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124 Cards in this Set
- Front
- Back
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bioavailability of AGs?
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Aminoglycosides are not absorbed orally (F < 3%) and must be administered either intravenously or intramuscularly for treatment of systemic infections
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how must AG be administered?
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AG must be administered either intravenously or intramuscularly for treatment of systemic infections
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how are AGs typically administered?
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Rapid (bolus) intravenous doses can be given but are not generally recommended; doses are generally given via slow IV infusion over 30-60 minutes
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ways AGs can be admin besides IV?
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Aminoglycosides may also be administered by the intrathecal, intraventricular, subconjunctival, and intravitreal routes for treatment of infections in systemic sites with poor antibiotic penetration
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Are AGs hydrophilic/hydrophobic?
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Hydrophilic, ionically charged compounds which tend to be restricted in distribution primarily to intravascular and interstitial fluids, i.e. blood, ascitic fluid, etc.
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which tissues is AG penetration poor?
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Penetration into pulmonary secretions/tissues, CNS, and avascular sites (e.g. diabetic foot ulcers) is relatively poor
*need high doses to penetrate |
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how well are AGs distributed? What's the apparent Vd?
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Relatively small apparent volume of distribution (Vd) = 0.20 - 0.30 L/kg based on IBW; a Vd of 0.25 L/kg is very commonly used in clinical practice
*found mainly in extracellular fluids |
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AG Vd commonly used in practice?
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0.25 L/kg
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which weight is used when calculating Vd of AGs?
(L/Kg) |
Kg's are in IBW
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which disease states have altered Vd for AG dosing???
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Spinal cord injury
Liver disease associated with low albumin and/or ascites Neonates Burns (initial phases) Acute and chronic renal failure Severe edema Peritonitis Critical illness (ICU patients) |
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how is Vd altered in the following patients:
Spinal cord injury Liver disease associated with low albumin and/or ascites Neonates Burns (initial phases) Acute and chronic renal failure Severe edema Peritonitis Critical illness (ICU patients) |
all have increased Vd
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what is the estimated Vd in ICU pts?
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0.35 L/kg
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what is the estimated Vd in neonates?
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0.4-0.5 L/kg
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what is the Vd of AGs into adipose tissue?
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Vd into adipose tissue is only approximately 0.1 L/kg due to its relatively avascular nature
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How do you calculate Vd for obesity or significant from IBW (TBW >20-30% more than IBW)?
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2 methods:
Vd = [0.25 L/kg x (IBW)] + [0.1 L/kg x (TBW - IBW)] **Most common method: Vd = 0.25 L/kg x [IBW + 0.4(TBW - IBW)] = 0.25 L/kg x ADW |
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how are AGs eliiminated?
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Aminoglycosides are normally not metabolized, and elimination is >98% through glomerular filtration and renal excretion of unchanged drug
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how does AG clearance related to CrCl?
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total body clearance (CL) = CLR = calculated CrCL
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T1/2 of AGs
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t½ = normally 2-3 hours, highly variable due to changes in Vd and CL
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how is AG clearance limited in hemodialysis patietns?
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Approximately 30-40% of total body stores are eliminated with each session of hemodialysis; limited clearance with peritoneal dialysis
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AG patients with altered CL?
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Cystic fibrosis
Spinal cord injury Neonates Burns Renal dysfunction/failure Dialysis |
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How is AG CL altered in the following patients?
Cystic fibrosis Spinal cord injury Neonates Burns Renal dysfunction/failure Dialysis |
Cystic fibrosis (increase)
Spinal cord injury (increase) Neonates (decrease initiallly, then increase after 1 yo) Burns (increase) Renal dysfunction/failure (decrease) Dialysis (decrease) *when decrease CL, T1/2 increases |
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Cockroft gault CrCl equation
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(140-age) x weight(IBW)
----------------------------------- 72 x Scr multiply by 0.85 in women |
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risk factors for AG nephrotoxicity
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- daily dose
*- cumulative dose *- duration of therapy (especially >10 days) *- dehydration - hypokalemia *- previous aminoglycoside therapy - female sex - liver disease (cirrhosis, biliary disease) *- concurrent nephrotoxins *- Cmin concentrations > 2 mg/L *- advanced age *- previous underlying renal dysfunction - sepsis - hemorrhage |
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at what Cmin are patients at risk for nephrotoxicity?
