In the Battle against B-Lactamases, Will Avibactam be our Inhibitor in Shining Armor?

Maren Cowley, PharmD PGY1 Pharmacy Practice Resident

University Health System, San Antonio, TX Division of Pharmacotherapy, the University of Texas at Austin College of Pharmacy

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

October 7, 2016

Learning Objectives

1. Discuss resistance mechanism and epidemiology of carbapenem resistant Enterobacteriaceae (CRE)2. Describe available treatment options for serious CRE infections and the limitations of each regimen3. Review available ceftazidime/avibactam pharmacokinetic and pharmacodynamic data4. Develop an algorithm for ceftazidime/avibactam use in CRE bacteremia and pneumonia

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In the Battle against β-Lactamases, Will Avibactam be our Inhibitor in Shining Armor?

Maren Cowley

PharmD, PGY-1 Pharmacy Practice Resident October 3 and 7, 2016

University Hospital and McDermott Building

Learning Objectives: At the completion of this activity, the participant will be able to:

1. Discuss resistance mechanisms and epidemiology of carbapenem resistant Enterobacteriaceae (CRE)

2. Describe available treatment options for serious CRE infections and the limitations of each regimen

3. Review available ceftazidime/avibactam pharmacokinetic and pharmacodynamic data 4. Develop an algorithm for ceftazidime/avibactam use in CRE bacteremia and pneumonia

Assessment Questions: Carbapenem resistant infections are associated with higher T F rates of mortality than carbapenem susceptible infections Colistin has relatively few side effects and results in high T F success rates when used to treat CRE infections Ceftazidime/avibactam is approved for use in cIAI and cUTI T F ***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com *** Faculty (Speaker) Disclosure: Maren has indicated she has no relevant financial relationships to disclose relative to the content of her presentation

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Antimicrobial Resistance

1. Antimicrobial resistance burden1 a. Incidence and mortality due to resistant bacteria

i. Caused 2,049,442 infections in 2013 ii. Caused 23,000 deaths in 2013

iii. Many more die from complications b. Costs of treating resistant infections

i. Estimated $20 billion per year, or $35 billion including productivity loss ii. Resistant infections are more expensive to treat

1. Prolonged or pricier treatments 2. Extended hospital stay 3. Cost associated with disability and death

c. New antibiotic development must be aggressively pursued2 i. The Generating Antibiotic Incentives Now (GAIN) act passed in 2012

1. Encourages the development of novel antimicrobials a. Qualified Infectious Disease Product (QIDP)

2. Receive an additional 5 years market exclusivity 3. Receive fast track and priority review status

ii. GAIN has already increased the number of new antibiotic approvals iii. Most new antibiotics have been approved for Gram-positive bacterial infections

Figure 1. Number of new antibiotics approved by the Food and Drug Administration (FDA)3

2. Mechanisms of resistance4 a. β -lactams are susceptible to all four resistance mechanisms

i. Enzyme inactivation 1. β-lactamase

ii. Decreased permeability 1. OprD protein loss resulting in porin loss in Pseudomonas aeruginosa

iii. Efflux pumps 1. Multidrug efflux pumps in Pseudomonas aeruginosa

iv. Altered target site 1. Change in penicillin binding proteins (PBP)

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Figure 2. Resistance mechanisms4

http://www.reactgroup.org/toolbox/category/understand/the-rise-and-spread-of-antibiotic-resistance/resistance-mechanisms-in-bacteria/

3. β-Lactamases1,4 a. Penicillinase seen around the same time as penicillin’s first document use

i. Spread via plasmid to Staphylococcus aureus ii. Only 10% of S. aureus isolates are susceptible to penicillin today

b. Occurs more often in Gram-negative bacteria i. Efficiently concentrate in the periplasmic space

c. The Ambler classification i. Four classes separated by amino acid structure

Figure 3. Evolution of β-lactamase resistance1

TEM: temoneira; SHV: sulfhydryl variable; ESBL: extended spectrum β-lactamase; KPC: Klebsiella pneumoniae carbapenemase

1940s: Penicillin

1960s: Cephalosporins

1980s: 3rd generation cephalosporins

1980s: Carbapenems

1940s: Penicillinase

1960s: TEM and SHV

1980s: ESBL

1990s: KPC

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Table 1. Ambler classification of β-lactamases4

