Pharmacokinetic and pharmacodynamic considerations are very much important while choosing any antibiotic specially in presence of comorbidities like chronic renal failure as the renal elimination is compromised in those patients and handling of antibiotics which excrete through kidney are altered hence needs judicious antibiotic selection and dose calculation.In this venture calculating eGFR through different online calculators make the physicians more aware of the underlying disease state and improve dose adjustment of the antibiotics. Examples are MDRD or CKD-EPI or Cockroft-Gault formula.

1. Use of Antimicrobials in CKD
patients: Critical Issues
Dr Chiranjib Bagchi
DGO.MD(Pharmacology). DM(Clinical Pharmacology)
Associate Professor
Clinical and Experimental Pharmacology
School of Tropical Medicine, Kolkata

2. PK-PD Concept in Antibiotic Use

6. Pharmacotherapy principle
“Start low, go slow,”
- Jerry Gurwitz, Gerontopharmacology
- “Go fast, start high”
- German, “Sofort und hoch dosieren,” as
stated by Paul Ehrlich
In Nephropharmacology

7. Dose adjustment in renal
insufficiency

8. Drug dosing in Renal disease
 A common approach is “start low and go slow” when
there is uncertainty in its dosage or pharmacokinetics -
a conservative approach
 But antiinfectives are prescribed to maximize the effect
of the initial dose
 Antibiotics also need to target a concentration–time
profile related to the markers of bacterial susceptibility
such as MIC

9. PD issues- Sigmoid effect-
concentration curve
Antibiotics whose effect depends on their concentration have a low Hill coefficient (H<1.5),
while antibiotics whose effect is time-dependent have a high Hill coefficient (H>1.5). The
therapeutically effective range of a drug thus depends on its Hill coefficient: the higher the
Hill coefficient, the narrower the desired range is, and the more closely it centers on CE50.

10. Aminoglycoside in renal failure
 Aminoglycosides: Shifting from Low dose short interval to
High dose extended interval (once-daily aminoglycoside
dosing)
 To maximize antibacterial efficacy as well as limit toxicities
 In impaired kidney function dose interval extended to 36-
48 hrs for complete drug elimination
 Takes advantage of optimum bactericidal activity,
postantibiotic effect, decreased resistance
 Caution: in Cr CL< 30-40/ml leading to high
aminoglycoside concentration
 Where traditional dosing with close TDM is still
recommended

11. Drug dose calculation in CKD
 For patients in CKD stage 3 or above whose GFR is below
60 mL/min, the dose must be adjusted
 Traditionally Cockcroft-Gault formula
 However, there is a movement toward using
GFR (calculated with either the Modification of Diet in
Renal Disease [MDRD] or Chronic Kidney Disease
Epidemiology Collaboration [CKD-EPI] equation) to dose
 24-hour urine CrCl was used in CG whereas iothalamate
clearance in MDRD and CKD-EPI equations – so
difference in estimation is expected
 Debate: Majority drug dosing studies used CG vs MDRD
/CKD-API accurately measures renal function in low GFR

12. Dosage regimen- Limitation
 Dosage adjustment in patients with kidney disease is
defined by the product label
 Considerable variability among recommendations
 Initially determined in patients with normal or mildly
impaired kidney function
 Then tested in a smaller number of patients with
advanced kidney disease before registration
 Data in ESKD treated with dialysis are particularly
limited before registration because of complex
pharmacokinetics
 Dose adjustment requires careful consideration of
patient and antibiotic-related factors

13. Dose regimen: adjustment
 Administering smaller doses maintains more steady
drug concentrations and is therefore preferred for time
dependent antibiotics
 Extending the time between antibiotic doses
maintains high peak and low trough concentrations
and is therefore preferred for concentration-
dependent antibiotics.

14. Dose adjustment for
ciprofloxacin: Mechanistic
model

15. Antibiotic Dosing-Critically Ill
 Critically ill patients are at high risk for development of life-
threatening infection
 Adequate antimicrobial therapy is pivotal
 Pathophysiological changes in critical illness impact on
pharmacokinetics of antimicrobials
 Concentrations of hydrophilic antimicrobials may be increased
because of decreased renal clearance due to acute kidney injury.
 Antimicrobial concentrations may be decreased because of
increased volume of distribution and augmented renal clearance
provoked by systemic inflammatory response syndrome,
capillary leak, decreased protein binding and administration of
intravenous fluids
 Often multiple other conditions influence pharmacokinetics
 In general, conditions leading to underdosing are predominant.