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Cmin > 2 mg/L
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Decision process for considerations in AG nephrotoxicity
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Clinical management of aminoglycoside-induced renal dysfunction depends on the relative risk vs. benefit of continuing aminoglycoside therapy
In many patients, the need for continuing aminoglycosides will necessitate adjusting the daily dose and continuing therapy In other patients, the aminoglycosides may be safely discontinued without adversely affecting clinical outcomes The decision of whether to continue or discontinue therapy in the face of aminoglycoside-related toxicity is made on purely clinical grounds and is entirely patient-specific. |
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consequences of AG ototoxicity?
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Cochlear damage begins in the base of cochlea and moves toward the apex with progressive loss of hair cells; once lost, no regeneration of these cells occurs
Hearing loss is initially in the high-frequency range and becomes progressively worse in lower frequencies as well; vestibular damage may also result in dizziness, vertigo, loss of balance Ototoxicity is less well correlated with serum concentrations, although prolonged Cmin concentrations of > 2 mg/L may place patients at increased risk |
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Cmax therapeutic ranges from gentamicin and tobramycin:
severe systemic infections; pneumonia) |
8 - 10 mg/L (severe systemic infections, pneumonia)
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Cmax therapeutic ranges from gentamicin and tobramycin:
(less severe systemic infections) |
6 - 8 mg/L (less severe systemic infections)
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Cmax therapeutic ranges from gentamicin and tobramycin:
(UTI) |
4 - 6 mg/L (urinary tract infections)
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Cmax therapeutic ranges for amikacin:
severe systemic infections; pneumonia |
25 - 30 mg/L (severe systemic infections, pneumonia)
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Cmax therapeutic ranges for amikacin:
other infections |
20 - 25 mg/L (other infections)
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True or False???
Peak = Cmax |
False
Cmax is a very defined parameter at the top of the conc. vs. time curve peak varies, and is the measurement that occurs when samples are obtained for analysis (below the Cmax ont he conc. vs. time curve) |
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what parameters do you need to know to do PK calculations?
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male/female
Scr weight age height dx being treated |
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IBW calculation: males
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50 + 2.3 x (inches>60)
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IBW calculation: females
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45.5 + 2.3 x (inches >60)
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which weight do you use when administering AG loading dose?
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ADW or TBW
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calculate AG loading dose
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approx. 2 mg/kg
(ADW or TBW) |
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how to calculate a maintenance dose for AGs?
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calculate CrCl (cockroft-gault)
drug CL = CrCl estimate Vd: 0.25 L/kg x IBW or 0.25 x (ADW) estimate eliminatin rate constant: k=Cl/Vd estimate T1/2= 0.693/k choose desired Cmax and Cmin(1.0 is easy) serum conc. choose the duration of IV infusion (30-60 mins) |
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therapeutic Cmin for gentamicin and tobramycin?
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< 2 ml
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therapeutic Cmin for amikacin?
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<10 ml
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calculate AG dosing interval:
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Tmax =
[ln(desiredCmax/desiredCmin)/k] + Tin |
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calculate AG dosing interval using Fish common sense method
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T = (3 x T1/2) + Tin
round up to the next most conventient dosage interval (8,12,24,48) |
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AG maintenance dose calculation
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Dose (mg) = (desired Cmax x CL x tin) x [1 – e^ -kτ/1 – e^ -ktin]
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Desc. vancomycin (VAN) absorption
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Oral absorption of this agent is extremely poor (F < 5%)
*therapeutic concentrations are only achieved after oral dosing in patients with severely impaired renal function who are unable to excrete the small amounts of drug absorbed after multiple doses |
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which microbe is good to treat due to lack of VAN absorption?
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Clostridium difficile colitis
b/c lack of absorption produces extremely high intraluminal conc. of ABs in small doses |
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how should VAN be administered?
