Clinical Trials to Reduce the Risk of Antimicrobial Resistance - Full Text View

Purpose

The primary objective of this study is to demonstrate a low rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp during the treatment of hospitalized patients with pneumonia requiring mechanical ventilation treated with PD optimized meropenem administered as a prolonged infusion in combination with a parenteral aminoglycoside plus tobramycin by inhalation (Group 1) compared to therapy with meropenem alone (Group 2 - control arm).

Condition	Intervention	Phase
Bacterial Pneumonia	Drug: IV meropenem; parenteral aminoglycoside Drug: I.V. Meropenem	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Impact of Aggressive Empiric Antibiotic Therapy and Duration of Therapy on the Emergence of Antimicrobial Resistance During the Treatment of Hospitalized Subjects With Pneumonia Requiring Mechanical Ventilation

Resource links provided by NLM:

MedlinePlus related topics: Antibiotics Pneumonia

Drug Information available for: Gentamicin Gentamicin sulfate Sulfate ion Tobramycin Amikacin sulfate Tobramycin sulfate Meropenem

U.S. FDA Resources

Further study details as provided by University of Florida:

Primary Outcome Measures:

Rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp [ Time Frame: Day 5 or Early Extubation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Efficacy(clinical outcome) and safety (numbers of SAEs) of PD optimized/combination therapy (Group 1) of meropenem (2g infused over 3 hours Q8h) plus aminoglycoside parenterally [ Time Frame: Test-of-Cure Visit (TOC, 7-14 days post therapy) and Late-Follow-Up (LFU 14 days after test of cure or up to 42 ± 3 days after study drug initiation) ] [ Designated as safety issue: No ]
The efficacy and safety of PD optimized/combination therapy (Group 1) of meropenem (2g infused over 3 hours Q8h) plus aminoglycoside parenterally (tobramycin/or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kgIV Q 24h) plus tobramycin nebulization in the treatment of hospitalized subjects with pneumonia requiring mechanical ventilation caused by P. aeruginosa, Acinetobacter spp, (or other Gram-negative pathogens) when compared to the Group 2 (control arm) of monotherapy meropenem
A pharmacodynamic relationship between meropenem exposure in plasma and extracellular lung fluid (ELF) [ Time Frame: Patients will participate up to 45 days ] [ Designated as safety issue: No ]
28 day all-cause mortality between the treatment groups. [ Time Frame: Late-Follow-Up (LFU, 30 (±2) days Post Therapy) ] [ Designated as safety issue: No ]
Microbiological response at EOT, TOC and LFU between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
Rates of pathogen response to those seen in the control arm. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
Rates of resistance of other Gram-negative bacteria (non-Pseudomonas or Acinetobacter spp) between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
The proportion of subjects whose repeat cultures are negative (e.g. rates of clearance of bacterial infection) at Day 5 between treatment groups and among fermentor and non-fermentor pathogens. [ Time Frame: Day 5/EE ] [ Designated as safety issue: No ]
Clinical outcome in proportion of subjects who received prior antibiotics vs. those with no prior antibiotics [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
Health care resource utilization (length of ICU stay, antibiotic usage, length of hospitalization, and duration of ventilation) between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]

Estimated Enrollment:	480
Study Start Date:	January 2013
Estimated Study Completion Date:	September 2016
Estimated Primary Completion Date:	September 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: IV meropenem; parenteral aminoglycoside Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization	Drug: IV meropenem; parenteral aminoglycoside Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization Other Names: Merrem I.V. Tobramycin for Injection USP Tobramycin Inhalation Solution USP Gentamicin Sulfate, Injection Solution Concentrate Amikacin Sulfate Injection USP
Active Comparator: I.V. Meropenem Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).	Drug: I.V. Meropenem Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Other Name: Merrem I.V.

