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Meropenem and Vaborbactam

Class: Carbapenems
Chemical Name: (4R,5S,6S)-3-[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;trihydrate
Molecular Formula: C17H31N3O8SC12H16BNO5S
CAS Number: 119478-56-7
Brands: Vabomere (combination)

Medically reviewed on Sep 17, 2018

Introduction

Antibacterial;1 fixed combination of meropenem (a carbapenem β-lactam antibiotic) and vaborbactam (a non-β-lactam β-lactamase inhibitor).1 2 6

Uses for Meropenem and Vaborbactam

Urinary Tract Infections

Treatment of complicated urinary tract infections, including pyelonephritis, caused by susceptible Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae species complex.1

Meropenem and Vaborbactam Dosage and Administration

Administration

Administer by IV infusion.1

IV Administration

For solution compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute single-dose vials labeled as containing 2 g (meropenem 1 g and vaborbactam 1 g) by withdrawing 20 mL of 0.9% sodium chloride injection from an infusion bag and adding that to the vial;1 mix gently.1

Volume of reconstituted solution in the vial is approximately 21.3 mL;1 approximate concentration is meropenem 50 mg/mL and vaborbactam 50 mg/mL.1

Dilution

Immediately after reconstitution and prior to IV infusion, the reconstituted solutions must be further diluted.1

To prepare indicated dose, withdraw appropriate volume of reconstituted solution from the vial(s) and add back into the 0.9% sodium chloride injection infusion bag.1 (See Table 1.) The final concentration of meropenem and of vaborbactam in the infusion solution is approximately 2–8 mg/mL.1

Table 1. Dilution of Reconstituted Meropenem and Vaborbactam1

Recommended Dose of Meropenem and Vaborbactam

Volume to Withdraw from Reconstituted Vial(s) for Further Dilution

Volume of Infusion Bag

4 g (meropenem 2 g and vaborbactam 2 g)

Entire contents of 2 reconstituted vials (approximately 21 mL from each vial)

250–1000 mL

2 g (meropenem 1 g and vaborbactam 1 g)

Entire contents of 1 reconstituted vial (approximately 21 mL)

125–500 mL

1 g (meropenem 0.5 g and vaborbactam 0.5 g)

10.5 mL of reconstituted solution

70–250 mL

Visually inspect reconstituted and diluted solution for particulate matter and discoloration prior to administration;1 the solution should appear colorless to light yellow.1

Discard unused portions of reconstituted and diluted solution.1

Rate of Administration

Administer by IV infusion over 3 hours.1

Dispensing and Dosage and Administration Precautions

Be aware that dosage of meropenem and vaborbactam is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of meropenem plus dosage of vaborbactam).1 Consider this dosage convention when prescribing, preparing, and dispensing meropenem and vaborbactam.1

Dosage

Available as fixed combination containing 1:1 ratio of meropenem to vaborbactam.1

Meropenem component provided as meropenem trihydrate (dosage of this component expressed in terms of meropenem).1

Dosage of meropenem and vaborbactam fixed combination expressed in terms of the total of the meropenem and vaborbactam content.1

Each single-dose vial of meropenem and vaborbactam contains a total of 2 g (i.e., 1 g of meropenem and 1 g of vaborbactam).1

Adults

Urinary Tract Infections
IV

4 g (meropenem 2 g and vaborbactam 2 g) every 8 hours for up to 14 days.1

Special Populations

Renal Impairment

Urinary Tract Infections
IV

Adjust dosage in adults with eGFR <50 mL/minute per 1.73 m2.1 (See Table 2.) Treatment duration is up to 14 days.1

Monitor Scr and eGFR at least daily in those with changing renal function; adjust dosage accordingly.1

Table 2. Dosage of Meropenem and Vaborbactam in Adults with Renal Impairment1

eGFR (mL/minute per 1.73 m2)

