February 2018 FAQs

Are there data to support an increased risk of heart failure exacerbation/decompensation with pregabalin use?

Introduction

Pregabalin package labeling states to exercise caution when using the agent in patients with New York Heart Association (NYHA) class III and IV heart failure (HF) or those taking concomitant thiazolidinediones (TZDs).¹ Recommendations are based on limited data from early controlled clinical trials showing higher frequencies of weight gain and peripheral edema in patients taking both pregabalin and a TZD. Notably, peripheral edema was reported in 3% of patients who were using TZD only, 8% of patients who were using pregabalin only, and 19% of patients on both therapies. Weight gain was not reported for patients receiving TZDs only, but occurred in 4% of patients on pregabalin only and 7.5% of patients on both therapies. Although the exact mechanism by which pregabalin exacerbates HF is unknown, the agent has been shown to bind to the α₂-δ calcium channels in the heart and vasculature. These effects may lead to decreased influx of calcium and potentially negative inotropic effects and vasodilatory-induced peripheral edema.²

In 2016, the American Heart Association (AHA) published a statement focused on drugs that may cause or exacerbate HF.³ For this publication, the AHA compiled prospective and observational data, along with information found in package labeling, in order to identify whether or not select medications cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction. The statement also included the magnitude and potential mechanism of HF induction or precipitation, the evidence supporting the recommendation, and the onset of adverse cardiac effects. Select agents from the following drug classes are included in this statement: analgesics, anesthetics, antidiabetics, antiarrhythmics, antihypertensives, antiinfectives, antipsychotics, oncolytics, neuroleptics, and various other hematologic, ophthalmologic, pulmonary, rheumatologic and urologic agents. A majority of these medications, including pregabalin, exacerbate underlying myocardial dysfunction rather than causing direct myocardial toxicity. Pregabalin is rated as evidence level C for induction or precipitation of HF which indicates the following: very limited populations were evaluated, and data have been reported in case reports, case studies, expert opinion, and consensus opinion. Similar to information found in the package labeling, the AHA states that pregabalin exacerbates underlying myocardial dysfunction through L-type calcium channel blockade. The magnitude of HF induction or precipitation is rated as minor to moderate and occurs in an immediate (within 1 week of drug administration) to intermediate (within weeks to months of drug administration) time frame.

Literature Summary

Pregabalin induced HF exacerbations

Table 1 summarizes 8 case reports of pregabalin-induced HF exacerbations; also summarized is a retrospective cohort study that tested the hypothesis that pregabalin would be associated with a greater risk of HF compared to gabapentin.^{2, 4-7} In the included case reports, all patients were prescribed pregabalin for neuropathic pain with total daily doses ranging from 100 to 150 mg.^{2, 5-7} Most of these case reports discuss the importance of dose adjustment for renal insufficiency, with Fong et al reporting confirmed inappropriate pregabalin dosing for renal function. All patients initially presented with shortness of breath and weight gain, and 6 of the 8 patients were hospitalized to receive intravenous or oral diuretics. Of note, none of the patients in these case reports were receiving concomitant TZDs.

Table 1. Summary of literature describing pregabalin induced HF exacerbations.^{2, 4-7}

Pregabalin-induced new-onset HF

In the retrospective cohort study by Ho et al, about 25% of the patients who experienced symptoms of HF exacerbations had no prior history of congestive HF.⁴ These findings suggest that pregabalin may not only be associated with HF exacerbations, but also with new-onset HF in previously healthy patients.

Several additional reports of new-onset HF after starting treatment with pregabalin are also available. In one case, a 64-year-old male with a pacemaker for complete atrial-ventricular block and no previous history of HF was started on pregabalin 150 mg (the recommended starting dose for his renal function) for paresthesia in his urethra after a rectal amputation.⁸ His dose was titrated up to 300 mg daily after a week in order to provide appropriate analgesia. Over a period of 3 months, he developed peripheral edema, weight gain of 6 kg, and was eventually hospitalized for facial edema and difficulty breathing. The patient was managed with diuretics and diagnosed with HF. In another case, a 54-year-old female with neuropathic back pain after a spinal surgery and no history of chronic disease was started on pregabalin 150 mg daily for a week and titrated to 300 mg daily for neuropathic pain.⁹ On day 17 of treatment, the patient presented with swelling in hands and ankles. A computed tomography (CT) scan showed cardiomegaly, and the appearance of pericardial and pleural fluid; she was diagnosed with new-onset HF. Following her diagnosis, pregabalin was discontinued, and cardiac function improved. This patient was later trialed on gabapentin due to persisting neuropathic pain, which led to edema 20 days after starting therapy. Gabapentin was discontinued, and edema improved.

