Therapeutic Drug Monitoring of Beta-Lactam Antibiotics: Does it Lead to “Beta” Outcomes?

Jessica F. Morales, PharmD PGY2 Infectious Diseases Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas Health Science Center San Antonio

October 30, 2015

Learning Objectives:

1. Discuss the necessity of developing new strategies for the treatment of bacterial infections

2. Specify the criteria identifying drugs for which therapeutic drug monitoring would be most useful

3. Describe how pathophysiological changes can alter pharmacokinetic and pharmacodynamic properties

4. Based on a review of the literature, identify patients that may derive the most benefit from therapeutic

drug monitoring of beta-lactams

2 | M o r a l e s

I. Background

A. Infection-related morbidity and mortality1,2

i. Infections can affect anyone – the young and old, the healthy and the chronically ill ii. Infectious diseases account for 43% of the global burden of disease iii. Approximately 2 million Americans develop an infection and 90,000 die each year iv. Approximately 50% of intensive care unit patients have infection, doubling mortality risk

B. Antibiotic resistance2-5

i. Antibiotic-resistant bacteria present a serious threat to public health and the economy ii. Approximately 2 million illnesses and 23,000 deaths in the United States have been

attributed to antibiotic-resistant bacteria

Figure 1. Increasing Prevalence of Resistant Klebsiella pneumoniae in All Patient Settings

4,6

C. Bad bugs, no drugs7

i. Pharmaceutical pipeline for antibiotics has become less productive over time ii. Antibiotics not as profitable as medications for chronic medical conditions

Figure 2. Number of New Systemic Antibiotics Approved in the United States

8

*Adapted from Spellberg, et al., Clinical Infectious Diseases, May 2004

0

2

4

6

8

10

12

14

16

18

1983-19871988-19921993-19971998-20022003-20072008-20122013-2015

New

An

tib

ioti

c A

gen

ts (

No

.)

Time Period

3 | M o r a l e s

i. Loss of effective antibiotics and increase in infection-related morbidity and mortality ii. Centers for Disease Control and Infection proposed following measures to help fight

antibiotic resistance:2 a. Prevention of infection and spread of antibiotic resistance b. Implementation of surveillance for resistant bacteria c. Development of strategies to optimize activity of currently available antibiotics d. Facilitation of the development of novel agents and new diagnostic tests

iii. Therapeutic drug monitoring (TDM) proposed as a strategy to optimize pharmacokinetics (PK) and pharmacodynamics (PD) of existing antibiotics

a. Limitations of standard dosing regimens9 1. Studied in young, healthy volunteers 2. Many established prior to extensive knowledge of PK/PD of antibiotics

b. Patient populations in which the PK of drugs has not been fully studied10 1. Critically ill 2. Obese 3. Elderly 4. Cystic fibrosis 5. Intravenous drug users

II. Therapeutic Drug Monitoring

A. Proposed goals of TDM11

Figure 3. Proposed Goals of TDM

B. Criteria for TDM11 i. Lack of easily measured clinical parameter of efficacy

a. No clinical parameter available to gauge drug efficacy b. Example: blood pressure as a measure of vasopressor efficacy

ii. Variable pharmacokinetics a. Fixed dose results in different concentration-time curves between/within patients b. Due to large between-subject differences and/or non-linear PK c. Unpredictable relationship between dose and clinical response

iii. Narrow therapeutic index a. Increased risk of toxicity or failure with concentrations outside narrow range b. Drug toxicity may lead to hospitalization, irreversible organ damage, or death

iv. Correlation between serum concentration and response a. Response can be efficacy, toxicity, or both

v. Availability of commercial assay

TDM

Increased efficacy

Decreased toxicity

Decreased antibiotic

resistance

4 | M o r a l e s

III. Beta-Lactam Antibiotics

A. Background

i. Most commonly used class of antibiotics ii. Includes penicillins, cephalosporins, monobactams, and carbapenems

B. Pharmacokinetics2,13

i. Concentration-time profile in serum for a specific drug dose and its absorption, distribution, and elimination

ii. Lower volume of distribution iii. Eliminated primarily by glomerular filtration and hepatobiliary system iv. Variable protein binding v. Only free (non-protein bound) concentration pharmacologically active; serum

concentration may not equal concentration at site of infection vi. Lowest concentration of an antibiotic that inhibits the visible growth of a microorganism

is the minimum inhibitory concentration (MIC) vii. Maximal bactericidal activity of beta-lactams occurs at concentrations 4-5xMIC14

Figure 4. Bactericidal Activity of Ticarcillin14

Figure 5. PK/PD Properties of Beta-Lactams

C. Pharmacodynamics

i. Relationship between drug concentration or exposure and effect ii. Higher the MIC, the less effect a fixed drug exposure will have

D. PK/PD

i. Relationship between drug exposure, organism susceptibility, and host response ii. Time above the MIC (T>MIC) most closely correlates with efficacy of beta-lactams iii. Goal of beta-lactam dosing regimens is to optimize duration of drug exposure iv. Fraction of time (%T>MIC) correlating with efficacy differs between beta lactams14-21