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IV infusion over 60 mins for normal doses
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why is IM admin. CI for VAN?
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intramuscular administration contraindicated due to extreme pain and potential for muscle necrosis
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what compartment model does VAN follow?
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Vancomycin distribution may be characterized by a two- or three-compartment model
Vd of the central compartment is approximately 0.2 - 0.6 L/kg, with an alpha distribution half-life of approximately 20 minutes |
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Vd of the central compartment of VAN?
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Vd of the central compartment is approximately 0.2 - 0.6 L/kg, with an alpha distribution half-life of approximately 20 minutes
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steady state Vd of VAN?
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Steady-state Vd is approximately 0.5 - 0.9 L/kg (TBW) with a terminal half-life of 6 - 8 hours in patients with good renal function
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protein binding of VAN?
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Vancomycin is approximately 50% protein-bound in patients with normal renal function
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tissue penetration of VAN?
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Penetration of vancomycin is adequate for most tissues/fluids, but distribution into the CSF is poor and intrathecal or intraventricular administration is often recommended for CNS infections
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VAN metabolism in normal renal fxn?
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Metabolism of vancomycin is very minimal (5%) in patients with normal renal function
Unclear whether metabolism occurs in the liver or in extra-hepatic sites |
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primary form of VAN elimination?
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Elimination of vancomycin is primarily by glomerular filtration and excretion of unchanged drug (apparently little or no tubular secretion)
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total body clearance of VAN?
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Total body clearance (CLs)
= 0.7 x CrCl |
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half life of VAN
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normally 6-8 hrs, but highly dependent on renal fxn
T1/2 in ESRD can reach 140-160 hrs |
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how is VAN cleared by hemo/peritoneal dialysis?
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poorly cleared, but some newer methods are more effecient
ESRD on dialysis, the dose can last up to a week high flux dialysis machin, the dose only last 2-3 days(dont use VAN) |
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what VAN nephrotoxicity originallky caused by?
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A high incidence of nephrotoxicity originally related to vancomycin has since been attributed to the presence of nephrotoxic impurities contained within the original product formulations
These impurities have been largely removed and the nephrotoxic potential of vancomycin is now generally felt to be quite low |
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factors that put pt. at higher risk for nephrotoxicity due to VAN?
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Combination therapy with aminoglycosides
Other concurrent nephrotoxins Increased age Previous underlying renal dysfunction ***Prolonged, elevated Cmin concentrations ( > 15 mg/L) Doses > 4 grams/day Patients with these risk factors may warrant closer clinical monitoring for signs of early toxicity (elevated creatinine) |
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most important factor regarding VAN nephrotoxicity
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***Prolonged, elevated Cmin concentrations ( > 15 mg/L)
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VAN otottoxicity
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Characteristically manifests clinically as tinnitus and/or hearing loss in the high-frequency range
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[VAN] associated with ototoxicity
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Ototoxicity has primarily been reported in patients with Cmax serum concentrations > 80 mg/L
*Since the minimum bactericidal concentration (MBC) of vancomycin for staphylococci and streptococci is usually < 2 - 4 mg/L, there is little to justify concentrations this high |
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Traditionally VAN dosing
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Vancomycin has traditionally been dosed to achieve Cmax = 30-40 mg/L and Cmin = 5-15 mg/L
*doesnt make sense to dose to a certain Cmax b/c VAN is TIME DEPENDENT |
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VAN clinical response/toxicities related to conc.
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Vancomycin clinical response, toxicities actually poorly correlated with serum concentrations
Data relating outcomes to Cmax mostly anecdotal and difficult to reproduce |
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how quickly do VAN antimicrobial effects occur?
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Antimicrobial effects of vancomycin occur relatively slowly (“slowly bactericidal”)
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standard VAN dosing
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Standard doses of vancomycin (~30 mg/kg/day, or 1 gram every 12 hours) usually achieve concentrations that provide favorable % Time>MIC
Typical MICs of usual pathogens are < 4 mcg/ml |
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monitoring VAN conc.
