gram + and - infections
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Goal:
AUC:MIC > 125 gram – organisms AUC:MIC > 30-50 gram + organisms |
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if you have a choice of cipro, levo, gati or moxi whos AUC ratios are all will above the MIC except cipro to treat MSSA does it matter which one you choose
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the only one that would not be efficacious is cipro all the others would work equally as well
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if you have a choice of cipro, levo, gati or moxi whos AUC ratios are all well above the MIC except cipro to treat MSSA does it matter which one you choose
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the only one that would not be efficacios is cipro all the others would work equally as well
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why are none of the fluoroquinolones used againts MRSA
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because none of their AUC ratios are above the AUC/MIC point where they are effective
MRSA is resistant |
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why are none of the fluoroquinolones used againts MRSA
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because none of their AUC ratios are above the AUC/MIC point where they are effective
MRSA is resistant |
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what 3 fluoroquinolones are effective against s. peumoniae and why
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gati, levo and moxi because the ration of AUC.MIC is well above the point to be efficacious
whereas cipro is not |
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what 3 fluoroquinolones are effective against s. peumoniae and why
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gati, levo and moxi because the ration of AUC.MIC is well above the point to be efficacious
whereas cipro is not |
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Aminoglycoside PK/PD Relationships in Pseudomonas Bacteremia (graph)
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when the cruve platues there is not better efficacy in the drug just more of a risk of toxicities
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Aminoglycoside PK/PD Relationships in Pseudomonas Bacteremia
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when the cruve platues there is no added benefit it puts the patient ar more of a risk of toxicities
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Aminoglycoside Pharmacodynamics
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Maximum bactericidal effects and improved clinical response correlated with Cmax 8-10 x MIC
Achieving high Cmax:MIC ratios also correlated with decreased selection of resistant bacteria Uptake of drugs into renal tubular cells and endolymph of ear most efficient with low, sustained concentrations High, transient concentrations may minimize this uptake Probably due to saturable active transport processes |
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what Cmax should be reached fro AG to be efficacious
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Cmax 8-10 x MIC
Achieving high Cmax:MIC ratios also correlated with decreased selection of resistant bacteria |
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is the uptake of AG saturable
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yes
Uptake of drugs into renal tubular cells and endolymph of ear most efficient with low, sustained concentrations High, transient concentrations may minimize this uptake Probably due to saturable active transport processes |
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Aminoglycoside PK/PD Relationships in Pseudomonas Bacteremia
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ther is no added benefits after the cruve has platued it just puts the patien at higher risk of toxicities
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traditional vs. extended dosing of AG
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traditional dosing: the drug was given multiple times throughout the day never reaching concetrations of 8-10 times the cmax
now the drug is given QD as a big dose in order to reach higher concentrations, initally clinitians were afraid of toxic affects on the kidney so did not want high concentrations However, the process of uptake into the kidneys is saturable so even though higher doses are given all at once the kidneys are not at higher risk of nephrotoxicities |
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Pharmacodynamic Considerations in Aminoglycoside Dosing
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Use of “once daily” or extended-interval dosing regimens provides:
More optimal pharmacodynamic parameters, enhanced bactericidal activity Efficacy similar to divided-dosing regimens Potentially decreased toxicities relative to divided-dosing regimens Decreased reliance on serum concentrations and pharmacokinetic monitoring Potentially decreased cost of therapy taking advantage of the PK/PD properties |
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why are infusion times extended
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so the time above MIC increase, therefore bugs that were previously resistant are now suscetable
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Continuous Infusions of -lactams for ICU Pulmonary Infections
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“Presently, there is insufficient evidence to warrant the replacement of intermittent infusion by continuous infusion -lactams as the new standard for all patient populations. Undoubtedly, continuous infusions can be used to maximize -lactam pharmacodynamics; however, it is still unclear whether continuous infusions will improve patient outcomes, reduce antibiotic resistance, minimize toxicities related to peak concentrations, or decrease healthcare costs.”
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Piperacillin/tazobactam for P. aeruginosa Infections: Extended vs. Intermittent Infusions
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Cohort study of patients receiving extended 4-hr infusions (N = 102) vs. standard intermittent infusions (N = 92)
18 gm/day extended vs. 12-18 gm/day intermittent Overall results showed no significant differences between groups in mortality or median LOS Extended infusion group showed significantly lower mortality (P = 0.04) and median LOS (P = 0.02) in subset of patients with APACHE II score ≥17 receiving extended infusion vs. intermittent infusions No significant differences in patients with APACHE II < 17 (the higher the score the sicker) overall, no difference in use of extended infusions, however in sicker patients extended infusions improved outcomes |
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ager, agri
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field, territory
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Clinical Efficacy of Doripenem 500 mg Q8H (4-hr infusion) vs. Imipenem 2-3 gm/day (0.5-1hr infusion) in Ventilator-Associated Pneumonia
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overall there was not much of a difference in outcomes, but when looking at the sicker patients they had better outcomes with extended infusion times
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Continuous Infusions of Time-Dependent Antibiotics for Gram-Positive Infections
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No formal recommendations for use of continuous infusion therapy
May consider for treatment of Gram-positive infections in patients who: Have not shown adequate clinical or microbiological response to conventional dosing regimens Have infections in which drug penetration to site of infection may play a role in treatment failure Clinical situations in which continuous infusions may be considered: Endocarditis caused by MRSA, coagulase-negative staphylococci, enterococci Gram-positive meningitis Septic arthritis, osteomyelitis Gram-positive pneumonia, pulmonary abscess Optimal doses, duration unknown |
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What Does Pharmacodynamics Do?
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Correlates drug activity in vitro with pharmacokinetic profile of individual agents
Relates pharmacologic features of drugs to predicted and/or observed clinical outcomes Aids clinicians in making decisions regarding selection of agents that are most likely to yield favorable clinical results Aids clinicians in selecting most favorable dosing strategies |
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What are Appropriate Pharmacodynamic Targets?
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Cephalosporins, penicillins
T > MIC of ≥40-50% of dosing interval Carbapenems Bacteristatic: T > MIC of 30% of dosing interval (not high enough) Bactericidal: T > MIC of ≥40-50% of dosing interval Fluoroquinolones Gram-positive (S. pneumoniae): AUC/MIC >30 Gram-negative: AUC/MIC >125 Aminoglycosides Cmax/MIC >8-10 |
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What Does Pharmacodynamics NOT Do?