Table 1. Target %T>MIC Parameters for Different Beta-Lactam Agents

14,22

%T>MIC

Bacteriostatic Bacteriocidal

Penicillins 30% 50% Cephalosporins 35-40% 60-70% Carbapenems 20% 40%

0

1

2

3

4

5

6

7

8

9

10

0 2 4 6 8

Lo

g10

CF

U m

L-1

Time (h)

Control

1/4 MIC

1 MIC

4 MIC

16 MIC

24 MIC

P. aeruginosa

5 | M o r a l e s

Figure 6. Relationship Between Beta-Lactam %T>MIC and, (A) Mortality in a Streptococcus pneumoniae Murine

Infection Model, and (B) Bacteriological Eradication in Acute Otitis Media and Sinusitis14,16,17,23

i. Some retrospective studies have suggested larger drug exposures are required20,21,24 a. Microbiological eradication 89% with 100%T>MIC vs. 0% if below 100%T>MIC b. Clinical cure and microbiological eradication lower if below 100%T>MIC

(33% and 44% vs. 82% and 97%, p < .05)

IV. Patient Populations and Pathophysiological Changes

A. Factors associated with antibiotic concentrations below MIC25,26

i. Younger age ii. Increased creatinine clearance (CrCL) iii. High organism MIC

Figure 7. Pathophysiological Changes and PK Effects in Septic Patients9

↑Clearance ↑Vd ↓Clearance

Sepsis

↑Cardiac output

Leaky capillaries

and/or altered protein binding

End organ dysfunction

Low plasma concentrations

High plasma concentrations

A B

6 | M o r a l e s

B. Critically ill patients27 i. Variable elimination half-life (t1/2) ii. Variable clearance (CL) iii. Increased volume of distribution (Vd) iv. Translesional diffusion of antibiotic in burn patients28,29

Figure 8. Development of Capillary Leak Syndrome9

C. Capillary leak syndrome

i. Bacterial endotoxins stimulate production of endogenous mediators that increase capillary permeability

ii. Fluid shifts from intravascular space to interstitial space result in increased Vd of drugs

D. Altered protein binding30,31 i. Albumin responsible for binding of most drugs ii. Hypoalbuminemia occurs in ~50% of critically ill patients

a. Higher levels of unbound drug means more is available for distribution, glomerular filtration, and hepatic clearance

b. Highly protein-bound antibiotics may be most affected32 1. Two-fold increases in Vd and CL33 2. Associated with failure to attain PD targets30

Table 2. Variations in Vd and CL of Highly Albumin-bound Antibiotics in Critically Ill Patients30

Antibiotic Study Group No. APACHE II

Score CrCL

(mL/min) Albumin

(g/L) CrCL (mL/min) Vd (L/kg)

Obs %Δ Obs %Δ

TRIAX Healthy adults 6 NA Within reference values 13 ± 2.6 0 0.12 ± 0.01 0 Critically ill patients

18 NA 112 ± 29 NA 18 ± 5.5 39 0.17 ± 4 42

Critically ill patients with severe sepsis

11 21.7 ± 3.8 98 ± 50 22.2 ± 6.1 25.8 99 0.32 ± 0.05 167

ERTA Healthy adults 10 NA Within reference values 20.2 ± 0.16 0 0.07 ± 0.003 0 Critically ill patients with VAP

17 23.1 ± 4.2 94 ± 52 15.9 ±5.7 43.2 ± 23.7 114 0.21 ± 0.05 200

Critically ill patients with severe sepsis

8 8.9 ± 5.1 89 ± 36 26.9 ± 9 200.5 ± 306.9

893 0.98 ± 1.42 1300

TRIAX, ceftriaxone; ERTA, ertapenem; CrCL, creatinine clearance; Vd, volume of distribution

Endotoxins

Vascular endothelium

Fluid shifts (intravascular interstitial)

Maldistribution of blood flow

Endothelial damage

Increased capillary

permeability

7 | M o r a l e s

Figure 9. Development of Augmented Renal Clearance

E. Augmented renal clearance (ARC)10,25,34

i. Defined as Cockcroft-gault estimated CrCL ≥ 130 mL/min ii. Renal perfusion often increased secondary to intravenous fluid administration and

vasopressor initiation iii. Development of ARC rarely considered in critically ill patients

a. Sensitivity of serum creatinine for identifying ARC is limited, making appropriate dosing in critically ill patients with seemingly normal renal function difficult

b. At highest risk of developing ARC: 1. Younger age 2. Polytrauma patients35 3. Patients with traumatic brain injury36 4. Critically ill postoperative patients37

Table 3. PK Parameters PD Target Achievement in Critically Ill Patients Without Renal Dysfunction

38

Antibiotic No. Dose Vd

(L/kg) CL

(mL/min) t1/2 (h)