17. A patient Case
KC is a 45yo patient with a history of a renal
transplant in 2007 who presents with respiratory
distress and hypotension. He is emergently intubated
in the ER and fluid resuscitated with 3L of NS.
 KC has NKDA, weighs 91kg and his admit SCr=3.2
mg/dl
 His SCr at a clinic visit one month prior = 1.3 mg/dl
 Cefepime, ciprofloxacin and vancomycin are written
for – What doses should be given?

18. Antibiotics in Critical care
Betalactam and
Carbapenem
Aminoglycoside
 Slow concentration-
independent continuous kill
 fT>MIC is the PK/PD index
best correlated to efficacy
 An improved PD profile vis-
à-vis efficacy is achieved
with a more frequent dosing
or extended or continuous
infusion (for a fixed total
dose)
 Conc-dependent kill
characteristics
 Prolonged persistent effects
– Cmax/MIC and AUC/MIC
are better than T>MIC.
 Optimize peak - Go for
once-a-day regime.
 High trough conc not high
peak indicates increased
risk of toxicity – TDM
recommended.

19. Antibiotics in Critical Care
Vancomycin Fluroquinolones
 A time dependent (T>MIC)
killing
 Protein binding: Moderately
high, in hypoalbuminemia Vd,
CL increased.
 Increased Vd and CL requiring
high maintanance dose
 TDM in the form of trough conc
monitoring is recommended
 Continuous infusion improves
the PD and minimizes the risk
of toxicity
 Dose reduction in renal
impairment,
 Lipophilic; fluid shifts have
minimal effect on Vd; Cmax is
decreased
 Conc-dependent kill
characteristic with time-
dependent effects
 AUC/MIC>125 in gm – ve
pathogens
 Suboptimal drug
exposure(AUC/MIC<100)
selection of antimicrobial
resistance

20. Antibiotics in Critical Care
Tigecycline Colistin
 Broad spectrum glycycline
antimicrobial – active against
gm +ve, gm –ve, and
anaerobic
 Lipophilic, large Vd, biliary
excretion, long t1/2
 Prolonged PAE – the
AUC/MIC ratio is the PK/PD
index correlated with efficacy
 No dosing adjustment in
renal dysfunction or mild to
moderate hepatic
dysfunction
 Current dosage regimens are
sub-optimal in the critically-ill.
 The ƒAUC/MIC of colistin is the
PK/PD index most predictive
 Attainment of steady-state
colistin conc is significantly
delayed.
 Renal function is crucial
determinant of maintenance
dosing
 A large colistin exposure during
the first ~12 h may be beneficial
and immune system will tackle
the rest

21. PK issues in nutshell
 Absorption
 Decreased gastric absorption due edema but rather increased due to
loss of barrier – Bioavailability increased
 Volume of distribution (Vd)
 Change of Vd during intradialytic wt gain is low
 Effect of severe edema on Vd is inconsistent may double or unchanged
 Vd often increase in AKI
 Hydrophilic medications generally stay in the plasma volume (Vd < 0.7
L/kg)
 Influenced by fluid administration and capillary leak
 Lipophilic medications distribute into intracellular and adipose tissue
(Vd > 1 L/kg)
 Not generally affected by fluid administration and third spacing

22. Loading Doses
Goal is to achieve therapeutic concentrations rapidly so
loading doses are usually recommended
Recommend giving high end of normal loading dose (or even
higher dose)
Example: Vancomycin (normal patient Vd ~0.7 L/kg)
100kg septic shock patient
Recommended loading dose for complicated infections in
seriously ill patients is 25-30 mg/kg based on actual body weight
Am J Health-Syst Pharm 2009;66:82-98