A systematic review evaluating whether or not there is an increased risk of HF or edema in individuals treated with pregabalin compared to placebo or gabapentin is currently ongoing.¹⁰ The results of this review will hopefully further assist clinicians in determining pregabalin’s risk for edema and congestive HF.

Conclusion:

Despite manufacturer recommendations to use pregabalin cautiously in patients with NYHA class III or IV HF receiving concomitant TZDs, the literature suggests caution with use in all classes of HF, regardless of TZD use. In addition, patients should also be monitored for new-onset HF after starting pregabalin. Results from an ongoing systematic review by Ho et al may provide practitioners with additional guidance concerning the risk of HF exacerbations with pregabalin use. However, given currently available evidence, it is important to exercise caution in all NYHA classes of HF. Patients initiated on pregabalin should be counseled on early detection of symptoms of HF exacerbations in order to reduce hospitalizations. If HF exacerbation is detected, possible management includes discontinuation of pregabalin and treating peripheral edema with an intravenous or oral diuretic.

References:

1. Lyrica (pregabalin) capsule [package insert]. New York, NY: Parke-Davis, Division of Pfizer; 2013.
2. Fong T and Lee AJ. Pregabalin-associated heart failure decompensation in a patient with history of stage I heart failure. Ann of Pharmacother. 2014;48(8):1077-1081.
3. Page RL, O’Bryant CL, Cheng D, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the american heart association. Circulation. 2016,134:00-00.
4. Ho JM, Macdonald EM, Luo J, et al. Pregabalin and heart failure: a population-based study. Pharmacoepidemiol Drug Saf. 2017;26:1087-1092.
5. Page RL, Cantu M, Lindenfeld J, et al. Possible heart failure exacerbation associated with pregabalin: case discussion and literature review. J Cardiovasc Med. 2008;9:922-925.
6. De Smedt RH, Jaarsma T, Van den Broek SA, and Haaijer-Ruskamp FM. Decompensation of chronic heart failure associated with pregabalin in a 73-year-old patient with postherpetic neuralgia: a case report. Br J Clin Pharmacol. 2008;66(2):327-328.
7. Murphy N, Mockler M, Ryder M, et al. Decompensation of chronic heart failure associated with pregabalin in patients with neuropathic pain. J Card Fail. 2006;(13)3:227-228.
8. Matsuki Y, Morikawa M, Nishimoto T, et al. Heart failure associated with pregabalin use. Pain Physician. 2012;15:E533-E540.
9. Erdogan G, Ceyhan D, Gulec S. Possible heart failure associated with pregabalin use: case report. AGRI. 2011;23(2):80-83.
10. Ho JM, Tricco AC, Perrier L, et al. Risk of heart failure and edema associated with the use of pregabalin: a systematic review. Systematic Reviews. 2013;2:25.

Prepared by:

Marisa Brizzi, PharmD

PGY1 Pharmacy Practice Resident

University of Illinois at Chicago

February 2018

The information presented is current as November 6, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What does the PRESERVE trial tell us about the prevention of contrast-induced acute kidney injury?

In November 2017, the PRESERVE trial was published in the New England Journal of Medicine. This trial sought to answer an important question – does the administration of intravenous sodium bicarbonate or oral acetylcysteine prevent acute kidney injury (AKI) in patients undergoing angiography? This was not a novel question. In fact, administration of sodium bicarbonate and acetylcysteine are seemingly ubiquitous practices used to prevent contrast-induced AKI (CI-AKI).^1,2 However, the underlying evidence for these therapies have been conflicting and unclear, despite the sheer volume of published clinical trials and meta-analyses. Previous data have generally been limited by small sample sizes, reduced generalizability, and the use of surrogate markers, mainly changes in serum creatinine.²