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Does not provide completely accurate predictions of clinical success for any given agent in a specific patient
Does not guarantee optimal therapy under all circumstances Does not provide easily obtainable information that allows point-of-care decision making for individual patients using population estimates, making predicitons for everyone therefore not individualizing the treatments |
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Limitations of Applying Pharmacodynamics in the Clinical Setting
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Pharmacodynamics still an evolving discipline
Most data supporting PK/PD applications derived from in vitro and in vivo animal models Most clinical data retrospective and/or modeled Prospective data generated in less severely ill populations, not ICU patients PK data used in studies often not derived from critically ill, may not properly reflect variability Nearly all data obtained from only a couple of organisms (e.g. S. pneumoniae, P. aeruginosa) & simply assumed that PD relationships are similar for all other organisms |
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is protein binding taken into account when dealing with PD properties of antibiotics
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no
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Calculate dosing interval, τ = may be done in one of two ways
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Tmax ={ [ln(desired Cmax/desireed Cmin)]/ k} + tin
tin is the infusion time - OR, the "Fish common sense method": τ = (3 * t½) + tin, round up to the next most convenient dosage interval (8, 12, 24, 48 hours, etc) |
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C=
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Co(e^-kt)
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i.FINALLY, calculate a maintenance dose:
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dose (mg)= (desired Cmax* CL* tin)* [(1- e^-kt)/1-e^ktin)}
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double check your work by
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At this point you should also take the time to double-check your Cmin to be sure that the calculations were done correctly:
Cmin= Cmax * e^-kt "t" is the amount of time elapsed between Cmax and Cmin Note that Cmax occurs at the end of the infusion, not when the infusion is started t= dosing interval-infusion time |
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EXAMPLE
M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides. what is your first step? |
calculate IBW and if needed calculate ABW
1.Calculate IBW= 45.5 kg + 2.3 kg * (5 inches)= 57.0 kg Calculate AD= IBW + 0.4 * (TBW - IBW) = 57.0 kg + 0.4 * (84.1 kg – 57.0 kg) = 57.0 kg + 11.0 kg = 68.0 kg |
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if start with a loading dose of 2 mg/kg what Cmax does it result in
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Cmax of about 6
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EXAMPLE
M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides. Calculate the loading dose |
2. Calculate a loading dose:
185 pounds = 84.1 kg Dose = 2 mg/kg * 84.1 kg = 168 mg (Round up to 170 mg so the IV room pharmacist don't hate you when they get the order) use TBW because it is only one dose, so be aggressive can also find the loading dose with the other equation this is the easy way |
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EXAMPLE
M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides. calculate a maintence dose start by.... |
estimate CrCL= [(140-age)(IBW or ABW(kg))]/72*Scr
=[(140 - 48) * 68/ 72*2.0]*0.85= 37 mL/min |
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EXAMPLE
M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides. after calculating CrCL for the maintence dose what is the next step? |
CL (L/hr)
= CrCL (mL/min) * 60 min/hr * 1L/1000mL = 2.22 L/hr |
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EXAMPLE
M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides. after calculating CrCL and CL for the maintence dose what is the next step? |
estimate Vd
= o.25 L/kg * ADW or IBW = o.25 L/kg * 68 kg = 17.0 L |
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EXAMPLE
M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides. after calculating CrCL, CL and Vd for the maintence dose what is the next step? |
estimate K=CL/Vd
= (2.22 L/hr)/(17L) = 0.130 hr^-1 |
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EXAMPLE
M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides. after calculating CrCL, CL, Vd and k for the maintence dose what is the next step? |
estimate half life= 0.693/k
= 0.693/ 0.130^-1 = 5.3 hrs |
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why do you not use TBW when calculating Vd for the maintence dose
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because you want to be more carefull at this point you are not just giving one dose
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M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides.
choose a desired Cmax and Cmin serum concetrations |
Since this could be a moderately severe systemic infection, we choose between either 6 - 8 mg/L or 8 - 10 mg/L as a desired Cmax concentration
A nice mid-point to aim for is 8 mg/L (Notice that there is room for clinical judgment in making this determination.) Since clinical pharmacokinetics is not an exact science and there is significant room for error, we don't want to cut the Cmin too low A desired Cmin of approximately 1.0 mg/L is a reasonable place to start (if the patient has more risk factors would go lower around 0.5) Choose duration of the IV infusion (tin) = 30 minutes (0.5 hr) |
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M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides.
After determining the maintence dose and Cmax and Cmin Calculate dosing interval, τ |
tmax= ln[(desired Cmax/desired Cmin)/k] +tin
= [(ln (8/10)/0.130^hr-1)+ 0.5 hr T= 16.5 hours--> round up to 24 hours or the "Fish common sense method" T = (3* t1/2) + tin= (3*5.3 hrs)+0.5 hrs = 16.4 hours--> round up to 24 hours (producing a Cmin of 0.3-0.4) if round down to Q12 hours Cmin increases to about 2 because that is close to 1 half life |
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MIC =
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Lowest concentration of antibiotic required to inhibit bacterial growth
Determined in vitro by several different techniques Used as a measure of antibiotic potency, i.e. the lower the MIC the more potent the antibiotic Commonly used for comparison of activities of various antibiotics measures pharmocologic activity |
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MBC=
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Lowest concentration of antibiotic required to inhibit bacterial growth
Determined in vitro by several different techniques Used as a measure of antibiotic potency, i.e. the lower the MIC the more potent the antibiotic Commonly used for comparison of activities of various antibiotics |
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if a drug has a MIC of 0.12 or 0.5 to a particular antibiotic what one is the most potent
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the one with 0.12
it is the most pharmacologically active bu tmay not be the most effective |
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factors influencing clinical outcomes
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host: genetics, underlying illness, altered PK/PD
bug: virulence factors, intrinsic susceptablility, resistance mechanisms drug: MOA, in vitro MIC, PK properties |
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Antimicrobial Pharmacodynamics
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Correlates the drug concentration with the clinical effect (i.e., bacterial killing or inhibition)
Uses surrogate markers such as minimum inhibitory concentration (MIC) Indexes serum concentration (pharmacokinetic profile) to MIC to predict clinical outcomes The pharmacodynamic relationship is different for different antimicrobial classes what drugs do to bacteria which is related to drug concentrations |
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Limitations of Applying Pharmacodynamics in the Clinical Setting
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Pharmacodynamics still an evolving discipline
Most data supporting PK/PD applications derived from in vitro and in vivo animal models Most clinical data retrospective and/or modeled Prospective data generated in less severely ill populations, not ICU patients PK data used in studies often not derived from critically ill, may not properly reflect variability Nearly all data obtained from only a couple of organisms (e.g. S. pneumoniae, P. aeruginosa) & simply assumed that PD relationships are similar for all other organisms These points should all make sense based on what we discussed in class. In the second bullet, by “modeled” I mean that many of the studies supporting PK/PD applications came from computer models where MICs and PK parameters are simulated and outcomes predicted based on the model rather than from actual clinical data. This is obviously not the ideal way to validate PK/PD applications in the real world when clinical outcomes of patients are at stake. The third bullet makes the point that, since PK parameters may be very different & highly variable in seriously ill patients compared to normal volunteers, the PK data used in deriving pharmacodynamic parameters & clinical decisions needs to be from the appropriate populations where the results of your predictions will actually be applied. |
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are PD predictions based on blood concentrations or tissue
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The point to be made here is simply that, as stated several times in class, current PD estimates and predictions are mostly based on drug concentrations in blood rather than what’s going on in the tissues at the site of infection. The pharmacokinetic behavior of drugs is obviously quite dynamic and quite complex. Even something as basic as protein binding of drugs is difficult to adequately account for with our current understanding of antibiotic pharmacodynamics – another reason why PD is still an evolving science.