Recommended Dosage of Meropenem and Vaborbactam

30–49

2 g (meropenem 1 g and vaborbactam 1 g) every 8 hours

15–29

2 g (meropenem 1 g and vaborbactam 1 g) every 12 hours

<15

1 g (meropenem 0.5 g and vaborbactam 0.5 g) every 12 hours

For patients receiving hemodialysis, administer after hemodialysis session.1

Geriatric Patients

Dosage adjustments based solely on age not needed.1 Select dosage with caution and consider monitoring renal function since geriatric patients more likely to have decreased renal function than younger adults.1

Cautions for Meropenem and Vaborbactam

Contraindications

  • Hypersensitivity to any component of meropenem and vaborbactam or other drugs in the same class.1

  • History of anaphylactic reactions to β-lactam antibacterials.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions reported.1 Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions reported in patients receiving β-lactam antibacterials.1 These reactions more likely to occur in individuals with history of sensitivity to multiple allergens.1 There are reports of individuals with history of penicillin hypersensitivity who experienced severe hypersensitivity reactions when treated with another β-lactam antibacterial.1

Before initiating meropenem and vaborbactam therapy, carefully inquire about patient's previous hypersensitivity reactions to cephalosporins, penicillins, other β-lactams, or other allergens.1

If an allergic reaction to meropenem and vaborbactam occurs, immediately discontinue the drug.1

CNS Effects

Seizures and other adverse CNS effects reported during meropenem treatment, a component of meropenem and vaborbactam.1 Occurred most commonly in patients with underlying CNS disorders (e.g., brain lesions, history of seizures), bacterial meningitis, and/or compromised renal function.1

Closely follow recommended dosage regimens, especially in those with known factors that predispose the patient to seizures.1 Continue anticonvulsant therapy in those with known seizure disorders.1 (See Risk of Breakthrough Seizures under Cautions.) If focal tremors, myoclonus, or seizures occur, evaluate patient neurologically, initiate anticonvulsant therapy, and reexamine meropenem and vaborbactam dosage to determine if it should be decreased or if the drug should be discontinued.1

Adverse effects, including seizures, delirium, headaches, and/or paresthesias, can occur and may interfere with mental alertness and/or cause motor impairment.1 Inform patients receiving meropenem and vaborbactam in an outpatient setting of the potential for such adverse effects.1 Advise patients not to operate machinery or motorized vehicles until it is reasonably well established that meropenem and vaborbactam is well tolerated.1

Risk of Breakthrough Seizures

Use of carbapenems, including meropenem, in patients receiving valproic acid or divalproex sodium has resulted in reduced valproic acid concentrations.1 Valproic acid concentrations may fall below the therapeutic range and increase risk of breakthrough seizures.1 Increased dosages of valproic acid or divalproex sodium may not be sufficient to overcome this interaction.1

Concomitant use of meropenem and vaborbactam with valproic acid or divalproex sodium generally not recommended.1 In patients whose seizures are well controlled on valproic acid or divalproex sodium, consider alternative to carbapenems.1 If concomitant use of meropenem and vaborbactam and valproic acid or divalproex sodium is necessary, consider alternative or supplemental anticonvulsant therapy.1

Hematologic Effects

Thrombocytopenia observed in patients with renal impairment receiving meropenem, but clinical bleeding not reported.1

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Possible emergence and overgrowth of nonsusceptible bacteria or fungi with prolonged use.1 Monitor carefully, institute appropriate therapy if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.1 12 14 15 C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including meropenem and vaborbactam, and may range in severity from mild diarrhea to fatal colitis.1 12 14 15 C. difficile produces toxins A and B which contribute to development of CDAD;1 12 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

Consider CDAD if diarrhea develops or after therapy and manage accordingly.1 12 14 15 Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.1

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible.1 12 Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1 12 14 15

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of meropenem and vaborbactam and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.1

When prescribing, preparing, and dispensing meropenem and vaborbactam, consider that dosage of the fixed combination is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of meropenem plus dosage of vaborbactam).1 (See Dispensing and Dosage and Administration Precautions under Dosage and Administration.)