Prevention of CI-AKI is an understandably important goal for patients receiving contrast media.^1,3 Specifically, CI-AKI is a reversible AKI that is caused by the exposure of iodinated contrast media during angiography or other medical procedures. It can be detected by an increase in serum creatinine that occurs approximately 48 hours after exposure, and peaking after 5 days. The development of CI-AKI is associated with increased hospital length of stays, morbidity, and mortality. Due to these risks, medical practice has changed over time to help mitigate them.¹ Particularly, the development and use of lower osmolality contrast media and use of aggressive hydration procedures during the time of exposure. Current guidelines addressing CI-AKI prevention include the 2016 American College of Radiology (ACR) manual on contrast media, the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guideline on AKI, and the 2011 American College of Cardiology Foundation (ACCF) guideline on percutaneous coronary intervention.^3-5 Overall, intravenous volume expansion with isotonic fluids, such as 0.9% sodium chloride (normal saline [NS]), are universally recommended in these guidelines. The ACR and ACCF guidelines both do not recommend use of intravenous sodium bicarbonate (over use of NS) or acetylcysteine due to insufficient evidence.^3,4 In contrast, the KDIGO guidelines recommend volume expansion with either NS or isotonic sodium bicarbonate solutions.⁵ Additionally, the use of acetylcysteine is endorsed by KDIGO, although not due to overwhelming supportive evidence, but based on the likelihood that it may help and is associated with a low risk of adverse events.

PRESERVE trial

The objective of the PRESERVE trial was to compare intravenous hydration with sodium bicarbonate versus NS and oral acetylcysteine versus placebo for the prevention of major adverse outcomes and CI-AKI in high-risk patients receiving iodinated contrast media for angiography.⁶ The trial was a multicenter, double-blind, 2 x 2 factorial randomized controlled trial (RCT). Patients eligible for inclusion were those undergoing a planned coronary or noncoronary angiography procedure who were at high risk for developing CI-AKI. High risk patients were defined as those with impaired renal function, either an estimated glomerular filtration rate (GFR) <45 mL/min or <60 mL/min, if the patient also had diabetes mellitus. Patients with unstable or severe renal dysfunction (GFR <15 mL/min or receiving any type of renal replacement therapy) were excluded. Patients were randomly assigned to intravenous isotonic sodium bicarbonate (1.26%) or NS and oral acetylcysteine or placebo. Administration of intravenous fluids was determined by a weight-based protocol-specified range, and initiated prior to angiography, continued through the procedure, and stopped 2 to 12 hours afterwards. Specific timing and rate of administration were determined by providers at each site. Oral acetylcysteine (1200 mg) or placebo was given 1 hour prior to the procedure, 1 hour after the procedure, and twice daily for the following 4 days for a total of 10 doses. The primary endpoint was the composite of death, need for dialysis, or persistence of a 50% elevation of serum creatinine from baseline at 90 to 104 days after the procedure. The rate of CI-AKI was measured as a secondary endpoint, and it was defined as an increase in serum creatinine ≥25%, or ≥0.5 mg/dL, from baseline 3 to 5 days after the procedure.

The primary analysis included 4993 patients.⁶ The trial originally sought to enroll 7680 patients; however, after a preplanned interim analysis, the trial was halted early due to futility. The average patient in the trial was 69.8 years of age and had a median GFR of 50.2. Approximately, 80% of patients enrolled had diabetes and the vast majority (90.5%) underwent coronary angiography. The sodium bicarbonate group did have more Hispanic patients than the NS group (4.3% vs 2.9%), but this was the only significant baseline characteristic difference. There was no difference in the incidence of the primary endpoint between sodium bicarbonate and NS (4.4% vs 4.7%; odds ratio [OR], 0.93; 95% confidence interval [CI], 0.72 to 1.22; p=0.62) or between acetylcysteine and placebo (4.6% vs 4.5%; OR, 1.02; 95% CI, 0.78 to 1.33; p=0.88). Further, there was no significant difference between groups for any single component of the composite primary endpoint, nor the rate of CI-AKI, hospitalization by 90 days, or serious adverse events. Lastly, a multivariable logistic regression model evaluating the relationship between sodium bicarbonate and acetylcysteine found no significant interaction.

Impact on clinical practice

Recent meta-analyses have generally shown that both sodium bicarbonate and acetylcysteine reduce the risk for CI-AKI, defined by most trials as a >25% relative increase or a 0.5 mg/dL absolute increase in serum creatinine.^7-11 However, these analyses are based on synthesizing many small RCTs. The largest previous RCTs evaluating acetylcysteine and sodium bicarbonate included 2308 and 592 patients, respectively.^12-13 Thus, the PRESERVE trial sets itself apart through a few unique aspects: use of a clinical primary endpoint, a large sample size, and inclusion of only high-risk patients.

