Ios 10 Exam 2

Front 1

bioavailability of AGs?

Back 1

Aminoglycosides are not absorbed orally (F < 3%) and must be administered either intravenously or intramuscularly for treatment of systemic infections

Front 2

how must AG be administered?

Back 2

AG must be administered either intravenously or intramuscularly for treatment of systemic infections

Front 3

how are AGs typically administered?

Back 3

Rapid (bolus) intravenous doses can be given but are not generally recommended; doses are generally given via slow IV infusion over 30-60 minutes

Front 4

ways AGs can be admin besides IV?

Back 4

Aminoglycosides may also be administered by the intrathecal, intraventricular, subconjunctival, and intravitreal routes for treatment of infections in systemic sites with poor antibiotic penetration

Front 5

Are AGs hydrophilic/hydrophobic?

Back 5

Hydrophilic, ionically charged compounds which tend to be restricted in distribution primarily to intravascular and interstitial fluids, i.e. blood, ascitic fluid, etc.

Front 6

which tissues is AG penetration poor?

Back 6

Penetration into pulmonary secretions/tissues, CNS, and avascular sites (e.g. diabetic foot ulcers) is relatively poor

*need high doses to penetrate

Front 7

how well are AGs distributed? What's the apparent Vd?

Back 7

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

Front 8

AG Vd commonly used in practice?

Back 8

0.25 L/kg

Front 9

which weight is used when calculating Vd of AGs?
(L/Kg)

Back 9

Kg's are in IBW

Front 10

which disease states have altered Vd for AG dosing???

Back 10

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)

Front 11

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)

Back 11

all have increased Vd

Front 12

what is the estimated Vd in ICU pts?

Back 12

0.35 L/kg

Front 13

what is the estimated Vd in neonates?

Back 13

0.4-0.5 L/kg

Front 14

what is the Vd of AGs into adipose tissue?

Back 14

Vd into adipose tissue is only approximately 0.1 L/kg due to its relatively avascular nature

Front 15

How do you calculate Vd for obesity or significant from IBW (TBW >20-30% more than IBW)?

Back 15

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

Front 16

how are AGs eliiminated?

Back 16

Aminoglycosides are normally not metabolized, and elimination is >98% through glomerular filtration and renal excretion of unchanged drug

Front 17

how does AG clearance related to CrCl?

Back 17

total body clearance (CL) = CLR = calculated CrCL

Front 18

T1/2 of AGs

Back 18

t½ = normally 2-3 hours, highly variable due to changes in Vd and CL

Front 19

how is AG clearance limited in hemodialysis patietns?

Back 19

Approximately 30-40% of total body stores are eliminated with each session of hemodialysis; limited clearance with peritoneal dialysis

Front 20

AG patients with altered CL?

Back 20

Cystic fibrosis
Spinal cord injury
Neonates
Burns
Renal dysfunction/failure
Dialysis

Front 21

How is AG CL altered in the following patients?
Cystic fibrosis
Spinal cord injury
Neonates
Burns
Renal dysfunction/failure
Dialysis

Back 21

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

Front 22

Cockroft gault CrCl equation

Back 22

(140-age) x weight(IBW)
-----------------------------------
72 x Scr

multiply by 0.85 in women

Front 23

risk factors for AG nephrotoxicity

Back 23

- 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

Front 24

at what Cmin are patients at risk for nephrotoxicity?

Back 24

Cmin > 2 mg/L

Front 25

Decision process for considerations in AG nephrotoxicity

Back 25

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.

Front 26

consequences of AG ototoxicity?

Back 26

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

Front 27

Cmax therapeutic ranges from gentamicin and tobramycin:
severe systemic infections; pneumonia)

Back 27

8 - 10 mg/L (severe systemic infections, pneumonia)

Front 28

Cmax therapeutic ranges from gentamicin and tobramycin:
(less severe systemic infections)

Back 28

6 - 8 mg/L (less severe systemic infections)

Front 29

Cmax therapeutic ranges from gentamicin and tobramycin:
(UTI)

Back 29

4 - 6 mg/L (urinary tract infections)

Front 30

Cmax therapeutic ranges for amikacin:
severe systemic infections; pneumonia

Back 30

25 - 30 mg/L (severe systemic infections, pneumonia)

Front 31

Cmax therapeutic ranges for amikacin:
other infections

Back 31

20 - 25 mg/L (other infections)

Front 32

True or False???

Peak = Cmax

Back 32

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)

Front 33

what parameters do you need to know to do PK calculations?