MIC target

PD target achieved

PIP 27 4g q6h 0.38 141 2.58 64 33%T>4xMIC

TRIAX 54 2g q24h 0.28 14.7 9.6 8 16%T>MIC

FEP

12 2g q12h 0.34 123 3.2 4 77%T>MIC

19 2g q8h 0.36 88 3.37 32 34%T>4xMIC

13 2g q12h 0.32 134 2.5 - -

7 2g q12h 0.47 125 3.42 7 80%T>MIC90

5 100%T>MIC90

MERO

8 2g q8h 0.38 157 2.4 - 100%T>MIC

7 2g LD + 3g CI/day 0.37 128 - - 100%T>MIC

16 1g q8h 0.43 131 2.05 8 57%T>4xMIC

10 1g q8h 0.39 191 2.13 0.25-1 100%T>MIC

PIP, piperacillin-tazobactam; TRIAX, ceftriaxone; FEP, cefepime; MERO, meropenem; CI, continuous infusion; LD, loading dose; Vd, volume of distribution; CL, clearance; t1/2, half-life; Cmax, peak serum concentration; AUC, area under the curve; MIC, minimum inhibitory concentration; PD, pharmacodynamic

Figure 10. Effect of Organism MIC on Achievement of PK/PD Parameters with Beta-Lactams

IV fluids

vasopressors

↑Cardiac output

↑Renal perfusion

↑Glomerular filtration

Augmented renal

clearance

8 | M o r a l e s

F. Less susceptible pathogens with high MICs i. Insufficient dosing is of particular concern for pathogens with a high MIC ii. Even with increased doses, attainment of PD targets is unreliable because of time-

dependent activity of beta-lactams

V. Alternative strategies

A. Dosing based on estimation of creatinine clearance26

i. Suboptimal in patients with augmented renal function25 ii. Not always reliable in estimating true renal function, particularly in patients with rapidly

fluctuating serum creatinine levels, low muscle mass, or who are critically ill

B. Prolonged infusions26 i. Theoretically more likely to attain target PK/PD parameters39 ii. Even prolonged infusions may fail to consistently achieve target exposures

a. DALI study – percentage not achieving 50%T>MIC40 1. Extended or continuous infusions: 7% 2. Intermittent dosing: 20%

b. Double blind, randomized, controlled study41 1. Trough antibiotic concentration samples drawn at steady state 2. Concentration/ MIC ratios not significantly different between continuous

infusion and intermittent bolus until 3rd sample iii. To date, high-quality, randomized controlled trials to support this practice are lacking

a. Small sample sizes b. Variability in dosing strategies c. Patients with low severity of illness and/or highly susceptible pathogens

iv. Studies suggestive of greatest benefit in: a. Critically ill patients with higher severity of illness42 b. Patients with Pseudomonas aeruginosa infections42,43 c. Infections with pathogens with higher MICs44

Table 4. Studies in Meta-Analysis of Prolonged Versus Intermittent Administration of Beta-Lactams

45

Study Subgroup

Mortality Clinical success

No. of studies

No. of patients

Summary RR (95% CI)

I2

No. of studies

No. of patients

Summary RR (95% CI)

I2

All Studies 19 1620 0.66 (0.53-0.83) 0 19 1546 1.12 (1.03-1.21) 63 RCTs 10 779 0.83 (0.57-1.21) 0 14 1125 1.05 (0.99-1.12) 0 Non-RCTs 9 841 0.57 (0.43-0.76) 0 5 421 1.34 (1.02-1.76) 90 Penicillins 8 974 0.60 (0.45-0.82) 0 6 491 1.08 (0.94-1.25) 60 Cephalosporins 5 191 0.92 (0.52-1.63) 33 9 662 1.11 (0.98-1.25) 65 Carbapenems 4 274 0.74 (0.42-1.28) 28 3 333 1.16 (0.93-1.46) 83 Equivalent daily dose

10 813 0.82 (0.56-1.20) 0 10 934 1.22 (1.05-1.43) 75

APACHE II Score ≥15

10 861 0.63 (0.48-0.81) 9 8 663 1.26 (1.06-1.50) 83

CI, confidence interval; RCT, randomized controlled trial; APACHE, Acute Physiology and Chronic Health Evaluation

9 | M o r a l e s

VI. Therapeutic Drug Monitoring of Beta-Lactams

A. Lack of easily measurable clinical parameter for resolution of infection

i. Clearly defined clinical parameter guiding dosage adjustments not available ii. The presence or absence of clinical response takes days to weeks to appear iii. Development of toxicities is often delayed until antibiotic doses accumulate

B. Variable pharmacokinetics9,10,25,30,31

i. Pathophysiological changes are present in critically ill and burn patient populations a. Increased volume of distribution b. Prolonged elimination half-life c. Decreased, unchanged, or augmented renal clearance d. Enhanced elimination due to hypoalbuminemia

ii. True PK variability between and within patients

C. Narrow therapeutic index i. Historically, beta-lactams have had a lower perceived risk for toxicity ii. Beta-lactams can lead to dose-dependent adverse effects46-48

D. Correlation between levels and response

i. Antimicrobial resistance49-51 a. Drug exposure preventing amplification of mutant subpopulations in vitro

1. P. aeruginosa and varying meropenem doses49 b. Concentrations below the MIC for more than half the dosing interval

(50%T>MIC)51 ii. Toxicity

a. Hepatic or renal impairment may be associated with toxic drug concentrations52 b. Neurotoxicity has been reported46-48

1. Encephalopathy, disorientation, hallucinations, agitation, reversible coma 2. Myoclonus, non-convulsive status epilepticus, ataxia, asterixis

Table 5. Characteristics of cefepime-induced toxicity in a case series

46

Age (years)