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β-Lactam Concentrations vs. MIC Breakpoints in the average patient
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In “normal” patients with “average” pharmacokinetics, standard dosing regimens for many drugs are already adequate to provide good pharmacodynamic performance, as in the case with all of these beta-lactams. Standard doses achieve concentrations that are far in excess of pathogen MICs and provide excellent %T>MIC. But this is assuming that all drugs exhibit “average” PK properties in all patients.
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Antimicrobial Pharmacokinetic Alterations in Critically Ill Patients
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Critically ill patients, e.g. those in the hospital and/or ICU, often exhibit PK parameters that are very different from those found in less-sick patients. Here are a few examples of the differences in PK parameters that can be seen in various populations. We’re obviously not always treating “average” patients and alterations in PK parameters need to be accounted for in order to appropriately determined PD properties.
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Application of Appropriate PK and MIC Data is Critical to Clinical Decision-Making
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Important limitations of PK data in severely ill populations
PK data often not available Specific drugs and regimens Specific patient populations (e.g. medical vs. surgical pts, organ failure) Great variability in antimicrobial PK, particularly in severely ill populations MICs not always available for individual patients Pathogens not identified in many infections Empiric treatment for entire duration of therapy is common MICs not routinely determined or reported by many clinical laboratories Immune status, other comorbidities may effect PK/PD relationships and host response but are not easily accounted for |
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Immune status, other comorbidities may effect PK/PD relationships and host response but are not easily accounted for
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another limitation of PD at this point in time is that we also have no way of taking into account patient-specific factors that may influence response to infections. Remember, for instance, that antibiotics often just suppress infections while the immune system catches up. Immunocompromised patients may respond very differently to our antibiotic regimens; the current state-of-the-art in pharmacodynamics can’t account for that.
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Clinical Application of Pharmacodynamics
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High, aggressive dosing (within reason) should be routinely used for systemic infections
The more severe the infection, the higher the doses that should be used Consider PK variability in critically ill patients Consider consequences of treatment failure with inadequate initial treatment Risk-versus-benefit considerations important Potential for increased efficacy Potential for increased toxicity |
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Consider consequences of treatment failure with PD
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with some infections you just can’t afford to take a lot of chances because if the patient fails due to under-dosing or incorrect dosing, there may be no second chance to get it correct. In a patient with endocarditis, you don’t want their heart valves getting chewed off by the bacteria because you didn’t dose them aggressively enough to meet PK/PD goals. High, aggressive dosing is the only way to make up for the PK variability that may be present, but you can’t overdo it either. You still have to be careful with potentially toxic drugs. If you don’t think you can achieve the desired PK/PD goals without putting the patient at risk for excessive toxicity in the process – pick a different drug.
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Pharmacodynamic Dosing Principles
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Attempt to choose drugs and dosing regimens that yield optimal pharmacodynamic relationships
Consider not only the appropriate drug, but also: Appropriate dose Appropriate dosing interval Appropriate route Appropriate application of pharmacodynamics has the potential to enhance bacterial eradication and decrease risk for development of resistance Using the wrong drug, or using the correct drug but given at too-low doses and/or improper intervals, tends to do the opposite |
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M.B. is a 48 year old female admitted to the hospital with abdominal trauma following a motor vehicle accident. She is to be started empirically on metronidazole and gentamicin for suspected peritonitis. The physician asks you to calculate a dose of aminoglycoside to begin her treatment. What do you recommend? M.B. weighs 185 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 2.0 mg/dL. Assume that your hospital uses 30 minute infusion times for aminoglycosides
calculate a maintenance dose k= 0.130hr^-1 desired Cmax= 8 mg/L CL = 2.22 L/hr tin= 0.5 hr |
(8 mg/L * 2.22L/hr * 0.5hr) [ 1-e^-(0.130/hr* (24 hrs)/1-e^-(0.130/hr)*(0.5 hrs)
= 8.8890.955/0.0634) = 135 mg Q 24 hrs |
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Double-check the calculated trough concentration to make sure that the math came out right:
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Cmin =Cmax * e ^-k * t
"t" is the amount of time elapsed between Cmax and Cmin Note that Cmax occurs at the end of the infusion, not when the IV bag is hung on the pole. "t" to be used in calculating Cmin is then: τ - tin = 24 hrs - 0.5 hr = 23.5 hours. Cmin = 8.0 mg/L * e^ -(0.130/hr) * (23.5 hrs) Cmin = 0.4 mg/L FINAL ANSWER = 170 mg IV loading dose, followed by 135 mg IV every 24 hrs |
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when does cmax occur for AG dosing
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Note that Cmax occurs at the end of the infusion, not when the IV bag is hung on the pole.
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Cmax and Cmin concentrations are first ideally drawn for AG when....
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either at the time of the first dose; or when the serum concentrations have achieved steady state, i.e. after the regimen has been continued for a minimum of 3.3 half-lives of the drug (at which time ~90% of steady-state concentrations have been reached)
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In actual practice, Cmax and Cmin AG concentrations are commonly first obtained at
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the time of the third maintenance dose
In our previous example, this would be 48 hours after the first maintenance dose, at which time the drug should certainly be at steady state |
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Samples should be drawn based on the calculated t½ and _____ based on the number of doses administered if you want serum concentrations which are able to be interpreted correctly
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NOT
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Blood drawn for AG Cmax concentration determination should be obtained...
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30 minutes after the END OF THE INFUSION
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AG Cmin blood samples should be drawn
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as close to the beginning of the next dose as possible
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how many half lives does it take to get to SS
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5
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drawing levels of AG is based on what?
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half lives
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T1/2=
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0.693 *Vd/CL
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t=
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dosing interval - infusion time
(T- tin) |
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Concentration Sampling Strategies
“Sawchuck-Zaske Method” |
Following the first dose of drug (often the loading dose), concentrations are obtained immediately after the end of the infusion + approximately midway through the dosing interval
Useful when accurate information regarding kinetic parameters are needed rapidly, e.g. critically ill patients Provides accurate information regarding both Vd and elimination rate (k). Vd and k are calculated by the following formula: (because starting from a concentraion of 0) Vd= (dose/tin/k)* [1-e^-k*tin/Cmax-(min*e^-k*tin)] where t = time between Cmax and midpoint serum samples |
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disadvantages of the “Sawchuck-Zaske Method”
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have to be there when the first dose is given (not convient)
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what is considered the most accurate measurement of Vd
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“Sawchuck-Zaske Method”
Considered most accurate method for determination of Vd because if the patient has not previously received any drug, the Cmin is known to be 0, and the term (Cmin *e-ktin) also simply becomes 0 |
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"Dose-Peak-Trough" method for AG
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Concentrations are obtained immediately after the end of the infusion and just prior to the next dose
Gives an accurate estimate of elimination rate but is less accurate for calculating Vd A disadvantage is that one must wait the entire dosing interval to obtain the second sample and the laboratory results will also be delayed accordingly Vd and k are calculated by the same equations as in the Sawchuck-Zaske method |
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"Trough-Dose-Peak" method for AG
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A sample is obtained just prior to the dose, the dose is administered, and a second sample is obtained after the end of the infusion
taking two leves from the same dose which is ok because at SS and the trough should be the same as the other dose because at SS Also gives a more accurate estimation of elimination rate than of Vd An advantage is that both peak and trough concentrations are obtained in a more timely, convenient manner Most common method used in actual clinical practice and should be the one that you are most comfortable with |
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Working with Serum Concentrations Rule #1: If it's not broken, don't try to fix it!