Back 33

male/female
Scr
weight
age
height
dx being treated

Front 34

IBW calculation: males

Back 34

50 + 2.3 x (inches>60)

Front 35

IBW calculation: females

Back 35

45.5 + 2.3 x (inches >60)

Front 36

which weight do you use when administering AG loading dose?

Back 36

ADW or TBW

Front 37

calculate AG loading dose

Back 37

approx. 2 mg/kg

(ADW or TBW)

Front 38

how to calculate a maintenance dose for AGs?

Back 38

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)

Front 39

therapeutic Cmin for gentamicin and tobramycin?

Back 39

< 2 ml

Front 40

therapeutic Cmin for amikacin?

Back 40

<10 ml

Front 41

calculate AG dosing interval:

Back 41

Tmax =
[ln(desiredCmax/desiredCmin)/k] + Tin

Front 42

calculate AG dosing interval using Fish common sense method

Back 42

T = (3 x T1/2) + Tin
round up to the next most conventient dosage interval (8,12,24,48)

Front 43

AG maintenance dose calculation

Back 43

Dose (mg) = (desired Cmax x CL x tin) x [1 – e^ -kτ/1 – e^ -ktin]

Front 44

Desc. vancomycin (VAN) absorption

Back 44

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

Front 45

which microbe is good to treat due to lack of VAN absorption?

Back 45

Clostridium difficile colitis

b/c lack of absorption produces extremely high intraluminal conc. of ABs in small doses

Front 46

how should VAN be administered?

Back 46

IV infusion over 60 mins for normal doses

Front 47

why is IM admin. CI for VAN?

Back 47

intramuscular administration contraindicated due to extreme pain and potential for muscle necrosis

Front 48

what compartment model does VAN follow?

Back 48

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

Front 49

Vd of the central compartment of VAN?

Back 49

Vd of the central compartment is approximately 0.2 - 0.6 L/kg, with an alpha distribution half-life of approximately 20 minutes

Front 50

steady state Vd of VAN?

Back 50

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

Front 51

protein binding of VAN?

Back 51

Vancomycin is approximately 50% protein-bound in patients with normal renal function

Front 52

tissue penetration of VAN?

Back 52

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

Front 53

VAN metabolism in normal renal fxn?

Back 53

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

Front 54

primary form of VAN elimination?

Back 54

Elimination of vancomycin is primarily by glomerular filtration and excretion of unchanged drug (apparently little or no tubular secretion)

Front 55

total body clearance of VAN?

Back 55

Total body clearance (CLs)
= 0.7 x CrCl

Front 56

half life of VAN

Back 56

normally 6-8 hrs, but highly dependent on renal fxn
T1/2 in ESRD can reach 140-160 hrs

Front 57

how is VAN cleared by hemo/peritoneal dialysis?

Back 57

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)

Front 58

what VAN nephrotoxicity originallky caused by?

Back 58

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

Front 59

factors that put pt. at higher risk for nephrotoxicity due to VAN?

Back 59

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)

Front 60

most important factor regarding VAN nephrotoxicity

Back 60

***Prolonged, elevated Cmin concentrations ( > 15 mg/L)

Front 61

VAN otottoxicity

Back 61

Characteristically manifests clinically as tinnitus and/or hearing loss in the high-frequency range

Front 62

[VAN] associated with ototoxicity

Back 62

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

Front 63

Traditionally VAN dosing

Back 63

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

Front 64

VAN clinical response/toxicities related to conc.

Back 64

Vancomycin clinical response, toxicities actually poorly correlated with serum concentrations

Data relating outcomes to Cmax mostly anecdotal and difficult to reproduce

Front 65

how quickly do VAN antimicrobial effects occur?

Back 65

Antimicrobial effects of vancomycin occur relatively slowly (“slowly bactericidal”)

Front 66

standard VAN dosing

Back 66

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

Front 67

monitoring VAN conc.

Back 67

Monitoring of serum concentrations is not routinely indicated for patients with normal renal function or mild-moderate insufficiency

Front 68

which is better sign of antimicrobial activity for VAN:
AUC/MIC or %T>MIC

Back 68

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

Front 69

therapeutic ranges of VAN:
higher trough

Back 69

More recently, the use of higher trough concentrations has been advocated for the treatment of more severe infections (e.g., pneumonia, CNS infections, sepsis).

Front 70

why are higher [VAN] used for severe infections?

Back 70

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

Front 71

what is recommended [VAN] trough level for pts failing therapy or with severe infections?

Back 71

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

Front 72

what are the 3 positions for when VAN conc. should be routinely monitored?

Back 72

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

Front 73

what is the best position to take for routine measurement of VAN conc.?

Back 73

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

Front 74

high risk patients that require routine monitoring of VAN conc?