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Monitoring of serum concentrations is not routinely indicated for patients with normal renal function or mild-moderate insufficiency
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which is better sign of antimicrobial activity for VAN:
AUC/MIC or %T>MIC |
More recent data suggest that AUC24/MIC ratios may actually be better predictors of vancomycin microbiological and clinical activity than %T>MIC
AUC24/MIC ratios 350-400 have been shown in several studies to be associated with better clinical outcomes in patients with pneumonias and other severe infections Higher Cmin concentrations are associated with increased AUC24/MIC ratios |
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therapeutic ranges of VAN:
higher trough |
More recently, the use of higher trough concentrations has been advocated for the treatment of more severe infections (e.g., pneumonia, CNS infections, sepsis).
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why are higher [VAN] used for severe infections?
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Reasons for increased concentrations include recognition of vancomycin’s poor distribution into lung tissues, increasing MICs of many staphylococcal and enterococcal strains, and little risk of increased toxicity.
Trough concentrations of 15-20 mg/L are now often recommended (or even higher, e.g. 20-25 mg/L) in patients who are failing vancomycin therapy or have very severe infections Some evidence for increased risk for nephrotoxicity with trough levels this high, also with doses >4 gms/day |
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what is recommended [VAN] trough level for pts failing therapy or with severe infections?
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Trough concentrations of 15-20 mg/L are now often recommended (or even higher, e.g. 20-25 mg/L) in patients who are failing vancomycin therapy or have very severe infections
Some evidence for increased risk for nephrotoxicity with trough levels this high, also with doses >4 gms/day |
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what are the 3 positions for when VAN conc. should be routinely monitored?
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Position #1:
Vancomycin concentrations should be routinely monitored due to the risk of potentially serious clinical failures and adverse effects which may be associated with serum concentrations outside of the therapeutic range In addition, routine monitoring of concentrations is an accepted standard of medical practice Position #2 Routine monitoring of vancomycin serum concentrations is unwarranted due to lack of hard clinical data relating serum concentrations to either efficacy or toxicity Monitoring should be reserved for high-risk patients, e.g.: Patients with significant renal dysfunction Patients receiving concurrent therapy with known nephrotoxins Critically ill patients in whom significant variation in pharmacokinetic parameters is likely to exist Patients with severe infections in whom treatment failure would have disastrous consequences Position #3 Vancomycin serum concentrations should NEVER be monitored in ANY patient, under ANY circumstances |
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what is the best position to take for routine measurement of VAN conc.?
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Routine monitoring of vancomycin serum concentrations is unwarranted due to lack of hard clinical data relating serum concentrations to either efficacy or toxicity Monitoring should be reserved for high-risk patients, e.g.:
Patients with significant renal dysfunction Patients receiving concurrent therapy with known nephrotoxins Critically ill patients in whom significant variation in pharmacokinetic parameters is likely to exist Patients with severe infections in whom treatment failure would have disastrous consequences |
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high risk patients that require routine monitoring of VAN conc?
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Patients with significant renal dysfunction
Patients receiving concurrent therapy with known nephrotoxins Critically ill patients in whom significant variation in pharmacokinetic parameters is likely to exist Patients with severe infections in whom treatment failure would have disastrous consequences |
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initiate VAN therapy:
loading dose? |
Loading doses of vancomycin are not typically recommended due to the very high peak concentrations produced with standard dosing regimens
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initiate VAN therapy:
calculate a maintenance dose |
The method for doing this is virtually identical to that used for the aminoglycosides; same steps, same equations. Remember to use kinetic parameters specific for vancomycin:
a.Estimate Vd = 0.7 L/kg(based on TBW; may also use ADW) b.Estimate CL = 0.7 x CrCL (remember, CrCL is based on IBW or ADW) c.Estimate kel d.Estimate t½ e. Choose desired Cmax and Cmin = anywhere within the accepted "therapeutic range“ (typically a Cmax of 30 mg/L and Cmin of 10 mg/L) f. Choose duration of infusion, tin = usually approx. 60 minutes g. Calculate dosing interval, t = traditionally, every 12, 24, 48, etc. hours h. Calculate dose i. Double-check Cmin |
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ἀγαθόs
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good
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concentration sampling strategies for VAN
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Same considerations as with the aminoglycosides, except vancomycin peak concentrations are usually drawn 60 minutes after the end of the infusion instead of 30 minutes as with aminoglycosides
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VAN dosage regimen serum concentrations
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a.Calculate k
b.Calculate CL from patient-specific serum concentrations c.Calculate t½ d.Calculate Vd e.Choose Cmax and Cmin f.Choose duration of infusion, tin g.Calculate dosing interval, t h.Calculate dose i.Double-check Cmin |
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basic tetracycline structure?