Sodium Content

Contains approximately 250 mg (10.9 mEq) of sodium in each single-dose vial.1

Specific Populations

Pregnancy

Human data insufficient to determine whether there is a drug-associated risk of major birth defects or miscarriages if fixed combination of meropenem and vaborbactam, meropenem alone, or vaborbactam alone is used in pregnant women.1

Fetal malformations (e.g., supernumerary lung lobes, interventricular septal defect) observed in rabbits receiving IV vaborbactam during organogenesis.1 Similar malformations or fetal toxicity not observed in offspring from pregnant rats receiving IV vaborbactam during organogenesis or from late pregnancy and through lactation.1 No fetal toxicity or malformations observed in pregnant rats or cynomolgus monkeys receiving IV meropenem during organogenesis.1

Lactation

Meropenem distribution into human milk reported.1 3 Not known whether vaborbactam is distributed into human milk.1

Consider benefits of breast-feeding along with importance of the drug to the woman; also consider potential adverse effects on breast-fed child from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No overall differences in safety and efficacy observed in patients ≥65 years of age compared with younger adults, but greater sensitivity in some older individuals cannot be ruled out.1

Meropenem substantially eliminated by kidneys;1 risk of adverse effects may be greater in those with impaired renal function.1 Because geriatric patients more likely to have reduced renal function, select dosage with caution and consider renal function monitoring.1 Adjust dosage in geriatric patients based on renal function.1

Hepatic Impairment

Hepatic impairment does not affect pharmacokinetics of meropenem; vaborbactam does not undergo hepatic metabolism.1 Hepatic impairment not expected to affect clearance of meropenem and vaborbactam.1

Renal Impairment

Plasma exposures of both meropenem and vaborbactam are increased in patients with renal impairment.1

Adjust dosage in patients with eGFR <50 mL/minute per 1.73 m2.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache,1 phlebitis or infusion site reactions,1 diarrhea,1 hypersensitivity,1 nausea,1 increased ALT concentrations,1 increased AST concentrations,1 pyrexia,1 hypokalemia.1

Interactions for Meropenem and Vaborbactam

Studies not available evaluating potential for meropenem to interact with CYP isoenzymes.1 Carbapenems as a class have not shown potential for inhibition or induction of CYP isoenzymes;1 clinical experience suggests such effects unlikely.1

Vaborbactam does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at therapeutic concentrations and does not show potential to induce CYP1A2, 2B6, or 3A4.1

Meropenem is a substrate of organic anion transporter (OAT) 1 and OAT3.1 Studies evaluating potential for meropenem to interact with active transport systems not conducted.1

Vaborbactam is not a substrate or inhibitor of OAT1 or OAT3.1 In vitro, vaborbactam is not a substrate or inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or organic cation transporter (OCT) 2.1 Vaborbactam does not inhibit OCT1, organic anion transporting polypeptide (OATP) 1B1 or 1B3, or bile salt export pump (BSEP).1

Drugs Affecting or Affected by Organic Anion Transporters

OAT1 and/or OAT3 inhibitors: Possible increased meropenem plasma concentrations.1

Specific Drugs

Drug

Interaction

Comments

Anti-infectives (amikacin, azithromycin, daptomycin, levofloxacin, linezolid, polymyxin, tigecycline, vancomycin)

Amikacin, azithromycin, daptomycin, levofloxacin, linezolid, polymyxin, tigecycline, or vancomycin: No in vitro evidence of antagonistic antibacterial effects1

Probenecid

Competes with meropenem for active tubular secretion;1 results in increased exposures and elimination half-life of meropenem1

Concomitant use with meropenem and vaborbactam not recommended1

Valproic acid, divalproex sodium

Valproic acid, divalproex sodium: Concomitant use with carbapenems, including meropenem, has resulted in decreased valproic acid concentrations, which may fall below therapeutic range and increase risk of breakthrough seizures1

Valproic acid, divalproex sodium: Concomitant use with meropenem and vaborbactam generally not recommended.1 (See Risk of Breakthrough Seizures under Cautions.)