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There's usually no reason to modify regimens if:
Concentrations look acceptable Patient is responding to therapy No suspicion of actual or impending toxicity have to look at the levels drawn: do they represent a tru Cmax and Cmin (don't make assumptions |
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calulate k with measured peak levels
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k= ln[Cpeak/Ctrough]/t
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are the peak values true cmax and cmin values
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no they are the measured values
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To correctly choose the correct value for "t" for AG, several different time intervals must be considered:
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τ = entire dosing interval, from start of one dose until the next dose
tin = duration of the infusion tinpk = time between end of infusion and when peak level is drawn tpktr = time elapsed between when peak is drawn until trough is drawn tend = time between when trough is drawn until the next dose is given τ=tin + tin-->pk + tpk-->tr + tend |
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If the peak concentration is drawn directly at the end of the infusion for AGs
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Cpeak = Cmax and tinpk = 0. Likewise, if the trough concentration is drawn immediately before the next dose, Ctrough = Cmin and tend = 0.
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what periodof time are you using for t in Ag dosing to figure out T
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between Cpeak and Ctrough
Tpk-->tr |
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example of finding T for AG:
dose was given at 12 pm Peak taken at 3 pm tin= 1 hr trough takne at 11 am dosing interval 200 mg Q24hrs |
24-1-2-1=20
T=24 tin=1 tin--pk=2 tend=1 |
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"t"=
(AG dosing) |
T-tin-tin-->pk-tend
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example of finding T for AG:
dose was given at 12 pm Peak taken at 3 pm tin= 1 hr trough takne at 11 am dosing interval 200 mg Q24hrs "the easy way" |
use the difference between trough and peak
24-4=20 |
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does the tin account for elimination
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nope
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example of finding T for AG:
Dose given at 8am tin= 0.5 hrs peak taken at 12 pm trough taken at 6:30 am 200mg Q 8 hours |
8-0.5-3.5-1.5= 2.5
the easy way 8-5.5=2.5 |
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If the "Trough-Dose-Peak" method of sampling is being used, there is a much easier and less confusing way of calculating "t":
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ttr-->pk = time between when the trough sample is drawn until the peak sample is drawn
To calculate k: "t" = τ - ttr-->pk |
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when using the patients actual serum concentrations how do you find cmax
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cmax= cpeak/e^-kt
In this equation, "t" = tin-->pk , which is the period of time between when Cmax actually occurred and when the peak level was drawn and measured. |
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when using the patients actual serum concentraions how do you calculate CL
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Cl= [dose/tin/cmax]* [1-e^-ktin/10e^-kT)
Dose =dose being used in the dosing regimen from which concentrations are being measured tin =infusion time actually used with the dose from which the concentrations are being measured Cmax =value for Cmax which was just calculated in step #4 above (may use Cpeak IF Cpeak = Cmax) τ =dosing frequency being used in the dosing regimen from which concentrations are being measured the dose and interval are the ones the patient was receiving when the samples were taken |
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when using the patients actual serum concentraions how do you calculate Vd
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Vd= Cl/k
Now that we have PATIENT-SPECIFIC values for k, CL, and Vd we can proceed to design a new dosing regimen in the same manner as we did previously with our empiric dosing recommendations. compare with the expected values calculated |
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what is the highest Vd obtainable with Ag
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about 1 L/kg
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once all the pateint specific PK values have been calculated for AG choose a desires Cmax and Cmin and calculate the dosing interval
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Choose duration of the IV infusion (tin) = usually either 30 minutes or 60 minutes (0.5 or 1 hour)
Calculate dosing interval, τ = may be done in one of two ways: Tmax={ ln[desired cmzx/desired cmin]/k}+tin or τ = (3 * t½) + tin, round up to the next most convenient dosage interval (8, 12, 24, 48 hours, etc.) |
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If the serum concentrations measured were fairly good for AG....
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make minor adjustments, the same dosing frequency which was previously being used in the patient can be kept
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If the serum concentrations were very unfavorable for AG
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large dosing adjustments will be necessary, and especially if the measured Cmin concentration was > 2 mg/L, the calculations for τ should be done and a new τ used (if necessary)
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what is the desired Cmin for AG
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< 2 mg/L
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M.B., the 48 year old female from the previous example, was begun on the antibiotic regimen which you previously calculated and recommended (gentamicin 135 mg every 24 hours). Serum concentrations are obtained around the third maintenance dose and the following data is reported:
Start of dose =08:00 End of dose =08:30 Trough level = 1.1 mg/L, obtained at 07:45 Peak level = 5.4 mg/L, obtained at 10:00 what needs to be changed?? M.B. continues to be febrile to 38.9 degreees, with a WBC of 24,500 and a differential of 78% segs and 16% bands. What do you recommend? M.B. now weighs 193 pounds, is 5 feet 5 inches tall, and has a serum creatinine of 1.8 mg/dL. |
Rule #1: If it's not broken, don't fix it! In this case, trough concentration is good, but the peak concentration is much lower than we predicted and the patient continues to show signs of active infection. The concentrations need to be examined more closely and the regimen will probably need to be modified.
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what happens if a patient is retaining fluid for Ag
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changes Vd so retaining more drug
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what happens to the half life of AG if kidney funciton declines
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the half life increases because the elimination rate constant (k) is less
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what does the elimination rate constant (k) represent
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the fraction of drug eliminated every hour
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Summary of “Traditional” AG Dosing
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No concentrations obtained (emperic dosing
estimated Vd estimated Cl estimated k estimated T1/2 (all obtained from AG pop parameters) Concetrations obtained for patients previous does calculatek calculated T1/2 calculate Cl calculate Vd (all obtained from pateint specific serum concentratins, not estimates both of the above lead to: choose Cmax and Cmin choose duration in infusion, tin calculate dosing interval calculate dose double check Cmin |
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the Ag population PK parameters are...
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average values
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graph comparing traditional and Conventional Ag dosing
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Efficacy Considerations
for QD dosing and AG |
Concentration-dependent bactericidal activity = Cmax:MIC ratio
Post-antibiotic effect (PAE) = suppression of bacterial growth after concentrations of an antibiotic fall below the MIC Adaptive resistance = if bacteria are not exposed to sufficient aminoglycoside concentrations, they can down-regulate uptake of the drug and become refractory to further exposure |
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do you worry about cmins with QD dosing of AG
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no because getting to non-detectable concentrations of drug, so toxicities are less of a concern
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Toxicity considerations: not necessarily related to peak concentrations for AG
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Nephrotoxicity = related to saturable intracellular accumulation of drug in the renal cortex. Less frequent administration has been shown in animal models and some human studies to result in lower renal cortical drug concentrations.