Classification Name Common Genes Substrates Class A Broad Spectrum

ESBL

Carbapenemases

PC1 SHV1 TEM1 SHV derived TEM derived CTX-M KPC

Penicillins, 1st generation cephalosporins Broad spectrum plus 3rd generation cephalosporins, aztreonam Extended spectrum plus cephamycins, carbapenems

Class B Metallo- β-Lactamases IMP VIM NDM

Extended spectrum plus cephamycins, and carbapenems

Class C Cephalosporinases AmpC Extended spectrum plus cephamycins

Class D Oxacillinases

OXA-48 Pseudomonas OXA- 11, 14, 15 Acinetobacter OXA

Penicillins, 1st generation cephalosporins Broad spectrum plus 3rd generation cephalosporins, aztreonam Extended spectrum plus Cephamycins, carbapenems

PC1: penicillinase; ESBL: Extended spectrum β-lactamase ; TEM: temoneira; SHV: Sulfhydryl variable; KPC: Klebsiella pneumoniae carbapenemase; CTX-M: Cefotaxime-β-lactamase Munich; IMP: Imipenemase metallo-β-lactamase; VIM: Verona integrin-encoded metallo-β-lactamase; NDM: New Delhi metallo- β-lactamase; OXA: Oxacillinase

Carbapenem Resistant Enterobacteriaceae

1. Enterobacteriaceae species4 a. Gram-negative, facultative anaerobes that ferment glucose, reduce nitrate to nitrite, and

produce catalase b. Inhabit lower gastrointestinal (GI) tract of humans and animals

i. Some live exclusively in the environment c. The most common species include

i. Escherichia coli ii. Klebsiella pneumoniae and oxytoca

iii. Enterobacter cloacae and aerogenes iv. Proteus mirabilis and vulgaris v. Citrobacter freundii and koseri

vi. Serratia marcescens vii. Morganella morganii

viii. Salmonella enterica ix. Shigella spp

2. Carbapenem resistant Enterobacteriaceae (CRE)1,5,6

a. A bacteria in the Enterobacteriaceae family that is resistant to at least one carbapenem i. Meropenem, doripenem, imipenem/cilastatin, ertapenem

ii. Clinical Laboratory Standards Institute (CLSI) breakpoints 1. Lowered to exclude all carbapenemase producers from susceptibility

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Table 2. CLSI breakpoints for carbapenems and Enterobacteriaceae Carbapenem Susceptible Intermediate Resistant

Meropenem <1 2 >4 Doripenem <1 2 >4 Imipenem <1 2 >4 Ertapenem <0.5 1 >2

3. Carbapenem resistance mechanisms7

a. First described as a hyperactive Class C AmpC β-lactamase plus a porin loss or efflux pump b. First Class A carbapenemase observed in a K. pneumoniae isolate in 1996

i. Klebsiella pneumoniae carbapenemase (KPC) ii. Most common carbapenemase

iii. Plasmid encoded iv. Observed in E. Coli, Citrobacter, and Enterobacter4

c. Class B metallo- β-lactamases that confer carbapenem resistance include VIM and NDM-1 d. Class D oxacillinases not typically observed in Enterobacteriaceae but

i. OXA-48 was observed in a K. pneumoniae isolate in 2004

4. Prevalence a. 2013 CDC Antibiotic Resistance Threats1

i. Estimated CRE causes 9,000 infections annually 1. 7,900 due to KPC

ii. The most common pathogen is K. pneumoniae with 11% of isolates reported as carbapenem resistant

iii. CRE infections result in 600 deaths annually b. National Healthcare Safety Network (NHSN), 2011-2014 report6

i. Nationally, 3.5% of Enterobacteriaceae are hospital acquired infections (HAI) resistant to carbapenems

Figure 4. Carbapenem resistance among K. pneumoniae from 1999-20108

1999-2001 2006-2010

Proportion of resistant isolates:

5. Outcomes9 a. Attributable mortality from CRE infections has been estimated as high as 72% b. Most common estimations at 50-60% mortality

i. Ranges based on differences in age, infection site, and underlying condition

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c. The mortality due to CRE is double the mortality of carbapenem susceptible Enterobacteriaceae i. Delay in appropriate antibiotics

ii. Decreased effectiveness of active agents iii. Increased toxicity of active agents iv. Improper or un-optimized dosing regimens

d. Carbapenem resistance has been independently associated with death

Treatment of Serious CRE Infections

1. Introduction a. Limited treatment options available to treat CRE infections b. Most available options result in significant toxicity or have limited efficacy c. Mortality rates of bloodstream infections and pneumonia caused by resistant Enterobacteriaceae

continue to be high, even when treated with antibiotics with in vitro activity

2. Antimicrobial options a. Tigecycline10

i. Bacteriostatic but retains activity against CREs ii. Glycylcycline, protein synthesis inhibitor

iii. Advantages 1. Large volume of distribution (7-9 L/kg)

a. Extensive tissue penetration11 iv. Disadvantages

1. Cannot achieve high concentrations in the blood a. Cmax after multiple doses of 50 mg every 12 hours: 0.63 mg/mL b. FDA breakpoint for Enterobacteriaceae: ≤2 mcg/mL