Previous investigations have not been powered to explore the impact of these interventions on the need for renal replacement therapy, cardiac events, or mortality.⁷ The primary endpoint in almost all previous RCTs has been tied to a change in serum creatinine within a few days of the procedure. While there are observational data linking changes in serum creatinine to clinical consequences, the PRESERVE trial directly measured whether the interventions could reduce the incidence of clinical outcomes.^2,6 Further, because the trial included almost 5,000 patients, it was adequately powered to find a difference in the composite endpoint of death, need for dialysis, or persistence of kidney dysfunction. Additionally, the inclusion of only high-risk patients should have made it easier to find a difference between groups, if it existed, as they would be expected to have higher baseline incidence rates; in patients without risk factors, the incidence is <1%, but in high-risk patients the risk can increase up to 15%.¹ Lastly, limiting the study population to only high-risk patients helped increase the generalizability of the trial.^2,6

Some limitations of the trial also exist, impacting its generalizability. The population was predominately male as it was conducted in Veteran’s Affairs hospitals.⁶ Additionally, the population received low osmolality, non-ionic contrast media, which is associated with a lower incidence of CI-AKI. Only 30% of the patients underwent a percutaneous intervention and many underwent diagnostic angiography, which uses a lower volume of contrast media that further decreases the risk for CI-AKI. Therefore, these results may not apply to patients who receive other types of contrast media or who receive contrast media for other types of radiological procedures.

Conclusion

Overall, guidelines were hesitant to promote acetylcysteine and sodium bicarbonate previously and PRESERVE will likely cement those recommendations that the agents do not impact outcomes.^3,4 The 2 largest trials investigating the addition of acetylcysteine have found no difference in clinical outcomes or incidence of CI-AKI.^6,12 And the sample size of the PRESERVE is much larger than previous studies evaluating sodium bicarbonate, by an almost ten-fold difference.^6,13 Interestingly, a recent study comparing intravenous hydration with NS to no prophylaxis in patients found the no prophylaxis strategy to be non-inferior, which raises the question if there should be a debate on the type of intravenous fluid used.¹⁴ Rather a focus on oral hydration strategies may be more appropriate. In conclusion, the PRESERVE trial found no clinical value in using acetylcysteine and sodium bicarbonate as preventative strategies in high-risk patients receiving low osmolality contrast media.

References

1. Mamoulakis C, Tsarouhas K, Fragkiadoulaki I, et al. Contrast-induced nephropathy: basic concepts, pathophysiological implications and prevention strategies. Pharmacol Ther. 2017;180:99-112.
2. Weisbord SD, Gallagher M, Kaufman J, et al. Prevention of contrast-induced AKI: a review of published trials and the design of the prevention of serious adverse events following angiography (PRESERVE) trial. Clin J Am Soc Nephrol. 2013;8(9):1618-31.
3. ACR Committee on Drugs and Contrast Media. ACR manual on contrast media, Version 10.3. American College of Radiology website. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf. Published May 31, 2017. Accessed January 11, 2018.
4. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):e574-e651.
5. KDIGO clinical practice guideline for acute kidney injury. Kidney Disease Improving Global Outcomes website. http://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf. Published March 2012. Accessed January 11, 2018.
6. Weisbord SD, Gallagher M, Jneid H, et al; PRESERVE Trial Group. Outcomes after angiography with sodium bicarbonate and acetylcysteine [published online ahead of print November 12, 2017]. N Engl J Med. doi: 10.1056/NEJMoa1710933.
7. Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of prevention strategies for contrast-induced nephropathy: a systematic review and meta-analysis. Ann Intern Med. 2016;164(6):406-416.
8. Li JX, Jin EZ, Yu LH, et al. Oral N-acetylcysteine for prophylaxis of contrast-induced nephropathy in patients following coronary angioplasty: A meta-analysis. Exp Ther Med. 2017;14(2):1568-1576.
9. Ali-Hasan-Al-Saegh S, Mirhosseini SJ, Ghodratipour Z, et al. Strategies preventing contrast-induced nephropathy after coronary angiography: a comprehensive meta-analysis and systematic review of 125 randomized controlled trials. Angiology. 2017;68(5):389-413.
10. Giacoppo D, Gargiulo G, Buccheri S, et al. Preventive strategies for contrast-induced acute kidney injury in patients undergoing percutaneous coronary procedures: evidence from a hierarchical Bayesian network meta-analysis of 124 Trials and 28 240 patients. Circ Cardiovasc Interv. 2017;10(5). doi: 10.1161/CIRCINTERVENTIONS.116.004383.
11. Navarese EP, Gurbel PA, Andreotti F, et al. Prevention of contrast-induced acute kidney injury in patients undergoing cardiovascular procedures-a systematic review and network meta-analysis. PLoS One. 2017;12(2):e0168726.
12. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation. 2011;124(11):1250-1259.
13. Manari A, Magnavacchi P, Puggioni E, et al. Acute kidney injury after primary angioplasty: effect of different hydration treatments. J Cardiovasc Med (Hagerstown). 2014;15(1):60-67.
14. Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet. 2017;389(10076):1312-1322.