CrCL (mL/min)

Duration of cefepime at time of symptoms

Dose Cefepime levels

(mg/L)

82 27 5 days 2 g daily x 3d, then 1 g daily 48.1 (8 h) 71 15 3 weeks 4 g bid 160 (20 h) 75 9 4 days 1 g q48h (after dialysis) 73 (48 h) 84 <20 6 days 2 g daily 74 (12 h) 49 12 3 days 2 g tid x 3d, then 2 g bid 37.6 (after HD) 82 20 2 days 1 g daily 67.2 (24 h) 77 15 54 hours 3 g daily 41 (31 h) 81 Anuric NA 2 g twice daily 224 (12 h) 61 14 NA 500 mg daily, then 2 g daily 60 (24 h)

iii. Efficacy

a. In vitro and animal data demonstrate %T>MIC predicts efficacy14,16,17 b. Observational data suggest a relationship between achievement of these target

exposures and clinical outcomes40,53 c. TDM may be of most benefit in critically ill patients, burn patients, patients with P.

aeruginosa infections and/or pathogens with high MICs

E. Availability of commercial assay to measure levels i. No readily available assay for beta-lactam concentrations ii. High-performance liquid chromatography (HPLC) assay is used in research setting iii. Approximately 1% and 2% of sites surveyed in one study performed TDM for piperacillin-

tazobactam and meropenem, respectively54

10 | M o r a l e s

VII. Literature review

A. Roberts JA, Ulldemolins M, Roberts MS, et al. Int J Antimicrob Agents. 2010;36:332-9. B. Aubert G, Carricajo A, Coudrot M, et al. Ther Drug Monit. 2010;32:517-9.

C. Patel BM, Paratz J, See NC, et al. Ther Drug Monit. 2012;34:160-4. D. Roberts JA, Paul SK, Akova M, et al. Clin Infect Dis. 2014;58:1072-83.

Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Roberts JA, Ulldemolins M, Roberts MS, et al. Int J Antimicrob Agents 2010;36:332-9.

Objective To evaluate the practicality and utility of beta-lactam TDM in critically ill patients

Design Prospective 11-month study at a 30-bed tertiary referral critical care unit

Population 236 patients prescribed beta-lactam antibiotic therapy

Endpoints Treatment outcome

Positive: completion of treatment course without change or addition of antibiotics within 48 hours, or de-escalation of therapy

Negative: patient death, escalation of therapy, or cessation of antibiotic secondary to an adverse drug reaction

Methods Drug serum concentrations determined twice weekly o Intermittent dosing: trough drawn after at least 4 doses o Continuous infusions: level drawn after at least 4 to 5 half-lives

Unbound concentrations calculated based on percent protein binding

PK/PD target of 100%fT>4-5xMIC o Dose/frequency increased if concentration <4-5xMIC o Dose/frequency decreased if concentration >10xMIC

Eight-hour urinary CrCL calculated for 47 patients at high risk of having augmented renal clearance for correlation with dose adjustments

Baseline Characteristics

Demographics: 59% male, mean age 53.5 ± 18.3 years, mean weight: 85.4 ± 27.7 kg

Mean SCr: 1.26 ± 1.03 mg/dL o Eight-hour urinary CrCL >150 mL/min in 21 of 47 patients (44.7%)

Presence of surgical drains: 25.4%

Results Overall positive treatment outcomes: 206/ 236 (87.3%)

Overall treatment failures: 30/236 (12.7%) o 14 deaths o 15 cases required escalation of antibiotic therapy

Mean duration of therapy: 8.5 ± 7.0 days Need for dose adjustment after first TDM level by antibiotic indication

Indication No. Maintained

No. (%) Increased No. (%)

Decreased No. (%)

Bacteremia 18 2 (11) 13 (72) 3 (17) HAP 89 14 (16) 53 (60) 22 (25) CAP 47 21 (45) 15 (32) 11 (23) Meningitis 17 7 (41) 8 (47) 2 (12) Wound 10 1 (10) 9 (90) 0 (0) SSTI 16 5 (31) 8 (50) 3 (19) Abdominal 28 7 (25) 10 (36) 11 (39) Neutropenic 4 3 (75) 1 (25) 0 (0) Urosepsis 7 1 (14) 2 (29) 4 (57) Total 236 61 (25.8) 119 (50.4) 56 (23.7)

HAP, hospital-acquired pneumonia; CAP; community-acquired pneumonia; SSTI, skin-and-soft-tissue infection

11 | M o r a l e s

Need for dose adjustment after first TDM level by antibiotic

Antibiotic No. Initiation Dose Same

No. (%) Increased No. (%)

Decreased No. (%)

PIP 116 4.5 g q6h 27 (23) 57 (49) 32 (28) Ampicillin 4 2 g q6h 0 (0) 1 (25) 3 (75) Meropenem 51 1 g q8h 8 (16) 29 (57) 14 (27) PCN G 9 2.4 g q4h 3 (33) 3 (33) 3 (33) Cefazolin 6 1 g q8h 0 (0) 6 (100) 0 (0) Ceftriaxone 33 1 g q12h 22 (67) 7 (21) 4 (12) Total 236 - 61 (25.8) 119 (50.4) 56 (23.7)