2. Tissue penetration in the epithelial lining fluid is poor 3. A pooled FDA analysis found an increased mortality rate compared to other

drugs, when used for pneumonia or bacteremia, resulting in a Black Boxed Warning from the FDA12

4. CRE bacteremia mortality rates in patients treated with tigecycline are 40-80% b. Colistin and polymyxin B10

i. Bactericidal against Gram-negative bacteria ii. Disrupts cell membrane integrity

iii. Advantages 1. Low baseline resistance

a. Of KPC isolates, 80% are susceptible to colistin iv. Disadvantages

1. Side effect profile a. Nephrotoxicity rates as high as 30-50%, potentially resulting in dialysis b. Neurotoxicity, including paresthesias and slurred speech, occurs in 7%

of patients i. Polymyxin B has a Black Boxed Warning for neurotoxicity

resulting in respiratory paralysis when combined with anesthesia or muscle relaxants

2. Dosing11 a. Colistimethate sodium (CMS) is converted to colistin in aqueous

solutions such as plasma and urine, instead of metabolized b. The conversion rate is widely variable within the population c. Therapeutic drug monitoring results in overestimation due to

spontaneous conversion in the sample

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d. CMS is renally eliminated and can be cleared rapidly before conversion in patients with good renal function

e. Lower total daily doses, as seen in patients with adequate renal function, are associated with higher mortality rates

3. Adaptive resistance11 a. Lipopolysaccharide binding site modification can develop during

therapy b. Can increase the MIC above the breakpoint c. Failure rates with colistin monotherapy can be 56%

c. Carbapenems13 i. Used in combination with other agents

ii. Cell wall agent with bactericidal activity iii. In 2010, CLSI dropped carbapenem breakpoints from 4 mcg/mL to 1 mcg/mL to ensure

organisms that produce carbapenemases would not be reported as susceptible 1. Some organisms that do not produce carbapenemases may be reported as

resistant based on MIC >1 mcg/mL iv. Optimizing pharmacokinetic parameters can result in pharmacokinetic and

pharmacodynamic target attainment 1. Time dependent antibiotics, relying on a concentration above the MIC for

>50% of the time to maximize bacterial killing a. Extending the infusion time increases time above MIC

2. Meropenem has a large therapeutic index a. Safety data up to 6 grams per day

3. Monte Carlo simulations demonstrate attainment of 50% T>MIC up to an MIC of 8 mcg/mL with a regimen of 2 grams every 8 hours infused over 3 hours

a. May be an option when CLSI interpretation is resistant Figure 5. Probability of target attainment for 50% time above MIC for each meropenem dosing regimen13

3. Combination Therapy9,14-16 a. Associated with decreased rates of mortality when compared to monotherapy

i. Retrospective study of 661 patients with KPC infections 1. 447 bloodstream infections, 84 lower respiratory tract infections

ii. Overall mortality was lower in the combination group (30.2 %) than the monotherapy group (38.4%)

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iii. Combination therapy may be most appropriate for critically ill patients with severe

infections like pneumonia and bacteremia9 1. Mortality was significantly lower in the combination group for blood stream

infections (BSI) and lower respiratory infections a. BSI combination and monotherapy mortality (32% vs 51.3%, p<0.001) b. Respiratory infection combination and monotherapy mortality (25% vs

49.1%, p=0.03) 2. Mortality was not significantly lower in intra-abdominal (IAI) and urinary tract

infections (UTI) a. IAI combination and monotherapy mortality (23.5% vs 32%, p=0.55) b. UTI combination and monotherapy mortality (9.1% vs 4.2%, p=0.48)

b. Combination therapy with a carbapenem9 i. Most common combination choice, 58% of patients on combination therapy

ii. Significant mortality benefit is seen with meropenem when the minimum inhibitory concentration (MIC) is <8