Meropenem and Vaborbactam Pharmacokinetics

Absorption

Plasma Concentrations

Peak plasma concentrations of meropenem and vaborbactam were 43.4 and 55.6 mcg/mL, respectively, in healthy adults following multiple doses of meropenem and vaborbactam (4 g [meropenem 2 g and vaborbactam 2 g]) given by IV infusion over 3 hours every 8 hours for 7 days.1

Peak plasma concentrations and AUCs of meropenem and vaborbactam increase in proportion to dose.1

No accumulation of meropenem or vaborbactam when the fixed combination (4 g [meropenem 2 g and vaborbactam 2 g]) is given by IV infusion every 8 hours for 7 days in healthy adults with normal renal function.1

Special Populations

Hepatic impairment: No effect on meropenem pharmacokinetics;1 not expected to affect vaborbactam pharmacokinetics.1

Mild renal impairment: Following a single dose of meropenem and vaborbactam, AUCs were 1.3- and 1.2-fold higher, respectively, compared with normal renal function.1

Moderate renal impairment: Following a single dose of meropenem and vaborbactam, AUCs were 2.1- and 2.3-fold higher, respectively, compared with normal renal function.1

Severe renal impairment: Following a single dose of meropenem and vaborbactam, AUCs were 4.6- and 7.8-fold higher, respectively, compared with normal renal function.1

Hemodialysis: Removes 38% of meropenem dose and 53% of vaborbactam dose.1

Geriatric patients: Pharmacokinetics similar to that in younger adults.1

Distribution

Plasma Protein Binding

Meropenem: Approximately 2%.1

Vaborbactam: Approximately 33%.1 10

Elimination

Metabolism

Meropenem: 22% of a dose undergoes hydrolysis of β-lactam ring.1

Vaborbactam: Does not undergo metabolism.1

Elimination Route

Meropenem: Principally eliminated by kidneys;1 approximately 40–60% of a dose eliminated in urine unchanged and 22% eliminated in urine as the hydrolysis product.1 Approximately 2% of a dose excreted in feces.1

Vaborbactam: Approximately 75–95% eliminated unchanged in urine.1 10

Half-life

Meropenem: 1.2 hours.1

Vaborbactam 1.7 hours.1

Stability

Storage

Parenteral

Powder for IV Infusion

20–25°C (may be exposed to 15–30°C).1

Following reconstitution and dilution, must complete IV infusion within 4 hours if stored at room temperature.1 Alternatively, must complete IV infusion within 22 hours if stored under refrigeration (2–8°C).1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1 18 HID

Compatible

Sodium chloride 0.9%

Drug Compatibility
Y-Site Compatibility

Compatible

Amikacin sulfate

Ampicillin sodium and sulbactam sodium

Azithromycin

Aztreonam

Bumetanide

Calcium gluconate

Cefazolin sodium

Cefepime

Ceftazidime

Ceftazidime and avibactam sodium

Ceftolozane sulfate and tazobactam sodium

Ceftriaxone sodium

Cefuroxime

Cisatracurium besylate

Colistimethate sodium

Dexamethasone sodium phosphate

Dexmedetomidine

Digoxin

Diltiazem

Dopamine

Doripenem

Doxycycline hyclate

Epinephrine

Eptifibatide

Ertapenem sodium

Esmolol

Esomeprazole sodium

Famotidine

Fentanyl citrate

Fosphenytoin sodium

Furosemide

Gentamicin sulfate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone

Imipenem and cilastatin sodium

Insulin, regular

Labetalol

Levofloxacin

Lidocaine

Linezolid

Lorazepam

Magnesium sulfate

Mannitol

Meperidine

Mesna

Methylprednisolone sodium succinate

Metoclopramide

Metronidazole

Micafungin sodium

Milrinone lactate

Morphine sulfate

Naloxone

Nitroglycerin

Norepinephrine bitartrate

Octreotide acetate

Pantoprazole sodium

Penicillin G potassium

Phenylephrine

Piperacillin sodium and tazobactam sodium

Potassium chloride

Potassium phosphates

Ranitidine

Rocuronium bromide

Sodium bicarbonate

Sodium phosphates

Tedizolid phosphate

Tigecycline

Tobramycin sulfate

Vancomycin

Vasopressin

Vecuronium bromide

Incompatible

Albumin human

Amiodarone

Anidulafungin

Calcium chloride

Caspofungin acetate

Ceftaroline fosamil

Ciprofloxacin

Daptomycin

Diphenhydramine

Dobutamine

Isavuconazonium sulfate

Midazolam

Nicardipine

Ondansetron

Phenytoin sodium

Actions and Spectrum

  • Meropenem and vaborbactam is a fixed combination of meropenem (a carbapenem β-lactam antibiotic) and vaborbactam (a non-β-lactam β-lactamase inhibitor).1 2 6