PIP, piperacillin-tazobactam; PCN, penicillin

Mortality rate based on achievement of target at initial TDM point Subtherapeutic Therapeutic Supratherapeutic

Mortality 3.3% 8.2% 9.3%

Only ↑ APACHE II scores predictive of negative treatment outcome

Only ↑ APACHE II scores and ↑ serum creatinine predictive of mortality

At first TDM: o Surgical drains: 61.5% required dose increase, 17.3% required dose decrease o Renal dysfunction: 80% with concentrations >10xMIC

Documented ADRs: 1 of 8 patients had antibiotic concentration likely to be associated with toxicity (PIP 137 mg/L; cholestasis)

Strengths Inclusion of patients with CVVHD, organ dysfunction, all antibiotic indications

Many beta-lactam antibiotics included

Parameters for dose adjustment provided

Weaknesses Low incidence of multidrug resistant organisms at study site

Aggressive PK/PD target of 100%T>4-5xMIC

Unbound concentrations calculated rather than measured

Twice-weekly frequency of TDM; only 21.6% of patients had second TDM

Take Home Points

74% of patients required dosage adjustments at initial TDM to achieve PK/PD target

100% fT>4-5xMIC is aggressive and difficult to achieve with standard doses

CrCL measurements were not always predictive of need for dose adjustment

Antibiotic concentrations were not found to be predictive of mortality; however, effect may have been blunted by the use of an aggressive PD target and a lower baseline APACHE II score in patients with subtherapeutic concentrations

Increased empiric doses for patients with surgical drains and/or augmented renal clearance could be considered

12 | M o r a l e s

Prospective determination of serum ceftazidime concentrations in intensive care units. Aubert G, Carricajo A, Coudrot M, et al. Ther Drug Monit. 2010;32:517-9.

Objective To assess the value of TDM for ceftazidime in critically ill patients

Design Prospective multicenter study from 2005 to 2008

Population 92 critically ill non-dialyzed patients receiving ceftazidime as a continuous infusion

Endpoints Achievement of ceftazidime concentration 40±10 mg/L and concentration/MIC ratio ≥5

Methods Initial 2 g loading dose followed by continuous infusion of 2 to 6 g/day

Serum assays obtained at 36-48 hours using agar plate diffusion method

Target concentration ≥40 ± 10 mg/L or >5xMIC when pathogen isolated

Baseline Characteristics

Demographics: 70% male, mean age 66 yo (20-94), mean weight: 73 kg (33-122)

Mean CrCL: 93.5 mL/min (14-258 mL/min) o CrCL >30 mL/min: 71/92 (77.2%) o CrCL ≤30 mL/min: 21/92 (22.8%)

Antibiotic indication: o Respiratory tract infections 52/92 (56.5%) o Urinary tract infections 10/92 (10.9%) o Septicemia 8/92 (8.7%) o Cutaneous infections 8/92 (8.7%) o Abdominal infections 5/92 (5.4%) o Other infection 9/92 (9.8%)

Documented infection: 69/92 (66.3%)

MICs obtained: 51/92 (55%) o P. aeruginosa 41/51 (80.4%) o Enterobacteriaceae 8/51 (15.7%) o Stenotrophomonas maltophilia 1/51 (2%) o Chryseomonas1/51 (2%)

Results Mean CAZ concentration: 46.9 mg/L

No local or systemic ADRs reported

Concentration-to-MIC Ratios for Subset of Patients with Organism MICs (N= 51) Concentration/MIC Ratio

< 5 ≥5

8/51 (15.7%)a 43/51 (84.3%) a 6/8 patients had MICs ≥8, antibiotic was changed; 2/8 patients required dose increases

Distribution of ceftazidime concentrations in patients at 36-48 hours

0

5

10

15

20

25

30

< 10 > 80 10-20 20-30 30-40 40-50 50-60 60-70 70-80

Nu

mb

er

of

Pati

en

ts

Ceftazidime concentrations (mg/L)

13 | M o r a l e s

Demographics of patients stratified by ceftazidime concentration Concentration

(mg/L) No. (%)

Age (years)

Weight (kg)

Dose (g/24h)

CrCL (mL/min)

<30 34 (37) 59.5 68 4 103 30-50 33 (36) 70 70 6 74 >50 25 (27) 76 81 4 51

Median values shown Strengths Broad range of infectious diseases treated with ceftazidime included

Descriptive data on ceftazidime concentration ranges achieved provided

Target concentration 40 mg/L extrapolated from ceftazidime susceptibility breakpoint of 8 mg/L and maximal cephalosporin activity reported at concentrations ≥5xMIC

Weaknesses Hemodialysis patients excluded

Findings limited to ceftazidime and patients with gram-negative infections

Use of agar plate diffusion method as serum assay

No protocol for dosage adjustment and no information provided on dose adjustment

Primary focus on target attainment, no objective clinical outcomes data

Take Home Points

Significant degree of variability in ceftazidime concentrations across patients

Good proportion of patients either at risk for subtherapeutic concentrations despite normal renal function or with high concentrations at risk for inducing toxicity

No ADRs were noted to occur despite high levels of ceftazidime, however toxicity is more likely to occur with prolonged high concentrations

TDM is likely necessary to achieve ceftazidime concentrations within a target range, but correlation between target attainment and clinical outcomes was not studied

Therapeutic drug monitoring of beta-lactam antibiotics in burns patients – a one-year prospective study. Patel BM, Paratz J, See NC, et al. Ther Drug Monit. 2012;34:160-4.