Arms

Assigned Interventions

Experimental: IV meropenem; parenteral aminoglycoside

Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization

Drug: IV meropenem; parenteral aminoglycoside

Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization

Other Names:

Merrem I.V.
Tobramycin for Injection USP
Tobramycin Inhalation Solution USP
Gentamicin Sulfate, Injection Solution Concentrate
Amikacin Sulfate Injection USP

Active Comparator: I.V. Meropenem

Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).

Drug: I.V. Meropenem

Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).

Other Name: Merrem I.V.

Detailed Description:

The goal of this clinical study is to demonstrate that the application of pharmacodynamic dosing principles to the antibiotic treatment of hospitalized subjects with culture-documented pneumonia (including HABP, VABP and HCAP) requiring mechanical ventilation can inhibit the emergence of antibiotic-resistant organisms during treatment and therefore may improve the rate of a satisfactory clinical response. Antibiotic resistance is defined as an increase in meropenem or aminoglycoside MIC by two tube dilutions (fourfold) from baseline. In animal models of infection, the pharmacodynamic driver for bactericidal effect by β lactam antibiotics such as meropenem is the proportion of the dosing interval during which plasma drug levels are maintained above the MIC of the causative pathogen. The hypothesis of this study is that prolongation of time above MIC by increasing total meropenem dose and the duration of infusion will counter-select for the emergence of antimicrobial resistance during the treatment of hospitalized subjects with pneumonia (i.e. HABP, VABP and HCAP) caused by P.aeruginosa, Acinetobacter species (spp), or other pathogens with intermediate susceptibility to meropenem, and that the addition of parenteral aminoglycosides (amikacin, tobramycin or gentamicin) and nebulized aminoglycoside (tobramycin) given along optimal pharmacodynamic principles will further reduce the likelihood of resistance emergence, particularly among the non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp. The observed incidence of resistance emergence to meropenem will be compared across therapeutic regimens.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

Written informed consent by the subject/subject's legal rep.
Hospitalized males or females, ≥ 18 yrs with respiratory failure requiring mechanical ventilation and clinical suspicion of HABP, HCAP or VABP.
Onset of exacerbation of pneumonia at least 72 hours after admission to an acute care facility or onset of pneumonia in a nursing home or rehabilitation facility with subsequent transfer to an acute care facility.
Women of childbearing potential if their pregnancy test is negative and they are instructed to abstain from sexual intercourse for the duration of the study;or contraceptive measures are used until all follow-up procedures are complete.
Subjects who have received previous antibacterial therapy within 14 days of pre-treatment bronchoscopy entry may be entered only if the subject has not responded clinically.
Patients should have clinical findings that support a diagnosis of HABP/VABP/HCAP.
Within 48 hours before starting empiric therapy a subject's chest radiograph should show the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of pneumonia.
Within 24 hours before the start of empiric study therapy, a quantitative culture of BAL fluid must be obtained.
Patients with VABP should have a CPIS of greater than 6, and at least one of the following present at enrollment:auscultatory findings on pulmonary exam of rales and/or evidence of pulmonary consolidation; acute changes made in the ventilator support system to enhance oxygenation, as determined by arterial blood gas, or worsening PaO2/FiO2.

Exclusion Criteria:

Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or equal to 16µg/ml) or a prior meropenem therapy failure.
Subjects with known or suspected type I hypersensitivity (e.g., anaphylaxis) to cephalosporins, penicillins, monobactams, or carbapenems.
Women who are pregnant or lactating.
Subjects taking anticonvulsant medications for a known seizure disorder.
Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of pneumonia.
Subjects with primary lung cancer or another malignancy metastatic to the lungs.
Subjects who were previously enrolled in this study.
Subjects who have had an investigational drug or have used an investigational device within 30 days prior to entering the study.
Subjects with another focus of infection requiring concurrent antibiotics that would interfere with evaluation of the response to study drug.
Subjects with cystic fibrosis, acquired immune deficiency syndrome (AIDS) with a CD4 lymphocyte count <200 cells/µl, neutropenia (absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis.
Subjects with little chance of survival for the duration of study therapy.
Subjects with an APACHE II score >35.
Subjects with underlying condition(s) which would make it difficult to interpret response to the study drugs.
Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock are not eligible for enrollment.
Subjects who have undergone bone marrow transplantation.
Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01570192