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All tetracyclines are derivatives of the basic naphthacene structure
(4 benzene rings) |
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what do diff. substitutions on naphthacene structure do?
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Different substitutions significantly alter the agents’ antibacterial activities and pharmacokinetic properties
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short acting tetracyclines?
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tetraxycline, oxytetracycline
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intermediate acting tetracyclines
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demeclocycline
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long acting tetracyclines
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doxycycline, minocycline
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importance of tetracycline stereochemistry?
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5 stereocenters
only one stereocenter, C6-OH, can be altered without destroying the activity of the drug If any other stereocenter is modified, the activity of the drug is destroyed |
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reactivity chemistry of tetracyclines
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Tetracyclines are chemically very reactive compounds
Chelation of di- and trivalent cations is clinically relevant |
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MOA tetracyclines
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In Gram-negative bacteria, passive transport through porin channels is followed by energy-dependent active transport across inner cytoplasmic membrane
Drug permeation in Gram-positive bacteria is not well characterized Drugs reversibly bind primarily to the 30S ribosomal subunit Block binding of the aminoacyl-transfer RNA to the acceptor site on the messenger RNA-ribosome complex Inhibition of bacterial protein synthesis Characterized as bacteriostatic **not O2 dependent, works MOA works in anaerobes too |
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tetracyclines cidal or static?
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inhibition of protein synthesis
=== bacteriostatic *AGs are the only cidal protein synthesis inhibitors |
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tetracycline resistance
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Decreased accumulation of drug due to decreased influx, or acquisition of an energy-dependent efflux mechanism
Mutations of ribosomal binding site also common Resistance often chromosomal and constitutive, but may also be plasmid-mediated Plasmid-mediated resistance is usually inducible Bacteria become resistant after exposure to drug Resistance to one tetracycline usually implies resistance to all -->Exception is minocycline |
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tetracycline absorption
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Good oral absorption from the GI tract
Bioavailability: Tetracycline, oxytetracycline, demeclocycline = 60-80% Doxycycline, minocycline = 90-100% Absorption substantially altered by presence of food and/or dairy products Tetracycline bioavailability decreased by >50% Doxy, minocycline reduced by up to 20-30% Very effective chelators of di- and trivalent cations Dairy products, aluminum hydroxide gels, calcium, magnesium, iron salts |
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decrease in tetracycline bioavailability when taken with food/dairy products
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Tetracycline bioavailability decreased by >50%
Doxy, minocycline reduced by up to 20-30% |
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tetracycline distribution
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Vd is quite large (1.5-2.5 L/kg)
Distribute well into nearly all tissues, although CNS penetration is less than other sites Inflammation of meninges is not required for drug entry into CSF |
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Vd tetracyclines
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large (1.5-2.5 L/kg)
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tetracycline excretion
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Most tetracyclines excreted as unchanged drug in the urine or feces, little to no hepatic metabolism
Tetracycline = >60-70% renal excretion as unchanged drug Demeclocycline = 45-55% renal, 30% fecal Doxycycline = 30-40% renal as unchanged drug Minocycline = 10-20% renal excretion as unchanged drug, seems to uniquely undergo hepatic metabolism Biliary excretion with enterohepatic recycling common |
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tetracycline absorption
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Good oral absorption from the GI tract
Bioavailability: Tetracycline, oxytetracycline, demeclocycline = 60-80% Doxycycline, minocycline = 90-100% Absorption substantially altered by presence of food and/or dairy products Tetracycline bioavailability decreased by >50% Doxy, minocycline reduced by up to 20-30% Very effective chelators of di- and trivalent cations Dairy products, aluminum hydroxide gels, calcium, magnesium, iron salts |
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decrease in tetracycline bioavailability when taken with food/dairy products
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Tetracycline bioavailability decreased by >50%
Doxy, minocycline reduced by up to 20-30% |
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tetracycline distribution
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Vd is quite large (1.5-2.5 L/kg)
Distribute well into nearly all tissues, although CNS penetration is less than other sites Inflammation of meninges is not required for drug entry into CSF |
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Vd tetracyclines
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large (1.5-2.5 L/kg)
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tetracycline excretion
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Most tetracyclines excreted as unchanged drug in the urine or feces, little to no hepatic metabolism
Tetracycline = >60-70% renal excretion as unchanged drug Demeclocycline = 45-55% renal, 30% fecal Doxycycline = 30-40% renal as unchanged drug Minocycline = 10-20% renal excretion as unchanged drug, seems to uniquely undergo hepatic metabolism Biliary excretion with enterohepatic recycling common |
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which tetracyclines need renal dosing adjustments?