Ototoxicity = In rat models, less frequent administration was shown to result in less uptake of drug into the inner ear tissues. |
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Post-antibiotic effect (PAE)
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suppression of bacterial growth after concentrations of an antibiotic fall below the MIC
AG penetrate bacterial cells at high concentrations and inhibti protein synthesis, which the bacteria take a while to overcome. So even when concentrations of AG or low there are still pharmocological effects it is much more dependent on the cmax/mic ration |
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Potential Advantages of Extended Interval Aminoglycoside Dosing
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More certainty peak drug concentrations will be high enough (much more dependable)
Enhanced bactericidal activity Decreased adaptive resistance Potentially decreased nephrotoxicity Potentially decreased ototoxicity Decreased reliance on drug monitoring Decreased costs Convenience |
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Potential Disadvantages of Extended Interval Aminoglycoside Dosing
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Comparatively little clinical experience (professional discomfort)
Lack of data in certain patient populations (ICU, renal dysfunction, transplants, immunocompromised, children, pregnancy) Monitoring methods/therapeutic (is there a certain Cmax we should aim for? is there a maximun cmax? Do we need to obtain a certain cmin?) |
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Controversies Surrounding Extended Interval Aminoglycoside Dosing
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Dosing
What is the appropriate mg/kg dose? How should adjustments for renal function be made: decreased dose or increased interval, or both? Appropriate patients |
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Caution is recommended in the following types of patients for QD dosing of AG
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Moderate-Severe renal impairment
Neutropenic infections Sepsis/life-threatening infections Endocarditis Infections caused by Staphylococcus or Enterococcus in which aminoglycoside is used in combination regimens Patients expected to have altered aminoglycoside pharmacokinetics: Critically ill Severe burns Pregnant/postpartum Cystic fibrosis Pediatrics/neonates |
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how should QD dosing of AG be monitored
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There is not a universally accepted answer to the question
Therefore, number and timing of sampling for drug concentrations varies widely with practice styles a lot of it depends on the population |
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The Hartford Nomogram what dose of AG is administer
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Administer initial dose of 7 mg/kg gentamicin or tobramycin
based on IBW it excludes obese patients |
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The Hartford Nomogram based on estimated renal function
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Creatinine clearance
>60 ml/min dosed Q24hrs 40-60 ml/mon Q36hrs 20-39 mL/min Q48 hrs <20 mL/min Q48hrs Obtain “midpoint” serum concentration between 6 and 14 hours after start of infusion, and plot on the nomogram to determine dosage interval adjustment |
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is the hartford nongram used with amikacin
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nope
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the hartforn nonogram (pic)
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Potential Limitations of the Hartford Nomogram
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Assumes that a 7 mg/kg dose will always be given and that a 1-hour infusion time will always be used
Nomogram was designed to provide a Cmax of 20 mg/L (to achieve a peak:MIC ratio of 10 for Pseudomonas aeruginosa at Hartford Hospital) and a drug free interval of 4 hours at the end of the dosing interval Based on volume of distribution of 0.3 L/kg. What about patients with altered volume of distribution? What about patients with changing renal function? Does not allow for wide inter-patient variability in drug clearance Patients expected to have abnormal aminoglycoside pharmacokinetics (ascites, burn >20% BSA, pregnant, ESRD) were excluded from the study that validated the Nomogram Patients with enterococcal endocarditis were also excluded. |
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what is the Vd that the hartforn nonogram is based on
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0.3 l/kg
a lot of patients do not have this Vd |
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what patients are excluded from the hartforn nonogram
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Patients expected to have abnormal aminoglycoside pharmacokinetics (ascites, burn >20% BSA, pregnant, ESRD) were excluded from the study that validated the Nomogram
Patients with enterococcal endocarditis were also excluded. |
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measuring peak only with qd dosing of ag
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Measuring the peak concentration facilitates assessment of adequacy of the dose amount (i.e. Cmax), but reveals little about the risk of toxicity (i.e. Cmin)
Not very useful in most situations doesn't tell anyting about drug elimination or risk of toxicity |
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measuring peak and trough with qd dosing of ag
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May consider monitoring peak and trough within first three doses when aminoglycoside pharmacokinetics are expected to be altered
However, runs the risk that trough concentrations will be undetectable and that the levels will therefore be useless |
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measuring peak and midpoint with qd dosing of Ag
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Because trough concentrations are often undetectable, obtaining peak and midpoint instead of peak and trough avoids undetectable trough level and allows calculation of pharmacokinetic parameters
Preferred in patients with deteriorating clinical status this gives 2 data points to work with and is good for the complicated pt because able to make adjustments |
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measuring the trough only with qd dosing of Ag
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Less aggressive. Allows assessment of drug accumulation/drug toxicity. Assumes Cmax is high enough because of large doses given
When undetectable, may raise question as to adequacy of dose because duration of drug-free interval remains unknown May consider this method in patients expected to have normal aminoglycoside pharmacokinetics Check within first three doses and repeat every four to five days. If patient has worsening renal function or signs of nephrotoxicity, check trough more often good for the uncomplicated patient because it is very limited and you are not able to make adjustments because only one data point saving your booty by documenting if the elimination of the drug is what it is expected tobe or if the patient is at risk of toxocty looking at the elimination of the drug and potential toxicities troughs can be non-detectable |
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image of vanco
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vanco histroy
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Classed as a glycopeptide antibiotic
Produced by bacteria, Nocardia orientalis, isolated from soil samples obtained in Indonesia and India (1956) Complex tricyclic glycopeptide having a molecular weight of nearly 1,500 Extensively used clinically since the late 1950s Has been remarkably overused without significant resistance – until recently |
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what makes vanco a glycopeptide
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the petide bonds throughout the molecule
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Vancomycin: Spectrum of Activity
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Narrow-spectrum bactericidal antibiotic
Activity against ONLY Gram-positive organisms Good activity against Staphylococcus aureus (including MRSA), S. epidermidis and other coagulase-negative staphylococci, and streptococci Active against most Enterococcus species Activity includes most Gram-positive anaerobes including Clostridium spp. No activity against Gram-negative bacteria because the large molecular weight prevents it from penetrating the outer membrane |
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is vanco cidal or static
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cidal
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vanco activity against gram +
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Activity against ONLY Gram-positive organisms
Good activity against Staphylococcus aureus (including MRSA), S. epidermidis and other coagulase-negative staphylococci, and streptococci Active against most Enterococcus species Activity includes most Gram-positive anaerobes including Clostridium spp. |
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vanco activity againt gram -
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No activity against Gram-negative bacteria because the large molecular weight prevents it from penetrating the outer membrane
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vanco MOA
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Inhibits cell wall synthesis by high-affinity binding to cell wall precursor
binds with high affinity to the D-alanyl-D-alanine portion of the cell wall precursor Vancomycin also inhibits synthesis of cell wall-associated phospholipids Mechanism of action does not involve PBPs Vancomycin is bactericidal, but not as rapid as β-lactam antibiotics (“slowly cidal”) |
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is vanco MOA enzymatic
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nope it is no-enzymatic it binds directly with high affinity to the D-alanyl-D-alanine portion of the cell wall precursor and interfers with the transpeptidase MOA