Back 74

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

Front 75

initiate VAN therapy:
loading dose?

Back 75

Loading doses of vancomycin are not typically recommended due to the very high peak concentrations produced with standard dosing regimens

Front 76

initiate VAN therapy:
calculate a maintenance dose

Back 76

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

Front 77

ἀγαθόs

Back 77

good

Front 78

concentration sampling strategies for VAN

Back 78

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

Front 79

VAN dosage regimen serum concentrations

Back 79

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

Front 80

basic tetracycline structure?

Back 80

All tetracyclines are derivatives of the basic naphthacene structure
(4 benzene rings)

Front 81

what do diff. substitutions on naphthacene structure do?

Back 81

Different substitutions significantly alter the agents’ antibacterial activities and pharmacokinetic properties

Front 82

short acting tetracyclines?

Back 82

tetraxycline, oxytetracycline

Front 83

intermediate acting tetracyclines

Back 83

demeclocycline

Front 84

long acting tetracyclines

Back 84

doxycycline, minocycline

Front 85

importance of tetracycline stereochemistry?

Back 85

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

Front 86

reactivity chemistry of tetracyclines

Back 86

Tetracyclines are chemically very reactive compounds

Chelation of di- and trivalent cations is clinically relevant

Front 87

MOA tetracyclines

Back 87

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

Front 88

tetracyclines cidal or static?

Back 88

inhibition of protein synthesis
=== bacteriostatic

*AGs are the only cidal protein synthesis inhibitors

Front 89

tetracycline resistance

Back 89

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

Front 90

tetracycline absorption

Back 90

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

Front 91

decrease in tetracycline bioavailability when taken with food/dairy products

Back 91

Tetracycline bioavailability decreased by >50%
Doxy, minocycline reduced by up to 20-30%

Front 92

tetracycline distribution

Back 92

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

Front 93

Vd tetracyclines

Back 93

large (1.5-2.5 L/kg)

Front 94

tetracycline excretion

Back 94

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

Front 95

tetracycline absorption

Back 95

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

Front 96

decrease in tetracycline bioavailability when taken with food/dairy products

Back 96

Tetracycline bioavailability decreased by >50%
Doxy, minocycline reduced by up to 20-30%

Front 97

tetracycline distribution

Back 97

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

Front 98

Vd tetracyclines

Back 98

large (1.5-2.5 L/kg)

Front 99

tetracycline excretion

Back 99

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

Front 100

which tetracyclines need renal dosing adjustments?

Back 100

Tetracycline = >60-70% renal excretion as unchanged drug

Demeclocycline = 45-55% renal, 30% fecal

Doxycycline = 30-40% renal as unchanged drug

Front 101

spectrum of activity for tetracyclines

Back 101

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)

Front 102

adverse effects of tetracyclines

Back 102

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

Front 103

drug interactions with tetracyclines

Back 103

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

Front 104

what is the result of tetracycline deposition in bone/teeth?

Back 104

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

Front 105

what is absolute CI to tetracyclines due to tetracycline depositon in bone/teeth?

Back 105

pregnancy
children < 8 yo

Front 106

which tetracycline causes vestibular symptoms?

Back 106

minocycline (30-90%)

Front 107

clinical uses of tetracyclines

Back 107

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

Front 108

why were glycylcyclines developed?

Back 108

drug resistance
glycylcyclines are not affected by major mechs. of tetracycline resistance: ribosomal modification, active drug efflux

Front 109

tigecycline spectrum of activity

Back 109

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

Front 110

tigecycline PK

Back 110

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

Front 111

can tigecycline be used for blood stream infections?

Back 111

NO, Cmax at steady state is only 0.87 micg/ml after 30 min infusion...extensive tissue distribution, doesnt stay in serum

Front 112

most common SE tigecycline

Back 112

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%

Front 113

clinical uses of tigecycline

Back 113

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

Front 114

colistimethate/colistin (polymixin E)

Back 114

colistimethate is a prodrug rapidly hydrolyzed to colistin

Front 115

MOA colistin

Back 115

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

Front 116

is colistin cidal or static?

Back 116

bactericidal

Front 117

PK colistin

Back 117

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

Front 118

colistin elimination

Back 118

Eliminated approx. 65% to 75% as unchanged drug in the urine

Front 119

plasma T1/2 colistin

Back 119

Plasma half-life ~ 4-8 hours, but may be increased to > 48-72 hours in severe renal impairment

Front 120

how must colistin be given?

Back 120

parentally for systemic infections b/c absorption <2-3% after oral admin.

Front 121

SEs colistin

Back 121

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