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Tetracycline = >60-70% renal excretion as unchanged drug
Demeclocycline = 45-55% renal, 30% fecal Doxycycline = 30-40% renal as unchanged drug |
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spectrum of activity for tetracyclines
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Gram + aerobes: intrinsic activity against streptococci and staphylococci, including some strains of MRSA and VRE
Best activity against MRSA: Minocycline > Doxycycline >> others Gram - aerobes: active against wide range of bacteria but limited by PK considerations urinary concentrations sufficient for treating UTI due to E. coli and other enteric bacteria Systemic use usually reserved for treatment of “unusual” infections, e.g. tularemia, plague Anaerobes: Originally active against many anaerobes, but resistance now limits use Atypicals: Good activity, especially against Chlamydia Other: H. pylori, rickettsial pathogens (e.g. Rocky Mountain Spotted Fever, Lyme Disease, Q fever) |
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adverse effects of tetracyclines
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Hypersensitivity reactions (rare) = anaphylaxis, urticaria, periorbital edema, fixed drug eruptions, rashes
Phototoxicity = most frequent with demeclocycline, least frequent with minocycline Occurs within minutes to hours after sun exposure Deposition in bone and teeth = chelation Tetracyclines cause discoloration of teeth Could cause temporary stunting of growth Should not be used during pregnancy or in children <8 years of age Gastric discomfort = irritation of gastric mucosa Hepatotoxicity = most common with tetracycline, esp. in pregnant women and those with hepatic or renal dysfunction CNS = vestibular symptoms with minocycline (30-90%) Superinfections = overgrowth of Candida Thrombophlebitis with IV administration |
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drug interactions with tetracyclines
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Drugs or food containing di- or trivalent cations
Aluminum, calcium, iron, magnesium Antacids, iron preparations including multivitamins Should be administered 2-3 hours before or 2 hours after antibiotic Warfarin (increase bleed risk) Oral contraceptives |
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what is the result of tetracycline deposition in bone/teeth?
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chelation (w/ Ca2+)
Tetracyclines cause discoloration of teeth Could cause temporary stunting of growth Should not be used during pregnancy or in children <8 years of age |
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what is absolute CI to tetracyclines due to tetracycline depositon in bone/teeth?
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pregnancy
children < 8 yo |
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which tetracycline causes vestibular symptoms?
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minocycline (30-90%)
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clinical uses of tetracyclines
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Considered to be very broad-spectrum agents, but resistance often limits clinical use for “routine” bacterial infections
Alternative therapy for a wide variety of bacterial, chlamydial, mycoplasmal, and rickettsial infections Minocycline becoming important in treatment of community-acquired infections caused by MRSA Doxycycline is usually the preferred agent within the class for most infections Well tolerated Improved compliance (BID dosing) May be administered intravenously Demeclocycline rarely used for infectious indications |
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why were glycylcyclines developed?