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is vanco time or concentration dependent
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time
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is daptomycin time or concentration dependent
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concetration
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pic of vanco moa
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Vancomycin binds with high affinity to D-alanyl-D-alanine terminus of cell wall precursor units, inhibits release of building block unit from carrier (D-alanine), thus prevents peptidoglycan synthesis
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Vancomycin: Mechanism of Resistance
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Several mechanisms of resistance have been identified:
Most important mechanism involves modification of cell-wall precursors that will no longer bind vancomycin Change of D-alanyl-D-alanine to D-alanyl-D-lactate → binding of vancomycin is prevented but cell wall synthesis is able to proceed Mechanism present in vancomycin-resistant enterococci (VRE), particularly E. faecium (VREF) Plasmid-mediated mechanisms also thought to involve interference of transport/entrance of vancomycin into bacteria (less common) |
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is vanco absorbed after PO admin
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nope
Vancomycin very poorly absorbed after oral administration Must be administered parenterally for treatment of systemic infections However, oral route can be used to treat Clostridium difficile colitis because infection usually localized to colonic mucosa in the lumen (so do not need systemic absorption) |
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is vanco distributed into the CNS
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Distribution into the CSF is limited
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how is vanco eliminated
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>70% of parenteral doses excreted by glomerular filtration
Remainder of dose eliminated via unknown routes |
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half life of vanco
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T1/2 = approx. 4-6 hours in normal renal function
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Vancomycin: Adverse Effects “Red man” or “Red neck” syndrome
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Infusion-related reactions
“Red man” or “Red neck” syndrome Pruritis and flushing of face, neck, and upper extremities and trunk Rash Hypotension, tachycardia True incidence unknown, but studies suggest range of 0-35% Occurs 10-20 minutes after start of infusion Mediated by drug-induced histamine release Managed by slowing rate of infusion, (60 min, 90 min, and 2 hr infusion times, can also dilute in a lot of fluids) when turn of the infusion this reaction disapates prior administration of antihistamines histamine mediated infusion reaction interaction with the mast cells |
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nephrotoxicity and vanco
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Incidence <5% when administered alone
Incidence increased by concomitant use of aminoglycosides or other nephrotoxic drugs (this is not an unusaul combo) Recent data also suggest daily doses >4 grams may increase risk not as prevalent as Ag |
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ototoxicty and vanco
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Very unusual
Tinnitis, vertigo, hearing loss can be reversible |
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hypersensitivity and vanco
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Range from rashes (common) to anaphylaxis (rare)
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Vancomycin: Adverse Effects
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Nephrotoxicity
Incidence <5% when administered alone Incidence increased by concomitant use of aminoglycosides or other nephrotoxic drugs Recent data also suggest daily doses 4 grams may increase risk Ototoxicity Very unusual Tinnitis, vertigo, hearing loss Hypersensitivity reactions Range from rashes (common) to anaphylaxis (rare) Neutropenia, thrombocytopenia (rare) (monitor CBCs) Phlebitis and pain at IV administration site (common) |
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Vancomycin: Drug Interactions
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Additive/synergistic nephrotoxicity when given concomitantly with other nephrotoxic agents
Aminoglycosides Amphotericin B Cisplatin Cyclosporine Mycophenolate Etc. etc. |
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Vancomycin: Clinical
Uses |
Remains a very important drug for treating variety of serious Gram-positive infections
Particularly useful in patients with severe β-lactam allergy Usual preferred agent when MRSA or methicillin-resistant S. epidermidis (MRSE) documented or suspected as cause of infection Also important in treatment of systemic Enterococcus infections, Gram-positive anaerobic infections (e.g. Clostridium) Used in oral treatment for C. difficile-associated colitis |
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what drug is you rfirst choince for the treatment of MRSA
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VANCO
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what is structurally different between vanco and telavancin
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telavacin has a lipophilic tail making it more active at the bacterial cell membrane than vanco
Membrane anchoring - Improved potency - Rapid cidality - Activity vs. VISA telavacin hs Favorable PK-ADME properties - Long half-life - Renal clearance |
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telavancin class
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Classed as a “Lipoglycopeptide”
Similar to vancomycin but not exactly Inhibits cell wall synthesis; also affects bacterial cell membrane function |
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is telavacin static or cidal
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Bactericidal activity
Much more rapidly cidal than vancomycin |
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is telavancin time or concentration dependent
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concentration
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bacterial resistance and telavancin
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Little resistance observed in vitro or in clinical studies
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half life of telavancin
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Dosed once daily (T1/2 = 7-11 hours)
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what formulation does telavancin come in
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IV only
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do you need to dose adjust for renal dysfunction with telavancin
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yep
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what it type of bacteria is telavancin active against
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Excellent activity against Gram-positive organisms including MRSA, MRSE, VRE
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pic of moa of vanco
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Cell Wall Synthesis in Gram-positive Bacteria
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pic of telavancin MOA (inhibition of cell wall syntesis)
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through transglycosylation the long side chanin inserts into the cell membrane interacting with lipid II
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televancin pic disrupting bacterail cell membrane
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creates false porins so the cell depolarizes and the cell membrane function is disrupted
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is televancin selectove for bacterial cell membranes
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no but we do not have lipid II so it creates less membrane dysfunctionin in us
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most common Se of telavacin
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altered taste (metallic)
foamy urine nephrotoxicity |
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Telavancin: Renal Adverse Events
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Renal adverse events were 3.4% in clinical studies
Occurred primarily in patients with risk factors: Preexisting renal disease, diabetes mellitus, congestive heart failure, hypertension Also more frequent in patients with concomitant medications known to affect renal function e.g., NSAIDs, ACE Inhibitors, loop diuretics Improving or recovered in the majority of patients in both treatment groups by the end of the cSSSI study Monitoring of serum creatinine is recommended in all patients receiving telavancin |
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pregnancy cat of telavancin
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Pregnancy category C
Reduced fetal weights and increased rate of limb & digit malformations in rats, rabbits, and pigs No human data Risk Evaluation and Mitigation Strategy (REMS) program in place due to pregnancy risk Mandated by FDA as condition of approval & marketing Requires “medication guide” be provided to patients “Dear Health Care Provider” letters to targeted providers Serum pregnancy test recommended prior to drug use Pregnancy registry to monitor outcomes in women exposed during pregnancy (1-888-658-4228) |
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telavacin and coagulation tests
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Certain tests are affected by telavancin through interactions with in vitro testing methods:
Prothrombin time (PT) International normalized ratio (INR) Activated partial thromboplastin time (aPTT) Activated clotting time (ACT) Coagulation-based factor Xa tests Blood samples should be obtained as close as possible before administration of next dose of telavancin Tests which are not affected: Thrombin time (TT) Whole blood (Lee-White) clotting time Ex vivo platelet aggregation Functional (chromogenic) factor X and Xa assays Bleeding time D-dimer, fibrin degradation products not effecting the liver and does not bind to proteins doesn't cause bleeding just interferes with the test this is a concentrated effect |