February 2018

The information presented is current as 01/12/2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What data supports the efficacy and safety of meropenem-vaborbactam?

Introduction

The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) infections in the United States and worldwide has been increasing over the past few years.^1-3 Historically, carbapenems have been used to treat multi-drug resistant (MDR) Gram-negative organisms but as usage of these agents has increased so has the spread of carbapenem-resistant organisms. According to the 2013 Centers for Disease Control and Prevention (CDC) Threat Report, over 9300 CRE infections occur yearly in the United States, which has led the CDC to classify these infections with a threat level of “urgent”.⁴ In the United States, production of Klebsiella pneumoniae carbapenemase (KPC) enzymes is the leading mechanism by which Gram-negative organisms achieve resistance to carbapenems as well as cephalosporins and beta-lactamase inhibitors.⁵ Combination regimens with multiple antibiotic agents, typically with a polymyxin backbone, are often used for life-threatening CRE infections.^1-3 However, resistance is developing against even these salvage regimens and some agents have clinically relevant tolerability concerns (eg, aminoglycosides, polymyxins, tigecyline). Therefore, new antibiotics for infections with MDR organisms are under investigation.^2,3,6

A recently-approved antibiotic with activity against CRE is meropenem-vaborbactam. Meropenem-vaborbactam is the first carbapenem and novel β-lactamase inhibitor combination to the US market.⁷ It is approved for treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, in patients ≥18 years of age. This article reviews the clinical characteristics and place in therapy of this agent.

Treatment options for resistant cUTIs

The 2010 Infectious Diseases Society of America (IDSA) guideline recommendations for the treatment of catheter-associated urinary tract infections are often extrapolated to the treatment of cUTIs and pyelonephritis.⁸ Treatment decisions are individualized based on patient-specific factors such as sex, immune status, urologic abnormalities, severity of illness, and risk for MDR organisms.^8,9 Treatment duration is also variable and depends on time to symptom resolution, adequate source control, and risk for recurrence. For patients who require empiric parenteral antibiotics based on disease severity and MDR risk, a traditional broad-spectrum agent is used based on local resistance patterns, such as a third-generation cephalosporin, carbapenem, or extended-spectrum beta-lactam (+/- an aminoglycoside).⁹ Empiric use of carbapenems is typically reserved for severely ill patients with risk factors for Pseudomonas aeruginosa or other MDR organisms. Once culture results are available or if a patient’s history warrants, new treatment options such as ceftazidime-avibactam or meropenem-vaborbactam (for CRE infections) or ceftolozane-tazobactam (for MDR P. aeruginosa cUTIs) can be used.

Meropenem-vaborbactam

Vaborbactam is a β-lactamase inhibitor with a high affinity for serine β-lactamases and activity against CRE organisms, including those producing KPCs.⁷ Meropenem-vaborbactam has in vitro and in vivo activity against the following organisms: Escherichia coli, K. pneumoniae, and Enterobacter cloacae species complex.^10-12 In vitro activity extends beyond these to include the following organisms: Citrobacter freundii and koseri, E. aerogenes, Morganella morganii, Proteus mirabilis, Providencia species, P. aeruginosa, and Serratia marcescens. Similar to other carbapenems, meropenem-vaborbactam lacks activity against Stenotrophomonas maltophilia and Acinetobacter species, likely due to resistance mechanisms beyond KPC production.¹⁰ An in vitro study by Castanheira et al. showed that adding vaborbactam increased meropenem activity ≥64-fold, resulting in a susceptibility rate of 67.6% to 97.1% among all tested isolates (including 93.3% of the KPC-producing K. pneumoniae isolates) compared to a 2.2% rate with meropenem alone.¹¹ In another study, the addition of vaborbactam 8 µg/mL caused a decrease in the meropenem minimum inhibitory concentration (MIC)₅₀ and MIC₉₀ values of 121 KPC isolates from 8 to 0.03 µg/mL and 64 to 0.5 µg/mL, respectively.¹²

The pharmacodynamic parameter of efficacy for meropenem is similar to other beta-lactams: the percentage of time that the free drug concentration remains above the MIC for the organism.⁷ Therefore, the efficacy of meropenem-vaborbactam can be predicted by the ratio of the 24-hour unbound plasma vaborbactam area under the curve (AUC) to meropenem-vaborbactam MIC.