23. What dose to give?
 Lack of information in patients with sepsis/shock and acute kidney
injury
 Since SCr is not at steady state -> not a reliable estimate of CrCl
 Concern for underdosing and treatment failure
 Recommendations from “A clinical update from Kidney Disease:
Improving Global Outcomes (KDIGO)”
 Loading dose: Volume of distribution is usually significantly increased in acute
kidney injury for hydrophilic medications
 Recommend: Aggressive loading doses (25-50% greater than normal)
 Maintenance dose: Need to estimate degree and rate of change in kidney status
Need to also take into account nonrenal clearance
 Recommend: Initiate at normal or near-normal dosage regimens
 Therapeutic drug monitoring: Most concern for drugs with narrow therapeutic
window
 Recommend: Check serum concentrations if possible
 Recommend: If no serum concentrations: watch for excessive pharmacologic effect or
toxicity
 Concern with cefepime use in renal dysfunction (Hosp Pharm 2009;44:557-61)

24. Intravenous Dosing of Antibiotics
 Loading dose followed by maintenance
 Intermittent infusion : 30-60 mins
 Extended infusion : 3-4 hrs
 Continuous infusion : 24 hrs

25. Extended and Continuous Infusion
for Time Dependent Antibiotics
 For time-dependent antibiotics, e.g., beta-lactams and
vancomycin, the CI obviously has certain theoretical
advantages toward efficacy but not in all.
 For vancomycin, CI can be chosen, not always for better
clinical efficacy, but because it is practical, cheaper,
associated with less AUC24h (area under the curve >24 h)
variability, and easier to monitor.

26. Meropenem – 30 min vs 3 hr
Infusion
Optimal meropenem extended infusion dosing in
critically ill elderly patients with reduced renal
function(Usman and colleagues)
 PTA(Probabilty of Target Attainment) was
analyzed for PD target of 40%, 60%, and 80% of T
>MIC at MIC ranges of 0.25 to 128 mg/L at various
levels of renal function.
 1000 mg of meropenem every 8 hours as a 3-hour
extended infusion result in optimal PD with CrCl
≤ 50 mL/min in the critical care setting

27. Adverse effects of Antibiotics in CKD
 Mostly related to inappropriate dosing, others due to pathologic
changes associated with uremia
 Neurologic toxicity, including psychosis, visual and auditory
hallucinations, myoclonus and seizures - penicillin, imipenem,
beta-lactams, acyclovir, amantadine, and quinolones
 Aminoglycoside or vancomycin-induced ototoxicity
Sulfonamide-induced hypoglycemia
 Platelet aggregation abnormalities induced by high doses of
penicillins add to HIT
 Cephalosporins containing the N-methyl-thiotetrazole side
chain - vitamin K deficiency in renal failure, seems to be the
culprit for coagulopathy
 Fluoroquinolones with increased risk for spontaneous Achilles
tendon rupture in renal failure

28. Drug dosing in Hemodyalysis
 Antibiotic dosing in hemodialysis is considerably different
than in CKD
 Considerable drug removal during hemodialysis, supplemental
doses administered at the end
 Alternatively, antibiotic doses may be held until after
hemodialysis
 If 30% of total drug clearance by HD – clinically relevant an
increased dose adjustments are needed
 Drug factors favouring hemodialysis clearance: smaller
molecular weight, smaller volume of distribution and lower
plasma protein binding

29. Drug dosing in Hemodyalysis
 The type of dialyzer used also determine drug clearance
 Conventional filters vs high-flux dialyzers with a larger
pore size(more common)
 It is prudent to consider the type of dialyzer studied while
reviewing references
 Increased frequency and time on dialysis on SDHD may
contribute to enhanced antibiotic clearance
 Drug dosing recommended for three times weekly HD
may contribute to antibiotic underdosing
 There are a number of references available to the clinician

30. Drug dosing in Peritoneal dialysis
 Peritonitis and exit-site infections are common
infections
 Intraperitoneal administration is the preferred route of
antibiotic delivery
 Antibiotics may be administered with every
intraperitoneal dwell (continuous dosing) or with
the long dwell (intermittent dosing)
 Intermittent dosing - Concentration dependent
antibiotics and continuous dosing for time-dependent
antibiotics.
 CAPD vs APD

31. Conclusion
 Knowledge gap related to drug dosing in renal disease and
hemodialysis
 In CKD, renal function estimates using available equations may be
inaccurate
 Ideally, therapeutic drug monitoring help guide dosing of antibiotics
but few antibiotics are available
 Clinicians need to carefully evaluate response to therapy
and monitor for dose-related toxicity
 Final decision needs to be informed by an understanding of drug
pharmacokinetics and clearance principles, therapeutic drug
monitoring, and sound clinical judgment

32. Thank You