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how can you avoid the affects telavacin has on coagualation tests
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collect a blood sample at the through to minimize this interaction
it is concentration related |
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telavancin efficacy and clinical role
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Excellent clinical efficacy shown in skin/soft tissue infections, pneumonia
FDA approved in late 2009 for complicated skin/soft tissue infections Clinical role has yet to be defined, although efficacy in pneumonia is potentially very useful not a first choice drug at this time |
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cyclic lipopetide pic
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Daptomycin (Cubicin™)
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Cyclic lipopeptides
Naturally occurring compounds derived from Streptomycin roseosporus, first discovered in 1980s Novel group of cyclic amino acid compounds Large molecules, molecular weight >1,600 Contain both hydrophillic and lipophilic properties Daptomycin = first cyclic lipopepetide approved for use Clinical trials conducted in early 1990s but stopped due to toxicity concerns Toxicity problems resolved, FDA approved 2003 |
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Daptomycin: Spectrum of Activity
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Narrow-spectrum agent active against only Gram-positive organisms
Very rapidly bactericidal Concentration-dependent rate of killing Highly active against: Staphylococcus aureus (including MRSA), S. epidermidis (including MRSE), and other staphylococci Streptococci Enterococcus species, including VRE Good activity against Gram-positive anaerobes No clinically relevant activity against Gram-negative bacteria |
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is daptomycin cidal or static
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very rapidly cidal
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what is daptomycin highly active against
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Staphylococcus aureus (including MRSA), S. epidermidis (including MRSE), and other staphylococci
Streptococci Enterococcus species, including VRE |
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Daptomycin Mechanism of Action
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Binds to Gram-positive bacterial cell membrane
Calcium-dependent insertion of lipid tail Rapidly depolarizes the cell membrane Rapid efflux of potassium Destroys ion-concentration gradient across membrane Cell death (this helps explain the rapid cidal effects) Multiple failures in biosystems, DNA, RNA, protein synthesis (not directly linked to membrane effects) |
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when a patient is hypocalcemic does daptomycin work
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no, because the activity when is forms porins and disrups the concentration gradients in the bacterial membrane is Ca dependent
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Cyclic Lipopeptides: Resistance
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Although resistance can be induced in the laboratory setting, in vivo resistance is rare
Mechanisms of resistance are therefore not well characterized Resistance may involve alteration in cell membrane potential leading to reduced drug binding No cross-resistance observed with other antibiotics (unique MOA) |
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Daptomycin Pharmacokinetics
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Not absorbed after oral administration
Must be administered parenterally Vd is relatively small, reflecting limited distributed throughout body Does not penetrate well into respiratory tissues, rapidly inactivated by surfactant >80% renally cleared, minimal known metabolism Dosage adjustment required for renal impairment T1/2 = 8 hours (QD dosing) |
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can daptomycin be used in respiratory infections such as pneumonia
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no it Does not penetrate well into respiratory tissues, rapidly inactivated by surfactant
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what inactivates daptomycin in the respiratory tract
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surfactants (rapidly)
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Daptomycin Adverse Effects
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Considered to be a safe, well tolerated drug
GI: constipation, nausea, vomiting, diarrhea (3-6%) CNS: Headache, insomnia, dizziness (2-5%) Rash (4%) Elevations in creatine phosphokinase (CPK) (created problems in early clinical trails) Occurs in <3% of patients, usually asymptomatic Muscle weakness, myalgias observed in early studies Elevation of hepatic transaminases (3%) (irrelevant) Injection site reactions |
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Daptomycin Drug Interactions
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No effect on cytochrome P450 system in vitro
Only pertinent drug-drug interaction is with the statins Increased risk of musculoskeletal toxicity, myopathy Risk is quite low, but patients should be carefully monitored during daptomycin therapy this is not an absolute CI and may be hard to avoid so just closely monitor |
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Daptomycin: Clinical Use
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Good activity against MRSA, MRSE, other Gram-positive organisms
Clinically effective against VRE Considered good alternative to vancomycin Better tolerated than Synercid™, easy to administer Bactericidal, while linezolid is static Alternative agent for treating variety of serious Gram-positive infections including skin/soft tissue, bone and joint, bloodstream, endocarditis infections Not useful for respiratory tract infections Useful in patients with severe β-lactam allergy Exact clinical role has yet to be defined |
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daptomycin spectrum of activity
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Good activity against MRSA, MRSE, other Gram-positive organisms
Clinically effective against VRE Considered good alternative to vancomycin Better tolerated than Synercid™, easy to administer Bactericidal, while linezolid is static |
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structure of oxazolidinones
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The Oxazolidinones
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Synthetic class of antibiotics
In 1978, series of agents were found to be effective against plant pathogens Further manipulations in molecule led to development of new agents for use in humans Orally absorbed Displayed activity against a variety of streptococci and staphylococci, comparable to vancomycin One agent approved for use in the U.S. Linezolid (Zyvox™) Approved in 2000 for treatment of a variety of gram-positive infections |
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what is the only drug active against multiple resistance gram + bacteria that is PO
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Linezolid
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Linezolid: Spectrum of Activity
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Narrow-spectrum
Bacteriostatic, not cidal Primarily active against only Gram-positive organisms Good activity against Staphylococcus aureus (including MRSA), S. epidermidis and other coagulase-negative staphylococci, and streptococci Active against Enterococcus species, including E. faecalis as well as vancomycin-resistant E. faecium (VREF) Activity includes many Gram-positive anaerobes No clinically relevant activity against Gram-negative bacteria Some activity against atypical bacteria |
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is linezolid static or cidal
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static
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what is linezolids primary activity
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Primarily active against only Gram-positive organisms
Good activity against Staphylococcus aureus (including MRSA), S. epidermidis and other coagulase-negative staphylococci, and streptococci Active against Enterococcus species, including E. faecalis as well as vancomycin-resistant E. faecium (VREF) Activity includes many Gram-positive anaerobes |
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is linezolid active against gram -
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no
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Linezolid: Mechanism of Action
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Inhibits an early step in bacterial protein synthesis
Prevents the formation of the tRNAfMet-mRNA-30S (or 50S) subunit ternary complex prevents formation of 70S ribosome complex that initiates protein synthesis Does not block the elongation or termination steps of translation Linezolid appears to bind to both 50S and 30S ribosomal subunits Unique mechanism seems to preclude cross-resistance with other existing antibiotics |
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pic of linezolid MOA
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Oxazolidinones: Mechanisms of Resistance
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Resistance usually related to specific point mutations in domain V of the 50S ribosomal subunit
Domain V very highly conserved region of the ribosome Integral part of peptidyl transferase center Resistance relatively unusual in clinical practice, but cases occasionally reported Usually in VRE, but recently in MRSA as well Usually associated with prolonged courses of therapy (often >21 days) Other risk factors include indwelling prosthetic devices, undrained abscesses, prior linezolid therapy |
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Absorption of linezolid PO
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Linezolid very well absorbed after oral administration