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drug resistance
glycylcyclines are not affected by major mechs. of tetracycline resistance: ribosomal modification, active drug efflux |
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tigecycline spectrum of activity
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Highly active against Gram-positive bacteria
Staphylococcus aureus (including MRSA) S. epidermidis (including MRSE) Most streptococci Enterococci (including VRE) Excellent activity against many Gram-negative organisms, including nosocomial strains Enterobacteriaceae, Citrobacter, Acinetobacter, Stenotrophomonas Poor activity against Pseudomonas aeruginosa Excellent activity against clinically relevant anaerobes Bacteroides fragilis, other Bacteroides group, Fusobacterum, Clostridium, Peptostreptococcus |
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tigecycline PK
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Mean Cmax at steady state = 0.87 μg/mL after 30-minute infusion
Mean T1/2 = 42 hours Extensively distributed into most tissues 60% eliminated through biliary/fecal excretion, 40% renal No adjustments needed in renal impairment, or Child-Pugh class A and B hepatic impairment |
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can tigecycline be used for blood stream infections?
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NO, Cmax at steady state is only 0.87 micg/ml after 30 min infusion...extensive tissue distribution, doesnt stay in serum
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most common SE tigecycline
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Generally well tolerated; GI adverse effects common
Nausea = 30% (usually during infusion), vomiting = 20% Most GI complaints mild in nature, subside after first 1-2 days Discontinuation rates due to GI adverse effects only ~1% |
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clinical uses of tigecycline
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Very broad spectrum of activity
Includes many important multidrug-resistant Gram-positive and Gram-negative pathogens Aerobic and anaerobic activity well suited to treatment of mixed infections Demonstrated clinical efficacy in complicated skin/skin structure and intra-abdominal infections Generally well tolerated, no significant toxicities Lack of P. aeruginosa activity is problematic *not 1st line for anything, alternative drug |
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colistimethate/colistin (polymixin E)
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colistimethate is a prodrug rapidly hydrolyzed to colistin
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MOA colistin
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Large cyclic polypeptide with MW ~ 1750
After IV or IM administration, colistimethate rapidly hydrolyzed to the pharmacologically active colistin base Colistin acts as a cationic detergent Disrupts & damages bacterial cytoplasmic membrane Causes leakage of intracellular components and eventual cell death Classified as a bactericidal drug |
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is colistin cidal or static?
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bactericidal
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PK colistin
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PK/PD properties of colistin not well described
Usually characterized as concentration-dependent Absorption <2-3% after oral administration, must be given parenterally for treatment of systemic infections Distribution into most tissues is considered to be good (except CNS) Often administered as aerosolized drug for adjunctive treatment of pulmonary infections Eliminated approx. 65% to 75% as unchanged drug in the urine Plasma half-life ~ 4-8 hours, but may be increased to > 48-72 hours in severe renal impairment |
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colistin elimination
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Eliminated approx. 65% to 75% as unchanged drug in the urine
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plasma T1/2 colistin
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Plasma half-life ~ 4-8 hours, but may be increased to > 48-72 hours in severe renal impairment
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how must colistin be given?
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parentally for systemic infections b/c absorption <2-3% after oral admin.
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SEs colistin
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Nephrotoxicity
May occur in up to 30-35% of patients Particularly problematic in patients receiving other nephrotoxins, or those with previous renal impairment or disease CNS toxicity Facial and peripheral paresthesias & numbness, dizziness, vertigo, slurring of speech Generalized rash and pruritis Gastrointestinal disturbances Hypersensitivity reactions Superinfections, e.g. Clostridium difficile |
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what is the most problematic SE of colistin?
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Nephrotoxicity (30-35%)
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spectrum of activity for colistin?
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Activity limited to primarily "Gram-negative aerobes"
Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species Resistance to colistin is quite unusual and activity is retained against organisms that are resistant to multiple other antibiotics “MDR” = multidrug-resistant |
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clincial use of colistin?
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Clinical use of colistin is limited to infections caused by MDR Gram-negative bacteria that:
Are not susceptible to other drugs, and/or Have already failed therapy with other drugs *works when nothing else does...drug of last resort b/c of toxicity |