1. Combination therapy and monotherapy morality (27.9 % vs 40.4 % p=0.03) iii. No significant mortality benefit is seen when the meropenem MIC is >16

1. Combination therapy and monotherapy morality (32 % vs 37.9 %, p=0.22) 2. Low probability of attaining those concentrations even with optimized

pharmacokinetics 3. As many as 46-47% of KPC isolates in some studies had a meropenem MIC

greater than 8

c. Combination without a carbapenem when the meropenem MIC is >814-16 i. Agents appropriate for combination include colistin, tigecycline, and aminoglycosides

ii. Associated with significant mortality benefit in bacteremia, with a mortality rates of around 40%

iii. Not associated with significant mortality benefits in pneumonia, however too few patients were included to discern a true difference

Figure 6. 14 day mortality rates of monotherapy vs combination therapy9

51.3 49.1

40.4 37.932

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20

30

40

50

60

Blood streamInfection

Lower RespiratoryInfections

Meropenem MIC<8

Meropenem MIC>16

Perc

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Monotherapy Combination Therapy

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4. Take home points a. Combination therapy, especially with a carbapenem, has the lowest mortality rates in treating

CRE bacteremia and pneumonia i. Up to half of patients with CRE infections, though, are unlikely to benefit from a

carbapenem due to elevated MICs b. Mortality rates, even with combination therapy, continue to be high for bacteremia and

pneumonia caused by CRE c. Treatment options can often result in significant adverse effects

Ceftazidime/Avibactam (Avycaz®)

1. Introduction17 a. Approved February 25, 2015 b. Designated a QIDP under the GAIN act

i. Evidence based on safety and efficacy phase II trials c. Indicated for adults with limited or no alternative treatment options

i. Complicated intra-abdominal infections (cIAI), in combination with metronidazole ii. Complicated urinary tract infections (cUTI) including pyelonephritis

2. Mechanism of action18

a. Ceftazidime i. 3rd generation cephalosporin

ii. Bactericidal effect through cell wall synthesis inhibition iii. Binds and inhibits penicillin binding proteins (PBP) responsible for cross-linking

peptidoglycan chains, leading to compromised cell wall structure, cell lysis, and death b. Avibactam

i. New non- β-lactam β-lactamase inhibitor ii. Contains diaza-bicyclo core which adds hydrogen binding sites and increases rigidity

during transition without dramatically increasing size iii. Covalently binds to the hydroxyl active site of the β-lactamase, inhibiting the β-

lactamase iv. Carbamate linkage creates a stronger position in the active site resulting in longer

deactivation of β-lactamase v. Improved spectrum

1. Ambler class A carbapenemases, class C, some class D β-lactamases

Table 3. Clavulanic acid and avibactam activity against β-lactamases by Ambler classification1

Classification Name Clavulanic Acid in vitro susceptibility

Avibactam in vitro susceptibility

Class A Broad-Spectrum ESBL KPC

Yes Yes No

Yes Yes Yes

Class B Metallo-B-Lactamases No No Class C AmpC No Yes Class D Oxacillinases Yes/No Yes/No

ESBL: extended spectrum β-lactamase ; KPC: Klebsiella pneumoniae carbapenemase

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Table 4. Ceftazidime and ceftazidime/avibactam activity against β-lactamases by Ambler classification18

Classification Name Common Genes

Ceftazidime in vitro susceptibility

Ceftazidime/Avibactam in vitro susceptibility

Class A Broad-Spectrum

ESBL

Carbapenemases

PC1 SHV1 TEM1 SHV derived TEM derived CTX-M KPC

Yes

No

No

Yes

Yes

Yes Class B Metallo-B-Lactamases IMP

VIM NDM

No No

Class C Cephalosporinases AmpC No Yes Class D Oxacillinases

OXA-48 Pseudomonas OXA- 11, 14, 15 Acinetobacter OXA

Yes No

No

Yes No

No

PC1: penicillinase; ESBL: Extended spectrum β-lactamase ; TEM: temoneira; SHV: Sulfhydryl variable; KPC: Klebsiella pneumoniae carbapenemase; CTX-M: Cefotaxime-β-lactamase Munich; IMP: Imipenemase metallo-β-lactamase; VIM: Verona integrin-encoded metallo-β-lactamase; NDM: New Delhi metallo- β-lactamase; OXA: Oxacillinase