Dosing of meropenem-vaborbactam is 4 grams (meropenem 2 grams and vaborbactam 2 grams) via intravenous (IV) infusion over 3 hours, given every 8 hours for up to 14 days in patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥50 mL/min/1.73m².⁷ Renal dose adjustments are needed in the setting of reduced eGFR. Doses should be administered after dialysis since both meropenem and vaborbactam are removed by hemodialysis.¹³ Separate IV sites are required if ceftaroline or ciprofloxacin are given concomitantly with meropenem-vaborbactam since physical incompatibility can occur.¹⁴ According to information from the manufacturer, 13 other medications are also physically incompatible with meropenem-vaborbactam.

Like meropenem alone, meropenem-vaborbactam may cause seizures and other central nervous system (CNS) abnormalities.⁷ Caution is advised in patients with underlying CNS disorders. This is particularly true in patients receiving concomitant valproic acid/divalproex sodium for seizure prophylaxis since the serum concentration of these medications is decreased in the presence of meropenem, increasing the risk of breakthrough seizures. Headache (8.8%), phlebitis (4.4%), and diarrhea (3.3%) were the most frequently reported adverse reactions with meropenem-vaborbactam in clinical trials.

Clinical efficacy and safety

The efficacy and safety of meropenem-vaborbactam have been evaluated in 2 Phase III clinical trials, TANGO 1 and TANGO 2.^15,16

TANGO 1 was a multicenter, double-blind, double-dummy, noninferiority trial that compared meropenem-vaborbactam and piperacillin-tazobactam for the treatment of cUTIs including acute pyelonephritis.¹⁵ The study randomized 550 patients 1:1 to IV infusions of either meropenem 2 g-vaborbactam 2 g every 8 hours or piperacillin 4 g-tazobactam 0.5 g every 8 hours. Patients were allowed to step-down therapy to levofloxacin 500 mg orally daily after ≥5 days of IV meropenem-vaborbactam or piperacillin-tazobactam, with the goal of completing a 10-day treatment course if clinically appropriate. Response to therapy was determined at the end of IV therapy (EOIVT). The primary endpoint was the proportion of patients in the microbiological modified intent-to-treat (m-MITT) population that achieved overall success, defined as either clinical cure or improvement and microbiological eradication (<10⁴ colony-forming units/mL) at the EOIVT visit. Noninferiority was upheld if the lower limit of the 2-sided 95% confidence interval was >-15%. The most common pathogens identified were E. coli and K. pneumoniae, with baseline beta-lactamase production identified in 28.9% of patients in the m-MITT population. In the m-MITT population, overall success rates were 98.4% in the meropenem-vaborbactam group compared to 94.0% in the piperacillin-tazobactam group, a treatment difference of 4.5% (95% CI, 0.7 to 9.1) which was both noninferior and statistically superior. Drug-related treatment-emergent adverse events (TEAEs) were reported in 41 (15.1%) and 35 (12.8%) subjects who received meropenem-vaborbactam and piperacillin-tazobactam, respectively. The most common adverse events (AEs) were headache (8.8% vs. 4%, respectively) and phlebitis (4.4% vs. 0.7%, respectively). These AEs were mild to moderate and did not require study drug discontinuation. Drug-related AEs that led to therapy discontinuation occurred in 2.9% (8/272) of patients who received meropenem-vaborbactam; the majority were infusion-related reactions and hypersensitivity. Two deaths unrelated to study drug occurred in each treatment group.