Objective To evaluate the utility of a beta-lactam TDM program in a cohort of burn injury patients

Design Prospective, 12-month single-center study at a tertiary referral burns center

Population 50 patients treated with beta-lactam antibiotics on admission to the burns unit

Endpoints Primary: rate of achievement of 100%T>MIC

Secondary: rate of achievement of 100%T≥4xMIC

Treatment outcomes: o Positive: completion of treatment course without change/addition of antibiotics o Negative: any change in antibiotic therapy or development of resistant infection

Methods Flucloxacillin, dicloxacillin, penicillin G, piperacillin-tazobactam, ampicillin, meropenem, ceftriaxone

Drug concentrations determined by HPLC

Trough levels drawn at every dosing interval after steady state (≥4 doses)

Unbound concentrations calculated based on percent protein binding

Administration frequency rather than dose was adjusted if necessary, up to administration of an extended infusion over 50% of dosing interval

Baseline Characteristics

Demographics: 82% male, mean age: 49 ± 16 yo

Mean % total body surface area burn: 17 ± 13%

Mean serum creatinine concentration: 97 ± 0.23 mg/dL

Antibiotic indication: o Skin-and-soft-tissue infection (SSTI): 44/50 (88%) o Urinary tract infection (UTI): 1/50 (2%)

Results Achieved a positive clinical outcome: 100%

Duration of treatment: o Patients who achieved trough concentration >MIC: 4.2 ± 1.1 days o Patients who did not achieve trough concentration >MIC: 5.3±2.3 days (p=0.03)

14 | M o r a l e s

TDM results and MICs by beta-lactam antibiotic prescribed

Antibiotic Initial Dose

No. Trough <MIC

100% T>MIC

100% T>4xMIC

MIC (mg/L)

Flucloxacillin 2g q6h 24 (48%) 12 (50%) 8 (34%) 4 (16%) 2 Dicloxacillin 2 g q6h 8 (16% 6 (75%) 0 (0%) 2 (25%) 2 PCN G 2 g q6h 8 (12%) 5 (63%) 2 (25%) 1 (12%) 0.25 PIP 4.5 g q6h 6 (16%) 4 (66%) 0 (0%) 2 (34%) 2 Ampicillin 2 g q6h 2 (4%) 1 (50%) 1 (50%) 0 (0%) 0.5 Meropenem 1 g q8h 1 (2%) 1 (100%) 0 (0%) 0 (0%) 2 Ceftriaxone 1 g q12h 1 (2%) 1 (100%) 0 (0%) 0 (0%) 0.5 Total 50 (100%) 30 (60%) 11 (22%) 9 (18%)

PCN, penicillin; PIP, piperacillin-tazobactam

Variation in PIP concentrations in relation to MICs

Variation in duration of therapy between patients with low and therapeutic concentrations

Strengths Many beta-lactam antibiotics included

Frequency of TDM performed at every dosing interval

Weaknesses Small sample size

Use of aggressive PD targets of 100%T>MIC and 100%T>4xMIC

Findings limited to burns patients predominantly with SSTIs

Unbound concentrations calculated based on antibiotics’ percentage protein binding determine in non-burns populations

Distribution of concentrations stratified by renal function not provided

Take Home Points

Significant variability in antibiotic concentrations exists in burn patients

Regardless of initial low or therapeutic concentrations of antibiotics, 100% of patients achieved a positive clinical outcome overall; however, all patients initially not at target did achieve 100%T>MIC after the one subsequent dose adjustment

Only 18% of patients overall achieved the higher target 100%T>4xMIC

Patients achieving the 100%T>MIC had shorter durations of therapy compared to those that didn’t

15 | M o r a l e s

DALI: Defining antibiotic levels in intensive care unit patients: Are current β-lactam antibiotic doses sufficient for critically ill patients? Roberts JA, Paul SK, Akova M, et al. Clin Infect Dis. 2014;58:1072-83.

Objective To determine whether standard beta-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal beta-lactam activity and correlate antibiotic concentrations to patient outcomes

Design Prospective, multinational, pharmacokinetic point-prevalence study

Population 361 critically ill evaluable patients in 68 ICUs across 10 countries

Endpoints Rate of achievement of target concentrations at 50%T>MIC and 100%T>MIC

Clinical outcome o Positive: completion of treatment course without change or addition of antibiotics o Negative: Any clinical outcome other than positive clinical outcome

Methods Concentrations determined at 50% and 100% of dosing interval by HPLC

When no pathogen isolated, highest MIC considered susceptible was used

De-escalation permitted but excluded from clinical outcome analysis

Baseline Characteristics

Demographics: 65% male, mean age 61 years (IQR, 48-73 years)

Median APACHE II score: 18 (IQR, 14-24)

Median SOFA score: 5 (IQR, 2-9)