3. Spectrum of activity18 a. Enterobacteriaceae

i. Increased susceptibility to nearly 100% of isolates tested in vitro 1. Including ceftazidime and meropenem non-susceptible isolates

b. Pseudomonas aeruginosa i. Susceptibility increased relative to ceftazidime

ii. Susceptibility to meropenem non-susceptible strains is poor at 50% c. Acinetobacter species

i. Remain largely resistant ii. Species contains Ambler class D OXA β-lactamase plus other resistance mechanisms

d. Anaerobic and Gram-positive bacteria i. No clinically relevant anaerobic activity

ii. Limited Staphylococcus aureus activity iii. Consistent β-hemolytic streptococci activity

4. Resistance mechanisms18

a. Avibactam does not inhibit Ambler class B or most class D β-lactamases b. The potential mechanism for resistance to Pseudomonas aeruginosa is diminished permeability

and overexpressed efflux pumps c. Spontaneous resistance seen in vitro with Pseudomonas aeruginosa isolates growing after 24

hours and an increase in MIC from 8 mcg/mL to >32 mcg/mL

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Table 5. Organism susceptibility to drug class based on designated CLSI breakpoints18

Clinical Safety and Efficacy Trials

1. FDA approved for cUTI and cIAI based on phase II trials, phase III trials have since been published20-22

Table 6. Ceftazidime/avibactam use in cUTI and cIAI clinical trials20-22 Trial Primary Outcome Results Comments

cUTI Phase II

Ceftazidime/avibactam Imipenem/cilastatin

≥4 days of therapy

De-escalation

Microbiologic response at TOC 1 week after end of

therapy in the mMITT group

C/A: 67.4% (31/46) I/C: 63.3% (31/49)

No difference

Carbapenem resistant isolates excluded

Lower dose of C/A used:

500/125 mg infused 30 min

Organism (n) Meropenem* Ceftazidime** Ceftazidime/ Avibactam**

Escherichia coli (2,767) 99.9 91.8 100 ESBL (161) 100 65 100 AmpC (94) 100 35.1 100 CTX-M (20) - 25 100 CAZ-NS (18) - 0 100

Klebsiella pneumonia (1,847) 93.8 85.4 99.9 ESBL (296) 61.1 8.8 99.3 MEM-NS (115) 0 0 98.3 CAZ-NS (14) - 0 100

Klebsiella oxytoca (442) 99.3 96.7 100 ESBL(44) 93.2 68.2 100

Proteus mirabilis (683) 100 99.1 100 ESBL (33) 100 81.8 100

Enterobacter cloacae (951) 99.5 79 100 CAZ-NS (200) 97.5 0 100

Enterobacter aerogenes (357) 99.4 77 99.7 CAZ-NS (82) 97.6 0 98.8

Citrobacter koseri 100 98.4 100 Citrobacter freundii 97.8 76.8 99.5 Serratia marcescens 99.2 97.4 99.6 Morganella morganii 100 85.8 99.7 Providencia spp. (268) 99.2 90.7 95.9 Pseudomonas aeruginosa (1,967) 82 83.2 96.9

MEM-NS (115) 0 46.6 87.3 CAZ-NS (330) 45.3 0 82.1

Acinetobacter (321) 47 41.7 31.2 ESBL: extended-spectrum b-lactamase; CAZ-NS: ceftazidime/avibactam non-susceptible; MEM-NS: meropenem non-susceptible *Meropenem considered susceptible at an MIC ≤4 mcg/mL **Ceftazidime and ceftazidime/avibactam susceptible at an MIC ≤4 mcg/mL for Enterobacteriaceae and ≤8 mcg/mL for Pseudomonas aeruginosa

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cUTI Phase III

Ceftazidime/avibactam Doripenem

≥5 days of therapy

de-escalation

Resolution of symptoms and microbiologic eradication at

TOC visit 3 weeks after end of therapy

C/A: 70.2% (269/383) D: 64.5% (269/417)

Non-inferior

CAZ-NS isolates only C/A: 64% D: 60%

Carbapenem resistant isolates excluded

14 resistant isolates excluded

but not discussed

cIAI Phase II

Ceftazidime/avibactam + metronidazole

Meropenem

5-14 days of therapy no de-escalation

Resolution of symptoms at TOC 2 weeks after end of

therapy in the mMITT group

C/A: 82.4% (70/85) M: 88.8% (79/89)