TANGO 2 was a multicenter, randomized, open-label trial that compared meropenem-vaborbactam to best available therapy (BAT) for the treatment of severe Gram-negative infections due to CRE organisms (confirmed or suspected).¹⁶ Infections included cUTI/acute pyelonephritis (n=15), complicated intra-abdominal infection (cIAI) (n=3), hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) (n=5), and/or bloodstream infection (BSI) (n=20). Drugs used for BAT included aminoglycosides (amikacin, gentamicin, tobramycin), carbapenems (ertapenem, imipenem-cilastatin, meropenem), ceftazidime-avibactam, polymyxin B, colistin, and tigecycline. The study randomized patients in a 2:1 ratio to IV infusions for up to 14 days of either meropenem 2 g-vaborbactam 2 g every 8 hours or BAT with one or more agents. Key efficacy endpoints were as follows: 1) clinical cure at end of therapy (EOT) as well as test of cure (TOC; 7 days after EOT) based on localizing signs and symptoms across all infection types; and 2) 28-day all-cause mortality across all infection types. Of the 72 patients enrolled, 43 (59.7%) had documented meropenem-resistant Enterobacteriaceae (KPC-production was the main mediator of resistance) and were in the microbiological CRE modified intent-to-treat (mCRE-MITT) population. Combination therapy was used in 66.7% (10/15) of cases in the BAT group. Clinical cure rates in the mCRE-MITT population at the EOT visit were 64.3% (18/28) in the meropenem-vaborbactam group and 33.3% (5/15) in the BAT group (p-value not reported). At the TOC visit, clinical cure rates were 16/28 (57.1%) and 4/15 (26.7%), respectively (p-value not reported). Mortality rates at Day 28 were 17.9% (5/28) in the meropenem-vaborbactam group and 33.3% (5/15) in the BAT group (p-value not reported). In total, 10 patients died in the meropenem-vaborbactam group, 4 of which were related to antibiotic failure prior to study treatment. No prior antibiotic failures occurred in the BAT group. Treatment-emergent adverse events were reported in 38 (84.4%) and 23 (92.0%) subjects who received meropenem-vaborbactam and BAT, respectively. The most frequent AEs (>10%) in the meropenem-vaborbactam group were diarrhea, anemia, and hypokalemia. No serious AEs due to meropenem-vaborbactam were reported; 5 patients discontinued meropenem-vaborbactam due to a TEAE unrelated to study drug. Nephrotoxicity (increases from baseline serum creatinine ≥0.5 mg/dL), acute renal failure, and renal impairment were numerically less frequent in the meropenem-vaborbactam group compared to the BAT group.

Selected subgroup analyses

A subgroup analysis of 18 immunocompromised patients in the TANGO 2 mCRE-MITT population revealed clinical cure rates in the meropenem-vaborbactam arm of 60% (6/10) and 70% (7/10) at EOT and TOC, respectively.¹⁷ In comparison, 2 of 8 immunocompromised patients (25%) in the BAT arm had clinical cure at EOT and none at TOC.

A pooled analysis of 41 patients with renal impairment (creatinine clearance <50 mL/min) from the TANGO 1 and TANGO 2 trials revealed that the efficacy of meropenem-vaborbactam was maintained compared to normal renal function.¹⁸ Overall success at EOIVT and TOC in TANGO I were similar among groups regardless of renal function at baseline. This was not the case in TANGO II; clinical cure rates at EOT were lower in patients with baseline renal dysfunction compared to patients without renal dysfunction. However, clinical cure was higher with meropenem-vaborbactam versus BAT even in the presence of renal dysfunction.

Discussion

The approval of meropenem-vaborbactam provides clinicians with another treatment option for MDR Gram-negative infections, particularly those involving CRE. The TANGO 1 trial concluded that meropenem-vaborbactam was noninferior and superior to piperacillin-tazobactam in the treatment of cUTIs including acute pyelonephritis.¹⁵ In the TANGO 2 trial, meropenem-vaborbactam monotherapy was more effective than BAT for severe CRE infections.¹⁶ Two additional clinical trials with meropenem-vaborbactam are ongoing.^19,20 One will evaluate the pharmacokinetics, safety, and tolerability of a single dose of meropenem-vaborbactam in children (birth to <18 years of age) with serious bacterial infections.¹⁹ The TANGO III trial will compare meropenem-vaborbactam to piperacillin-tazobactam in adults with HAP/VAP.²⁰

There are some limitations to the use of meropenem-vaborbactam for the treatment of MDR Gram-negative infections. Meropenem-vaborbactam is active against some, but not all, CRE organisms.^10-12 Notable exceptions include A. baumannii, S. maltophilia, and carbapenem-resistant P. aeruginosa strains.¹⁰ Meropenem-vaborbactam also lacks activity against organisms that produce metallo-β-lactamases or oxacillinases. Clinicians should be aware that the meropenem-vaborbactam formulation contains a large sodium load (1.5 g/day with standard dosing) which may be problematic in patients with hypernatremia or who require sodium restriction.⁷ Finally, meropenem alone still adequately covers AmpC- and ESBL-producing Enterobacteriaceae, as well as select isolates of A. baumannii and P. aeruginosa.²¹ The addition of vaborbactam in patients with meropenem-susceptible organisms may stimulate downstream resistance and increase the cost of therapy; therefore, meropenem-vaborbactam should only be used after the presence of CRE has been established.