  • Meropenem is a synthetic carbapenem antibiotic structurally and pharmacologically related to other carbapenems (e.g., doripenem, ertapenem, imipenem).1 3 4 5 Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis mediated through binding to penicillin-binding proteins (PBPs).1 3 4 5 6

  • Vaborbactam is a cyclic boronic acid non-β-lactam β-lactamase inhibitor that protects meropenem from degradation by certain β-lactamases, primarily Ambler class A serine carbapenemases (e.g., K. pneumoniae carbapenemase [KPC]) and some class C serine carbapenemases.1 2 6 7 10 26 Vaborbactam's boronate moiety forms a covalent bond with the catalytic serine side chain of the β-lactamase, thereby inhibiting the enzyme from degrading meropenem.7 8 Does not inhibit class D carbapenemases (e.g., OXA-48) or class B β-lactamases (e.g., metallo β-lactamases [MBLs]).2 8 9

  • Vaborbactam does not have antibacterial activity and does not decrease activity of meropenem against meropenem-susceptible organisms.1 7 16

  • Meropenem and vaborbactam is bactericidal in action.6 11

  • Meropenem and vaborbactam active in vitro and in clinical studies against E. cloacae species complex,1 7 9 17 E. coli,1 7 9 16 17 and K. pneumoniae.1 7 9 11 16 17

  • Although clinical importance not known, meropenem and vaborbactam active in vitro against other gram-negative bacteria, including Citrobacter freundii,1 7 9 C. koseri,1 7 E. aerogenes,1 7 K. oxytoca,1 7 9 Morganella morganii,1 Proteus mirabilis,1 Providencia species,1 Pseudomonas aeruginosa,1 and Serratia marcescens.1 7 9 Efficacy of the drug for treatment of clinical infections caused by such bacteria not established in adequate and well-controlled clinical studies.1

  • In vitro, meropenem and vaborbactam active against Enterobacteriaceae in the presence of some β-lactamases and extended-spectrum β-lactamases (ESBLs), including KPC, SME, TEM, SHV, CTX-M, CMY, and ACT.1 7 8 16 17 Not active against bacteria that produce MBLs or oxacillinases with carbapenemase activity.1 8 9

  • Resistance or reduced susceptibility can occur.1 Mechanisms of resistance to carbapenems include production of β-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin.1 3 4 8 May not be active against gram-negative bacteria with porin mutations and overexpression of efflux pumps.1

  • Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to meropenem and vaborbactam.1 Cross-resistance with other classes of anti-infectives not reported.1

Advice to Patients

  • Advise patients that antibacterials (including meropenem and vaborbactam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1

  • Importance of completing full course of therapy, even if feeling better after a few days.1

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with meropenem and vaborbactam or other antibacterials in the future.1

  • Advise patients that allergic reactions, including serious allergic reaction, can occur and that serious reactions require immediate treatment.1 Ask patients about previous hypersensitivity reactions to meropenem and vaborbactam, penicillins, cephalosporins, other β-lactams, or other allergens.1

  • Inform patients receiving meropenem and vaborbactam on an outpatient basis that adverse effects, including seizures, delirium, headaches, and/or paresthesias, could occur and interfere with mental alertness or cause motor impairment.1 Advise patients not to operate machinery or motorized vehicles until it is reasonably established that meropenem and vaborbactam is well tolerated.1

  • Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as ≥2 months after the last dose.1

  • Importance of informing clinician if currently being treated with valproic acid or divalproex sodium.1 If meropenem and vaborbactam used concomitantly with these drugs, valproic acid concentrations in the blood may drop below therapeutic range and increase risk of seizures.1 (See Risk of Breakthrough Seizures under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Meropenem and Vaborbactam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

2 g (1 g of meropenem and 1 g of vaborbactam)

Vabomere

Medicines Company

AHFS DI Essentials™. © Copyright 2018, Selected Revisions September 17, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. The Medicines Company. Vabomere IV (meropenem and vaborbactam) for injection for intravenous use prescribing information. Parsippany, NJ; 2017 Aug.