No difference

Carbapenem resistant isolates excluded

Patients unlikely to respond excluded but not described

Excluded patients CrCl<50

C/A resistance 6/147 isolates

cUTI: complicated urinary tract infection; cIAI: complicated intra-abdominal infection; TOC: test of cure; mMITT: microbiologic modified intent to treat; C/A: ceftazidime/avibactam; I/C: imipenem/cilastatin; D: doripenem; CAZ-NS: ceftazidime non-susceptible; M: meropenem; CrCl: creatinine clearance; A: best alternative therapy

2. Adverse events20-22 a. Most adverse events are mild to moderate

i. Commonly reported adverse events (1-10%) 1. GI side effects 2. Anxiety 3. Headache

b. Serious adverse events seen in trials include diarrhea, acute renal failure, and elevated liver enzymes

3. Take home points

a. Ceftazidime/avibactam showed equivalent or non-inferior clinical success rates to carbapenems in cUTI and cIAI treatment

b. All trials excluded carbapenem resistant isolates which are known to have higher MICs than susceptible isolates

c. Clinical success rates may not be similar in CRE infections d. Ceftazidime/avibactam resistant isolates were seen in several trials e. Considered a safe drug with a few non-serious adverse events

Pharmacokinetic (PK) and Pharmacodynamic (PD) Data

1. PK and PD for antibiotics a. Determines effective antibiotic dosing regimens b. PK parameters

i. Volume of distribution 1. Determines dose required to achieve certain plasma concentrations 2. Plasma concentrations over time are critical when determining if drug

concentration to MIC ratio are achievable ii. Clearance

1. Determines how often the drug must be dosed

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c. PD parameters i. Describes the relationship between drug concentration and organism inhibition or death

using three possible parameters 1. Duration of time the free drug concentration remains above MIC (T>MIC) 2. Area under the curve (AUC) to MIC ratio (AUC/MIC)

a. Commonly referred to as total 24 hour drug exposure above the MIC 3. Peak serum concentration to MIC ratio (Peak/MIC)

Figure 7. Antibiotic pharmacodynamic parameters

ii. The pharmacodynamic parameter guides the plasma concentration goal to achieve optimal effect

iii. PD goals for enzyme inhibitors, such as a β-lactamase inhibitor, are dependent on the inhibitor to antibiotic ratio since the inhibitor has no antibacterial activity

1. Concentration ratio and a time above designated ratio that adequately protect the antibiotic are determined

d. Monte Carlo simulations i. Runs simulations to determine probability of attaining the PD goal based on the PK

parameters using multiple dosing regimens ii. If simulation show a low probability of attaining goal concentrations, successful

infection treatment is unlikely

2. Ceftazidime/avibactam Pharmacokinetics19 a. PK parameters are usually based on healthy volunteers

a. Linear without accumulation b. Similar as a single dose or multiple doses c. Similar alone or in combination

b. Absorption a. Not applicable b. Intravenous only

c. Distribution a. Ceftazidime and avibactam have a large volume of distribution indicating good tissue

penetration d. Metabolism

a. Insignificant e. Elimination

a. Renally eliminated and renal function based dosing adjustments are recommended

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Table 7. Pharmacokinetics of ceftazidime/ avibactam 2.5 g every 8 hours as a 2 hour infusion for 11 days19

Parameter Ceftazadime Avibactam Cmax (mg/L) 90.4 14.6 AUC (mg-h/L) 291 38.2 T1/2 2.76 2.71 CL (L/h) 6.86 13.1 V ss (L) 17 22.2 Protein Binding, % 21 8 Elimination, % 83 urine >97 urine Cmax: peak concentration; AUC: area under the curve; T1/2: half-life; CL: clearance; Vss: volume of distribution at steady state

3. Pharmacodynamics19 a. β lactams are time dependent antibiotics

a. The PD goal for ceftazidime is time above MIC of 50% (50% T>MIC) b. β-lactamase inhibitors require time above threshold concentration (CT) of the β-lactam

i. The PD goal for avibactam is bacteria specific 1. Enterobacteriaceae: 0.25-0.5 mg/L for 50% of the dosing interval 2. Pseudomonas aeruginosa: 1 mg/L for 40% of the dosing interval

c. Monte Carlo simulation in patients with cIAI have determined a 98% probability attaining target concentrations using the free drug fraction (ceftazidime: 85%, avibactam 92%) 2.5 g every 8 hours infused over 2 hours 23

ii. Targets were conservatively set 1. Ceftazidime concentration above MIC for >50% of the time 2. Avibactam concentration of 1 mg/L (CT) for >50% of the time

a. Probability of target attainment i. 98% for MIC of 8 mcg/mL

ii. 51% for MIC of 16 mcg/mL iii. 1% for MIC of 32 mcg/mL,

Table 8. Probability of target attainment with normal renal function achieving pre-specified PK/PD targets with 2.5 g ceftazidime/avibactam every 8 hours infused over 2 hours by MIC23