Bioavailability approaches 100% Food slightly decreases rate but not extent of absorption Only agent available both IV and PO for treatment of multidrug-resistant Gram-positive infections with or wothout food |
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how is linezolid metabolized
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Metabolized by non-enzymatic oxidation to aminoethoxyacetic acid and hydroxyethyl glycine
~80% of drug is eliminated in urine 30% active drug and 50% metabolites No metabolism by, or interaction with, CYP 450 Dosage adjustment required for neither renal nor hepatic dysfunction |
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T1/2 of linezolid
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T1/2 = 5-7 hours
BID |
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Vd of linezolid
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Vd = 40-50 L, well distributed throughout body
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are PO and IV doses of linezolid interchangable
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yep
because oral absorption is that good |
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Linezolid: Adverse Effects
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Considered to be a safe & well tolerated drug in most patients
GI: nausea, vomiting, diarrhea (3-6%) Headache (2-4%) Elevation of hepatic transaminases (3-7%) Reversible bone marrow suppression (1-5%) Thrombocytopenia, leukopenia, anemia Usually occurs late in therapy (>10-14 days) Most common in severely ill patients Taste alterations, tongue discoloration (2-3%) Injection site reactions |
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what is the most important SE of linezolid and what do you do if it happens
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overall bone marrow suppression
Reversible bone marrow suppression (1-5%) Thrombocytopenia, leukopenia, anemia Usually occurs late in therapy (>10-14 days) Most common in severely ill patients if happens switch drugs do not treat through |
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Linezolid: Drug Interactions
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No effect on cytochrome P450 system
Reversible monoamine oxidase inhibitor Mild, reversible, and competitive inhibition of both MAO-A and MAO-B Potential interaction with adrenergic and serotonergic agents In Phase I studies, mild to moderate changes in blood pressure seen in normal healthy volunteers given concomitant pseudoephedrine or phenylpropanolamine Serotonin syndrome has been reported in patients receiving SSRIs and linezolid, but uncommon |
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Linezolid: Clinical Uses
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Good activity against MRSA, MRSE, other Gram-positive organisms
Clinically effective, widely used for VRE Considered good alternative to vancomycin Better tolerated than Synercid™, easy to administer Availability in oral form fills important role in outpatient treatment Alternative agent for treating variety of serious Gram-positive infections including respiratory tract, skin/soft tissue, bone and joint infections Useful in patients with severe β-lactam allergy |
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what are the 2 antibiotics in the streptogramins combo product
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Quinupristin
Streptogramin B and Dalfopristin Streptogramin A |
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Streptogramins Antibiotics
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Macromolecular antibiotics produced by Streptomyces pristinaespiralis
Members of the MLS (macrolide-lincosamide-streptogramin) group of antibiotics since they share a common mechanism of action Act at ribosome to inhibit protein synthesis Streptogramins consist of two types, A and B, which are both macrocyclic lactone rings Type A are cyclopeptides with a MW of approx. 500 Type B are cyclic hexadepsipeptides with MW of approx. 800 |
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quinupristin (tpye B0 structure (pic)
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dalfopristin (type a) structure (pic)
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dalfopristin (type a) structure (pic)
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Quinupristin/Dalfopristin (Synercid™)
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First streptogramin antibiotics in U.S.
novel antibiotic consisting of two components Synercid™ approved for use in 1999 Combination of quinupristin (type B) and dalfopristin (type A) in a 30:70 w/w ratio Streptogramins A and B inhibit bacterial cell growth by blocking bacterial protein synthesis Separately, A and B components are bacteriostatic, temporarily halting protein synthesis Combined, A and B components are bactericidal, acting synergistically to permanently inhibit protein synthesis |
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Quinupristin/Dalfopristin (Synercid™) are they cidal or static when alone
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static and cidal when together
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Quinupristin/Dalfopristin (Synercid™) are they cidal or static when together
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cidal
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Synercid™: Spectrum of Activity
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Narrow-spectrum bactericidal antibiotic
Primarily active against only Gram-positive organisms Good activity against Staphylococcus aureus (including MRSA), S. epidermidis and other coagulase-negative staphylococci, and streptococci Active against certain Enterococcus species, including vancomycin-resistant E. faecium (VREF) Not active against E. faecalis Activity includes many Gram-positive anaerobes No clinically relevant activity against Gram-negative bacteria Some activity against atypical bacteria |
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Synercid™: Primarily active against
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Good activity against Staphylococcus aureus (including MRSA), S. epidermidis and other coagulase-negative staphylococci, and streptococci
Active against certain Enterococcus species, including vancomycin-resistant E. faecium (VREF) Not active against E. faecalis Activity includes many Gram-positive anaerobes |
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Type A streptogramin (Dalfopristin)
MOA |
binds to the 50S ribosome to prevent peptide chain elongation (early phase)
inhibits protein elongation by interfering with the binding site of peptidyl transferase, the enzyme that facilitates protein synthesis by transporting amino acids to the ribosome produces conformational changes in the 50S ribosome, increasing its affinity for the type B streptogramin |
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Type B streptogramin (Quinupristin)
MOA |
binds to the 50S ribosome at L24, a protein that is part of the polypeptide exit channel
Stable drug-ribosome complex constricts the ribosomal exit channels prevents further polypeptide chain formation and results in early chain termination with release of incomplete peptide chains Interruption of protein synthesis eventually results in cell death |
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how does A streptogramin (dalfopristin) increase the the binding affinity of B streptogramin (quinupristin)
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produces conformational changes in the 50S ribosome, increasing its affinity for the type B streptogramin
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Mechanisms of Bacterial Resistance to Quinupristin/Dalfopristin
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Most important is plasmid-mediated target modification
Causes resistance to quinupristin by methylation of common binding sites Infrequently, resistance mediated by drug-modifying enzymes or efflux (dalfopristin) Quinupristin hydrolase Dalfopristin acetylase |
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Synercid™: Adverse Effects
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Phlebitis
Incidence up to 75% of patients Can be very severe, including thrombophlebitis (clot fromation at site of inflammation) Necessitates use of central venous catheter for long-term administration Arthralgia, myalgia (very painful and do not become tolerant too) 3%–12% of patients May be very severe, often requiring analgesics (APAP, NSAIDs, opiates) to maintain therapy Diluting drug in large volumes for infusion may help Elevated hepatic enzymes, increased bilirubin Other: headache, nausea, vomiting, diarrhea, rash |
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how is synercid administered
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Necessitates use of central venous catheter for long-term administration
very necrotic od small vessels |
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Synercid™: Drug Interactions
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CYP 3A4 significantly inhibited by Synercid
Dose reductions necessary for drugs metabolized via CYP 3A4 pathway CYP 3A4 substrates with associated QTc prolongation should be avoided Quinupristin/dalfopristin is not itself metabolized by cytochrome P450 enzymes No alterations in Synercid pharmacokinetics by other CYP 3A4-metabolized drugs No interactions with drugs metabolized by other CYP 450 pathways |
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what are synercids affects on the p450 system
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CYP 3A4 significantly inhibited by Synercid
Dose reductions necessary for drugs metabolized via CYP 3A4 pathway CYP 3A4 substrates with associated QTc prolongation should be avoided |
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Synercid™: Clinical Uses
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Good activity against MRSA, MRSE, other Gram-positive organisms
First antibiotic in U.S. to be clinically effective against VREF Lack of activity against E. faecalis problematic Overall clinical usefulness limited by administration issues, toxicities, drug interactions Not as widely used as other agents, e.g. vancomycin, linezolid, daptomycin Alternative agent for treating variety of serious Gram-positive infections Useful in patients with severe β-lactam allergy became obsolete when linezolid came onto the market |