Antibiotic indication: o 248/361 (68.7%) treatment of infection

Primarily lung infections (41%) and intra-abdominal infections (14%) 67% intermittent dosing and 33% extended or continuous infusion

o 113/361 (31.3%) prophylaxis against infection

Beta-lactam monotherapy: 67/361 (18.6%)

Results Treated for infection: 248/361 (68.7%) o Positive clinical outcome: 58.1% o Bacterial pathogen isolated: 72.9%

P. aeruginosa: 18%, median MIC 8 mg/L (IQR, 2-16) Escherichia coli: 16%, median MIC 4 mg/L (IQR, 1-16)

o Did not achieve 50%T>MIC: 16% Extended or continuous infusions: 7% Intermittent dosing: 20% 32% less likely to have positive clinical outcome, 95% CI, 0.52-0.91

Dosing and achievement of PK/PD target by beta-lactam antibiotic %, unless otherwise specified

Characteristic

AMOX N=71

AMP N=18

FAZ N=14

FEP N=14

TRIAX N= 33

DOR N=13

PIP N= 109

MER N=89

Total N=361

24h dose, g 6 12 3 6 2 1.75 12 3 - 50%T>MIC 52.1 55.6 100 78.6 97 100 80.6 95 78.9 50%T>4xMIC 16.9 27.8 50 50 93.9 69.2 48.9 68.8 48.9 100%T>MIC 18.3 33.3 78.6 78.6 93.9 76.9 67 69.7 60.4 100%T>4xMIC 11.3 22.2 14.3 71.4 87.9 30.8 30.3 41.6 35

AMOX, amoxicillin-clavulanate; AMP, ampicillin; FAZ, cefazolin; FEP, cefepime; TRIAX, ceftriaxone; PIP, piperacillin-tazobactam; MER, meropenem

Multivariate regression results of clinical outcome (N= 220)

50% T>MIC 100%T>MIC

Parameters OR 95% P OR 95% P

APACHE II Score 0.94 0.92-0.96 <.001 0.94 0.92-0.96 0.97 SOFA Score 0.97 0.94-1.00 0.53 0.97 0.94-1.01 0.13 50%T>MIC 1.03 1.01-1.04 0.001 - - - 100%T>MIC - - - 1.02 1.01-1.05 0.04

Patients receiving renal replacement therapy excluded from analysis

30-day mortality rate: 21.9%

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Total infection-related mortality rate: 8.9%

Higher PK/PD ratios associated with a higher likelihood of a positive clinical outcome o 50%T>MIC: OR 1.02; 95% CI, 1.01-1.04 o 100%T>MIC: OR 1.56; 95% CI, 1.15-2.13

The probability of achieving a positive clinical outcome in patients with bloodstream infections (n= 24) was significantly correlated with increasing concentrations at 50%T>MIC (OR 1.13; 95% CI, 1.07-1.19)

Patients with a pathogen with an MIC ≤ 2 mg/L were more likely to achieve a positive clinical outcome (OR 2.27; 95% CI, 1.79-2.87)

Strengths Large sample size

Severity of illness provided via APACHE II scores and SOFA scores

Correlated attainment of PK/PD target parameters with clinical outcomes

Measured unbound plasma concentration of highly-protein bound antibiotics

Weaknesses Point-prevalence study, no dose adjustment based on levels

PK/PD ratios based on assumptions of worst-case scenario MICs in majority (66%) of patients with an isolated pathogen; only 34% of patients with pathogen MIC

Take Home Points

Achievement of PK/PD targets for beta-lactams is inconsistent with standard doses

The use of prolonged infusions did not guarantee achievement of PK/PD parameters; 7% of patients treated for infection did not achieve concentrations above the MIC

Higher PK/PD indices of 50%T>MIC and 100%T>MIC (but not ≥4xMIC) were significantly associated with positive clinical outcome

Patients with bloodstream infections demonstrated an increased probability of achieving a positive clinical outcome with increasing 50%T>MIC ratios

Patients with pathogens with MIC ≤ 2 mg/L were more likely to achieve a positive clinical outcome

VIII. Summary

A. Background

i. Antibiotic-resistant bacteria present an ongoing threat and production of novel antibiotics may not be enough to mitigate infection-related morbidity and mortality

ii. Ensuring appropriate dosing of beta-lactams that is targeted to PK/PD parameters associated with efficacy could optimize their antibacterial activity

B. PK/PD variability

i. Pathophysiological changes leading to alterations in PK/PD parameters have been demonstrated in various patient populations, particularly critically ill patients

ii. Standard dosing regimens and even prolonged infusions of beta-lactams may fail to consistently achieve target PK/PD parameters in these patients

iii. Other patient populations with data demonstrating altered PK include obese, elderly, cystic fibrosis, intravenous drug users, febrile neutropenia patients56-59

C. Therapeutic Drug Monitoring

i. TDM is an attractive strategy to help ensure attainment of target PK/PD parameters ii. The impact of TDM on clinical outcomes remains to be definitively established

D. Clinical data

i. Current studies relatively small and limited by heterogeneous patient populations and varying target PK/PD parameters

ii. Studies suggestive of benefit in critically ill patients, bloodstream infections, P. aeruginosa infections, and infections caused by pathogens with high MICs