Pharmacokinetic and pharmacodynamic target definition MIC

(mcg/mL) 40% fT>MIC 40% fT>CT

CT=0.5 mg/L

50% fT>MIC 50% fT>CT

CT=0.5 mg/L

40% fT>MIC 40% fT>CT CT=1 mg/L

50% fT>MIC 50% fT>CT CT=1 mg/L

2 100 100 100 98.9 4 100 100 100 98.9 8 99.8 98.3 99.8 98.1 16 75.4 50.8 75.4 50.8 32 5.1 1.3 5.1 1.3 MIC: minimum inhibitory concentration; fT>MIC: time that free fraction of drug is above the minimum inhibitory concentration; fT>CT: time that free drug is above the concentration threshold; CT: concentration threshold

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Figure 9. Percentage of simulated cIAI patients achieving PK/PD target attainment following ceftazidime/avibactam infusion overlaid on a histogram of MIC distributions for Enterobacteriaceae23

1. PK and PD changes in critically ill patients11 a. Patients with sepsis experience fluid shifts to extravascular space

i. Increased Vd for hydrophilic antibiotics 1. Decreased serum concentrations

b. Similar changes seen in patients with hypoalbuminemia, postsurgical drains, and burns c. Ceftazidime/avibactam is a hydrophilic drug, and may be susceptible to increased Vd and a

decrease in serum concentrations i. Monte carlo simulation may be an overestimate of the percent chance of target

attainment in a critically ill patient ii. If target concentration is not met, therapeutic failure is more likely

2. Conclusions

a. Plasma concentrations necessary to effectively treat Enterobacteriaceae with an MIC of ≤8 are achievable in healthy populations with normal renal function

b. Critically ill patients may have increased Vd, which can decrease serum concentrations, decreasing the probability the necessary concentrations can be obtained

c. CLSI has conservatively set the breakpoint at ≤4 Ceftazidime/Avibactam use in CRE Bacteremia and Pneumonia

1. Case Reports24-26 a. Case reports for ceftazidime/avibactam use in CRE bacteremia have been reported on 6 patients

Table 9. Summary of case reports describing ceftazidime/avibactam use in CRE bacteremia24-27 Age, Sex, Hospital Course

Source, Organism

Susceptibilities Course of Infection Clinical Outcome

77 y, Female Septic shock

UTI, Enterobacter aerogenes

C/A 1.5 Imipenem ≥4 Ertapenem ≥2 Polymyxin B 6 Tigecycline 0.5

Ceftazidime/avibactam monotherapy 15 days

Microbiologic eradication, cure, discharged

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89 y, Female Endocarditis, UTI, Respiratory Failure

Unknown, Klebsiella pneumoniae

C/A 1.5 Imipenem ≥4 Ertapenem ≥2 Polymyxin B 1.5 Tigecycline 1.5

Ceftazidime/avibactam monotherapy 42 days

Microbiologic eradication, cure, discharged

72 y, Female

UTI, Klebsiella pnumoniae

C/A 0.5 Imipenem ≥4 Ertapenem ≥2 Polymyxin B 48 Tigecycline 1

Ceftazidime/avibactam monotherapy 10 days

Microbiologic eradication, cure, discharged

47 y, Female Kidney and pancreas transplant, exploratory laparotomy

Intra-abdominal abscess, possible line infection, Klebsiella pneumoniae

C/A 0.5 Meropenem >32 Colistin 0.25 Polymyxin B 1 Tigecycline 16

Ceftazidime/avibactam + tigecycline + colistin 23 days Then ceftazidime/avibactam monotherapy 9 days

Clearance, death 5 days after antibiotics stopped

62, Female Splenectomy, Pancreatic cancer, pancreatico-duodenectomy

Intra-abdominal abscess, Klebsiella pneumoniae

3 susceptibilities C/A 4, 32, 8 Meropenem 16, 128 Tigecycline 1, 8 Colistin 0.5

Colistin + EI high-dose meropenem + tigecycline Hospital day 21 Ceftazidime/avibactam + meropenem + tigecycline + polymyxin B

Clearance, on-going treatment at time of publication

64 y, Female Clostridium difficile, toxic megacolon, total colectomy, small bowel resection, intestinal transplant