Other new antimicrobial agents are in late-stage development for the treatment of CRE infection.^2,3,22 These include imipenem-relebactam and avibactam-aztreonam. As additional beta-lactams and new cephalosporins are developed to combat MDR Gram-negative bacteria, optimal treatment of infections that involve these organisms will continue to evolve.

References

1. Trecarichi EM, Tumbarello M. Therapeutic options for carbapenem-resistant Enterobacteriaceae infections. Virulence. 2017;8(4):470-484.
2. Wong D, van Duin D. Novel beta-lactamase inhibitors: unlocking their potential in therapy. Drugs. 2017;77(6):615-628.
3. Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017;8(4):403-416
4. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. https://www.cdc.gov/drugresistance/threat-report-2013/index.html. Accessed December 13, 2017.
5. Arnold RS, Thom KA, Sharma S, et al. Emergence of Klebsiella pneumoniae carbapenemase-producing bacteria. South Med J. 2011;104(1):40-45.
6. Shields RK, Chen L, Cheng S, et al. Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during rreatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother. 2017;61(3). doi: 10.1128/AAC.02097-16
7. Vabomere [package insert]. Parsippany, NJ: The Medicines Company; 2017.
8. Hooton TM, Bradley SF, Cardenas DD. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625–663.
9. Gupta K, Grigoryan L, Trautner B. Urinary tract infection. Ann Intern Med. 2017;167(7):ITC49-ITC64.
10. Castanheira M, Huband MD, Mendes RE, et al. Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including carbapenem-resistant KPC-producing, multidrug-resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61(9). doi: 10.1128/AAC.00567-17
11. Castanheira M, Rhomberg PR, Flamm RK, et al. Effect of the beta-lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing enterobacteriaceae. Antimicrob Agents Chemother. 2016;60(9):5454–5458.
12. Lapuebla A, Abdallah M, Olafisoye O, et al. Activity of meropenem combined with RPX7009, a novel β-lactamase inhibitor, against Gram-negative clinical isolates in New York City. Antimicrob Agents Chemother. 2015;59(8):4856-4860.
13. Rubino CM, Griffith DC, Bhavnani SM, et al. Meropenem-vaborbactam (Vabomere) pharmacokinetics in subjects with chronic renal impairment, including hemodialysis. Poster presented at: 6th Annual ID Week; October 2017; San Diego, CA.
14. Vabomere Intravenous (IV) Physical Compatibility Information. The Medicines Company. Data on File. December 2017.
15. Clinical Efficacy and Safety in Patients with Complicated Urinary Tract Infection and Acute Pyelonephritis (TANGO I Clinical Trial). The Medicines Company. Data on File. December 2017.
16. Clinical Efficacy and Safety as Monotherapy in Patients with Selected Serious Infections due to Carbapenem-Resistant Enterobacteriaceae (TANGO II Clinical Trial). The Medicines Company. Data on File. December 2017.
17. Paterson D, Kwak EJ, Bhowmick T, et al. Meropenem-vaborbactam (VABOMERE) vs. best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO-II: Outcomes in immunocompromised patients. Poster presented at: 6^th Annual ID Week; October 2017; San Diego, CA.
18. Mathers A, Hope W, Kaye KS, et al. Meropenem-vaborbactam (VABOMERE): Outcomes in subjects with renal impairment in Phase 3 studies TANGO I and II. Poster presented at: 6^th Annual ID Week; October 2017; San Diego, CA.
19. U.S. National Library of Medicine. Dose-finding, Pharmacokinetics, Safety, and Tolerability of Meropenem-Vaborbactam in Pediatric Subjects With Serious Bacterial Infections. https://clinicaltrials.gov/ct2/show/NCT02687906. Accessed January 1, 2018.
20. U.S. National Library of Medicine. A Study of Meropenem-Vaborbactam Versus Piperacillin/Tazobactam in Participants With Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (TANGO III). https://clinicaltrials.gov/ct2/show/NCT03006679. Accessed January 1, 2018.
21. Gilbert DN, Eliopoulos GM, Chambers HF, Saag MS, Pavia AT, eds. The Sanford Guide to Antimicrobial Therapy. 47^th ed. Sperryville, VA: Antimicrobial Therapy, Inc; 2017.
22. Fernandes P, Martens E. Antibiotics in late clinical development. Biochem Pharmacol. 2017;1(133):152-163.

Prepared by:

Jovan Borjan, PharmD

PGY1 Pharmacy Practice Resident

University of Illinois at Chicago

February 2018

The information presented is current as of December 14^th, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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