Contacts

Contact: George L. Drusano, M.D.	518-641-6996	gdrusano@ufl.edu
Contact: Evelyn J. Ellis-Grosse, Ph.D.	484-597-0232	evelyn@e2gconsulting.com

Locations

United States, California
InClin, Inc.	Active, not recruiting
San Mateo, California, United States, 94403
United States, Florida
UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine	Not yet recruiting
Gainesville, Florida, United States, 32610
Contact: Hassan Alnuaimat,, MD 352-273-8740 alnuah@medicine.ufl.edu
Contact: Pamela Schreck, RN 352-294-5195 pamela.schreck@alphaone.ufl.edu
Principal Investigator: Hassan Alnuaimat, MD
United States, Georgia
Emory University	Active, not recruiting
Atlanta, Georgia, United States, 30322-4250
United States, Illinois
Northwestern University	Recruiting
Chicago, Illinois, United States, 60611
Contact: Richard Wunderink, MD 312-695-1878 r-wunderink@northwestern.edu
Contact: Helen Donnelly, RN 312-695-1881 h-donnelly@northwestern.edu
Principal Investigator: Richard Wunderink, MD
United States, Iowa
JMI Laboratories	Active, not recruiting
North Liberty, Iowa, United States, 52317
United States, Missouri
Washington University in St. Louis School of Medicine	Active, not recruiting
St. Louis, Missouri, United States, 63130
United States, New York
Weill Cornell Medical Center of Cornell University	Not yet recruiting
New York, New York, United States, 10065
Contact: Thomas J Walsh, MD 301-693-1890 thw2003@med.cornell.edu
Contact: Ruta Petraitiene, RN 301-693-1890 rop2016@med.cornell.edu
Principal Investigator: Thomas J Walsh, MD
United States, North Carolina
Wake Forest University Health Sciences	Active, not recruiting
Winston-Salem, North Carolina, United States, 27157
France
Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere	Active, not recruiting
Paris, France, Cedex 13
Germany
Medizinische Hochschule	Active, not recruiting
Hannover, Germany, 30625
Hannover Clinical Trial Center GmbH	Active, not recruiting
Hannover, Germany, 30625
Spain
Hospital Vall d'Hebron	Not yet recruiting
Barcelona, Spain, 08035
Contact: Jordi Rello, MD 34 932746209 jrello@crips.es; jrello@vhebron.net
Contact: Anais
Principal Investigator: Jordi Rello, MD

Sponsors and Collaborators

University of Florida

Investigators

Principal Investigator:

George L Drusano, MD

University of Florida

More Information

Publications:

Calandra GB, Hesney M, Brown KR. Imipenem/cilastatin therapy of serious infections: a U.S. multicenter noncomparative trial. Clin Ther. 1985;7(2):225-38.

Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998 Jan;26(1):1-10; quiz 11-2. Review.

Craig WA. The pharmacology of meropenem, a new carbapenem antibiotic. Clin Infect Dis. 1997 Feb;24 Suppl 2:S266-75. Review.

Dandekar PK, Maglio D, Sutherland CA, Nightingale CH, Nicolau DP. Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion. Pharmacotherapy. 2003 Aug;23(8):988-91.

Drusano GL. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin Infect Dis. 2003 Jan 15;36(Suppl 1):S42-50.

Drusano GL, Liu W, Fregeau C, Kulawy R, Louie A. Differing effects of combination chemotherapy with meropenem and tobramycin on cell kill and suppression of resistance of wild-type Pseudomonas aeruginosa PAO1 and its isogenic MexAB efflux pump-overexpressed mutant. Antimicrob Agents Chemother. 2009 Jun;53(6):2266-73. Epub 2009 Mar 16.