Breakthrough bacteremia, Klebsiella pneumoniae

Tigecycline >256 Colistin 12

Ceftazidime/avibactam + ertapenem

Clearance in 24 hours, transfer out of ICU 14 days

CAD: coronary artery disease; CHF: congestive heart failure; CKD: chronic kidney disease; UTI: urinary tract infection; C/A: ceftazidime/avibactam; EI: extended infusion; VAP: ventilator associated pneumonia; CLABSI: central line associated blood stream infection; ICU: intensive care unit

2. Case Series28,29 a. First study analyzing ceftazidime/avibactam use in CRE infections (n=37)

i. Bacteremia (n=10), pneumonia (n=12) b. Combination therapy with gentamicin, colistin, or tigecycline occurred in 30% (11/37) patients c. Clinical success occurred in 59% (22/37)

i. Bacteremia: 70% (7/10), 1. 59% with primary bacteremia

ii. Pneumonia: 50% (6/12) iii. Continuous renal replacement therapy (CRRT): 17% (1/6),

d. Recurrence occurred in 27% (10/37) at 30 or 90 days e. Resistance developed in 3 patients during therapy, leading to failure

i. Resistance occurred on day 10, 15, and 19 of therapy ii. First cases of resistance while on therapy described for ceftazidime/avibactam

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3. Comparator trial30 a. Multicenter, prospective, observational cohort study is currently underway with preliminary data b. Compared outcomes of 91 patients treated with colistin (74%), ceftazidime/avibactam (15%), or

combination (10%) c. Infections included BSI, UTI, wound infection, respiratory tract infection, or abscess d. Many patients were receiving combination therapy with other active agents in all three groups e. Patients taking ceftazidime/avibactam had increased survival and trend of less nephrotoxicity

i. Any ceftazidime/avibactam hazard ratio 0.17, 95% confidence interval 0.03-0.62, p<0.01 ii. Renal failure developed in 8/36 at risk patients

1. Ceftazidime/avibactam: none 2. Colistin: 7/23 (30%) 3. Colistin + ceftazidime/avibactam: 1/4 (25%)

Figure 10. KPC infections treated with colistin, ceftazidime/avibactam or combination survival curve30

4. Take home points a. Very little real world use has been reported b. Clinical success rates and mortality rates appear to be similar to other regimens such as

combination colistin and meropenem c. Combination therapies have been attempted

i. No evidence to suggest which agent is most appropriate to add to ceftazidime/avibactam

d. The most alarming result is the 3/37 patients in the case series who developed resistance while on therapy

Recommendations for CRE Bacteremia or Pneumonia Treatment

1. When the patient is not critically ill or rapidly declining I recommend ceftazidime/avibactam a. If patient is rapidly declining after 24 hours of therapy refer to next recommendation

2. When the patient is critically ill or rapidly declining use meropenem MIC

a. If MIC is ≤8 I recommend meropenem plus colistin/polymyxin b. If MIC is >8 I recommend ceftazidime/avibactam plus either colistin, tigecycline, or an

aminoglycoside

3. Ceftazidime/avibactam should not be used in patients on CRRT at this time a. Low success rates (17%) seen in this subgroup

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Figure 11. CRE bacteremia and pneumonia treatment algorithm

Conclusion

1. Infections caused by CRE are considered an urgent threat due to the lack of clinically efficacious and safe treatment options

2. Mortality for patients infected with CRE is double that of carbapenem susceptible infections 3. Best available treatment option is polymyxin/colistin in combination with meropenem when the MIC is ≤8

a. Mortality rates remain around 50% in bacteremia b. Many patients experience severe drug related adverse events

4. Ceftazidime/avibactam is a 3rd generation cephalosporin in combination with a new non- β-lactam β-lactamase inhibitor, which improves spectrum to include KPC

5. Ceftazidime/avibactam is approved for cUTI and cIAI based on phase II studies in which CRE isolates were excluded

6. Post approval use in bacteremia and pneumonia CRE infections suggests the mortality rate and clinical success rate is similar to other currently available options

a. Baseline resistance and the development of resistance during therapy has been reported

CRE bacteremia or pneumonia

Is the patient critically ill, or

rapidly declining

Ceftazidime/avibactam Meropenem MIC >8

Colistin/polymyxin + meropenem

Ceftazidime/avibactam + colistin/polymyxin, tigecycline, or an aminoglycoside

Yes

Yes

No

No

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