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E. Obstacles to widespread implementation of beta-lactam TDM i. Absence of a prospective randomized, controlled trial demonstrating benefit ii. Chromatography-based assay used to measure beta-lactam concentrations

a. Turnaround time (6-24 h) relatively longer than for other techniques b. Costs associated with equipment, skilled operators, 24/7 availability

iii. Demonstration of changes such as reduced duration of therapy or patient length of stay is needed to mitigate or negate cost burden associated with TDM

iv. Establishment of a collaborative approach between clinicians and the laboratory and development of a protocol for sampling and dose modification is strongly recommended

IX. Conclusion and Recommendations

A. Conclusion

i. Data for TDM of beta-lactams is still very preliminary ii. Current studies are small and have many limitations iii. Evidence to support beta-lactam TDM thus far remains circumstantial, but logical

a. Increased attainment of target PK/PD parameters that are associated with beta-lactam efficacy lead to increased likelihood of positive outcome40

b. TDM demonstrated to increase likelihood of attaining target parameters52,53,55,61 c. Therefore, TDM likely increases the likelihood of achieving a positive outcome,

but a large randomized controlled trial is needed to test this hypothesis

B. Benefits of beta-lactam TDM i. Populations with highly varied and unpredictable pharmacokinetics

a. Critically ill patients b. Burn patients

ii. With risk factors for augmented renal clearance a. Younger age b. Postoperative patients c. Septic patients d. Major trauma patients

iii. Patients with severe renal dysfunction iv. Infections due to multidrug-resistant or high-MIC pathogens v. Infections caused by P. aeruginosa

C. Recommendations

i. Pending results of a large randomized controlled trial, it is reasonable to limit TDM to situations in which it would be extremely useful to know concentrations of beta-lactams

a. Serious infections with multidrug-resistant or high-MIC pathogens b. Patients at high risk of morbidity/mortality not improving on antibiotic regimens

considered to be appropriately dosed c. Patients suspected to be suffering from dose-related beta-lactam toxicity

(e.g. neurotoxicity)

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Appendix

Daily serum piperacillin monitoring is advisable in critically ill patients. Blondiaux N, Wallet F, Favory R, et al. Int J Antimicrob Agents 2010;35:500-3.

Objective To evaluate the benefit of piperacillin TDM in critically ill patients

Design Prospective, observational 11-month study at a single intensive care unit

Population 24 critically ill patients with evidence of bacterial sepsis

Endpoints Rate of achievement of serum piperacillin concentrations >4xMIC

Incidence of convulsions, changes in WBC, changes in CrCL, cutaneous intolerance

Methods Initial 66 mg/kg IV bolus followed by continuous infusion (CI) at 200 mg/kg/24 h

Serum concentrations drawn 1.5 hours post-bolus dose, then daily at steady state

Target concentration >4xMIC to ≤150 mg/L o Dose increased when ≤4xMIC o Dose decreased when >150 mg/L

Baseline Characteristics

Demographics: 92% male, mean age 62.5 years, mean weight 78.8 kg

CrCL: ≤30 mL/min 7/22 (29%)

Antibiotic indications: HAP or cellulitis 22/24 (92%)

Documented infections: 9/24 (38%) o P. aeruginosa, Escherichia coli, Klebsiella pneumoniae, Acinetobacter

baumannii, MRSA, Enterobacter aerogenes o MIC mean (range): 7.6 ± 5.1 mg/L (4-16 mg/L)

Results Mean duration of therapy: 9 ± 5.2 days (3-20 days) Distribution of Piperacillin-Tazobactam Concentrations T≤4xMIC

No. (%) T>4xMIC and ≤150 mg/L

No. (%) >150 mg/L

No. (%)

At initial TDM point PIP Concentration 8/24 (33) 12/24 (50) 4/24 (17)

a

After 1st

dosage adjustment PIP Concentration 6/24 (25)

b-d 18/24 (75)

e 0/24 (0)

PIP, piperacillin-tazobactam a All with baseline severe renal dysfunction; dose subsequently reduced, no ADRs observed

b Mean %T>4xMIC before and after adjustment: 7.1± 5.9% vs 27.3 ± 8.6% (p= 0.03)

c Concentrations >4xMIC never achieved despite multiple dosage adjustments up to 18g PIP/day

d 5/6 (83%) with extensive cellulitis

e 50% before adjustment vs 75% after adjustment (p< 0.006)

Strengths Initial dosing and dosing adjustments of piperacillin-tazobactam provided

Good proportion of patients with severe renal dysfunction included (29%)

Daily frequency of TDM

Highest MIC considered susceptible used for patients without an isolated pathogen

Collected information on adverse drug reactions

Weaknesses Small sample size

Pathogen isolated in only 38% of patients, data on isolated pathogens not reported

Predominantly included patients with HAP and cellulitis

Patients’ severity of illness unclear; ‘bacterial sepsis’ undefined

Determination of ‘toxicity threshold’ of 150 mg/L based on ‘personal data’

Primary focus on target attainment, no objective clinical outcomes data

Take Home Points

Patients with renal dysfunction are at high risk of high serum piperacillin-tazobactam concentrations despite dosage adjustment for calculated CrCL

TDM implementation resulted in a significantly higher proportion of patients achieving the target PIP concentration >4xMIC (p= 0.03)