2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209776Orig1s000: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209776Orig1s000SumR.pdf

3. AstraZeneca. Merrem IV (meropenem) for injection for intravenous use prescribing information. Wilmington, DE; 2018 Jan.

4. Papp-Wallace KM, Endimiani A, Taracila MA et al. Carbapenems: past, present, and future. Antimicrob Agents Chemother. 2011; 55:4943-60. http://www.ncbi.nlm.nih.gov/pubmed/21859938?dopt=AbstractPlus

5. Codjoe FS, Donkor ES. Carbapenem Resistance: A Review. Med Sci (Basel). 2017; 6 http://www.ncbi.nlm.nih.gov/pubmed/29267233?dopt=AbstractPlus

6. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209776Orig1s000: Clinical review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209776Orig1s000MedR.pdf

7. Hackel MA, Lomovskaya O, Dudley MN et al. In Vitro Activity of Meropenem-Vaborbactam against Clinical Isolates of KPC-Positive Enterobacteriaceae. Antimicrob Agents Chemother. 2018; 62 http://www.ncbi.nlm.nih.gov/pubmed/29084745?dopt=AbstractPlus

8. Lomovskaya O, Sun D, Rubio-Aparicio D et al. Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. Antimicrob Agents Chemother. 2017; 61 http://www.ncbi.nlm.nih.gov/pubmed/28848018?dopt=AbstractPlus

9. Castanheira M, Rhomberg PR, Flamm RK et al. Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016; 60:5454-8. http://www.ncbi.nlm.nih.gov/pubmed/27381386?dopt=AbstractPlus

10. Griffith DC, Loutit JS, Morgan EE et al. Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects. Antimicrob Agents Chemother. 2016; 60:6326-32. http://www.ncbi.nlm.nih.gov/pubmed/27527080?dopt=AbstractPlus

11. Sabet M, Tarazi Z, Rubio-Aparicio D et al. Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-resistant Enterobacteriaceae in an In Vitro Hollow Fiber Model. Antimicrob Agents Chemother. 2017; 62:1-9. http://www.ncbi.nlm.nih.gov/pubmed/29133570?dopt=AbstractPlus

12. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55. http://www.ncbi.nlm.nih.gov/pubmed/20307191?dopt=AbstractPlus

14. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol. 1997; 92:739-50. http://www.ncbi.nlm.nih.gov/pubmed/9149180?dopt=AbstractPlus

15. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health-Syst Pharm. 1998; 55:1407-11. http://www.ncbi.nlm.nih.gov/pubmed/9659970?dopt=AbstractPlus

16. Weiss WJ, Pulse ME, Nguyen P et al. Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in a Murine Model of Pyelonephritis. Antimicrob Agents Chemother. 2018; 62 http://www.ncbi.nlm.nih.gov/pubmed/29038270?dopt=AbstractPlus

17. Sabet M, Tarazi Z, Nolan T et al. Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2018; 62 http://www.ncbi.nlm.nih.gov/pubmed/29109160?dopt=AbstractPlus

18. Kidd JM, Avery LM, Asempa TE et al. Physical Compatibility of Meropenem and Vaborbactam With Select Intravenous Drugs During Simulated Y-site Administration. Clin Ther. 2017; http://www.ncbi.nlm.nih.gov/pubmed/29290374?dopt=AbstractPlus

26. Drawz SM, Papp-Wallace KM, Bonomo RA. New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother. 2014; 58:1835-46. http://www.ncbi.nlm.nih.gov/pubmed/24379206?dopt=AbstractPlus

28. Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010; 23:160-201. http://www.ncbi.nlm.nih.gov/pubmed/20065329?dopt=AbstractPlus

HID. ASHP’s interactive handbook on injectable drugs. McEvoy, GK, ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; Updated [September 29, 2017]. From HID website. http://www.interactivehandbook.com/

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