Edwards JR, Turner PJ, Wannop C, Withnell ES, Grindey AJ, Nairn K. In vitro antibacterial activity of SM-7338, a carbapenem antibiotic with stability to dehydropeptidase I. Antimicrob Agents Chemother. 1989 Feb;33(2):215-22.

Fagon JY, Chastre J, Novara A, Medioni P, Gibert C. Characterization of intensive care unit patients using a model based on the presence or absence of organ dysfunctions and/or infection: the ODIN model. Intensive Care Med. 1993;19(3):137-44.

Fink MP, Snydman DR, Niederman MS, Leeper KV Jr, Johnson RH, Heard SO, Wunderink RG, Caldwell JW, Schentag JJ, Siami GA, et al. Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group. Antimicrob Agents Chemother. 1994 Mar;38(3):547-57.

Hamacher J, Vogel F, Lichey J, Kohl FV, Diwok K, Wendel H, Lode H. Treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease in hospitalised patients--a comparison of meropenem and imipenem/cilastatin. COPD Study Group. J Antimicrob Chemother. 1995 Jul;36 Suppl A:121-33.

Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1249-56.

Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999 Feb;115(2):462-74.

Kollef MH, Silver P, Murphy DM, Trovillion E. The effect of late-onset ventilator-associated pneumonia in determining patient mortality. Chest. 1995 Dec;108(6):1655-62.

Lode H, Hamacher J, Eller J, Schaberg T. Changing role of carbapenems in the treatment of lower respiratory tract infections. Scand J Infect Dis Suppl. 1995;96:17-23. Review.

Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C, Matera J, Jolly EC. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest. 1997 Mar;111(3):676-85.

McEachern R, Campbell GD Jr. Hospital-acquired pneumonia: epidemiology, etiology, and treatment. Infect Dis Clin North Am. 1998 Sep;12(3):761-79, x. Review.

Meduri GU, Chastre J. The standardization of bronchoscopic techniques for ventilator-associated pneumonia. Chest. 1992 Nov;102(5 Suppl 1):557S-564S. Review.

Moellering RC Jr, Eliopoulos GM, Sentochnik DE. The carbapenems: new broad spectrum beta-lactam antibiotics. J Antimicrob Chemother. 1989 Sep;24 Suppl A:1-7. Review.

Quinn JP, Studemeister AE, DiVincenzo CA, Lerner SA. Resistance to imipenem in Pseudomonas aeruginosa: clinical experience and biochemical mechanisms. Rev Infect Dis. 1988 Jul-Aug;10(4):892-8. Review.

Scheld WM, Mandell GL. Nosocomial pneumonia: pathogenesis and recent advances in diagnosis and therapy. Rev Infect Dis. 1991 Jul-Aug;13 Suppl 9:S743-51. Review.

Torres A, Aznar R, Gatell JM, Jiménez P, González J, Ferrer A, Celis R, Rodriguez-Roisin R. Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Respir Dis. 1990 Sep;142(3):523-8.

Torres A, Bauer TT, León-Gil C, Castillo F, Alvarez-Lerma F, Martínez-Pellús A, Leal-Noval SR, Nadal P, Palomar M, Blanquer J, Ros F. Treatment of severe nosocomial pneumonia: a prospective randomised comparison of intravenous ciprofloxacin with imipenem/cilastatin. Thorax. 2000 Dec;55(12):1033-9.

Trouillet JL, Chastre J, Vuagnat A, Joly-Guillou ML, Combaux D, Dombret MC, Gibert C. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am J Respir Crit Care Med. 1998 Feb;157(2):531-9.

Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT01570192 History of Changes
Other Study ID Numbers:	10-0060
Study First Received:	March 22, 2012
Last Updated:	April 18, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Florida:

gram negative pathogens
Pseudomonas aeruginosa
Acinetobacter

HCAP
VABP
HABP

Additional relevant MeSH terms:

Pneumonia, Bacterial
Pneumonia
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Amikacin
Tobramycin
Gentamicins

Meropenem
Anti-Infective Agents
Anti-Bacterial Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 19, 2013