Infection DOI 10.1007/s15010-015-0784-8
ORIGINAL PAPER
Ertapenem usage in cancer patients with and without neutropenia: a report on 97 cases from a comprehensive cancer center L. Nesher1 · F. P. Tverdek1 · S. N. Mahajan1 · R. F. Chemaly1 · Kenneth V. I. Rolston1
Received: 9 March 2015 / Accepted: 21 April 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Ertapenem is being increasingly utilized in cancer patients, but published data regarding its usage are limited. Our objective was to describe the various indications for ertapenem therapy and its safety and efficacy in cancer patients. Methods We conducted a retrospective cohort study of cancer patients who received monotherapy with ertapenem for at least 72 h, between January 2007 and February 2013. Results Among 97 unique patients who received ertapenem monotherapy, the most common indications were: (1) To facilitate discharge from the hospital of stable patients still requiring antimicrobial therapy (46 %). (2) Primary therapy of various documented infections (bacteremia, pneumonia, urinary tract infection, skin and skin structure infection) with ertapenem (28 %). (3) De-escalation from a different broad-spectrum agent or regimen to ertapenem within the hospital setting in patients not ready for discharge (25 %). The median age of the 97 patients studied was 59 years (range 9–87 years) with 52 % being men. Most patients had underlying hematologic malignancies (54 %), and 7 % were recipients of hematopoietic stem cell transplantation. Twenty-nine patients (30 %) were neutropenic, 26 % were diabetic, and 6 % had chronic lung disease. Primary ertapenem monotherapy was successful in all patients, de-escalation in 95.8 % of patients, and the strategy of discharge on outpatient therapy with ertapenem in 95.6 % of patients. Patients failing de-escalation * Kenneth V. I. Rolston [email protected] 1
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (Unit 1460), Houston, TX 77030, USA
or early discharge responded to alternative regimens. We documented no significant ertapenem associated toxicity or adverse events. Conclusions Ertapenem appears to be safe and effective for several indications in cancer patients. Keywords Ertapenem · De-escalation · Neutropenia · Cancer patients
Introduction Patients with cancer develop bacterial infections frequently, especially, but not exclusively during episodes of neutropenia [1, 2]. Many recent epidemiologic surveys have shown that ~40–60% of these infections are caused by Grampositive organisms, ~20–25% by Gram-negative organisms, and ~20–25% are polymicrobial [3–6]. Due to the presence of a multitude of immunologic deficits in cancer patients, infections can develop and progress quite rapidly. Consequently, empiric therapy with broad-spectrum antimicrobial agents (e.g. the carbapenems, extended spectrum cephalosporins, and piperacillin/tazobactam), either alone, or in combination with agents such as the aminoglycosides or vancomycin, is recommended in this setting by various societies including the Infectious Diseases Society of America (IDSA), and the National Comprehensive Cancer Network (NCCN) [7, 8]. The duration of broad-spectrum therapy remains controversial, especially in patients with prolonged neutropenia. Some experts recommend continuation of broad-spectrum coverage until recovery from neutropenia (defined as an absolute neutrophil count of >500/mm3 for 2 consecutive days) in all patients. Others favor discontinuation of the broad-spectrum regimen when clinical, radiographic, and microbiologic
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evidence of infection has resolved, even if neutropenia persists. Regardless of which approach is adopted, antimicrobial usage in neutropenic cancer patients is frequent and often prolonged. This practice, albeit necessary in these high-risk patients, has been associated with the emergence of resistant pathogens due to selection pressures, particularly among organisms such as Enterococcus species, and Gram-negative bacilli such as Pseudomonas aeruginosa [9, 10]. This problem has been magnified by the fact that the pipeline for the development of novel agents with activity against resistant bacteria remains relatively dry [11–14]. Judicious use of currently available antimicrobial agents (referred to as antimicrobial stewardship) is of paramount importance, and national guidelines recommend strategies such as de-escalation of broad-spectrum regimens as soon as clinically feasible [15]. Ertapenem, a Group 1 carbapenem, has a narrower spectrum of activity than Group 2 carbapenems (imipenem, meropenem, doripenem) and other frequently used broadspectrum agents, and may exert less selective pressure. At least one study has documented that more than 5 years of ertapenem use was not associated with the selection of resistant isolates [16]. Most Gram-negative pathogens isolated from cancer patients treated at The University of Texas MD Anderson Cancer Center with the exception of P. aeruginosa, Acinetobacter species and S. maltophilia, are susceptible to ertapenem [17]. It is uniformly active against quinolone-resistant Escherichia coli, which have become frequent pathogens in cancer patients at institutions such as ours, due to the high volume of quinolone usage for antibacterial prophylaxis [18, 19]. Additionally, once a day dosing of ertapenem increases convenience of administration in the outpatient/clinic setting and may facilitate early discharge of stable patients from the hospital, particularly those unable to take oral medications, those in whom parenteral therapy is preferred, and those with an infection caused by organisms resistant to oral agents (e.g. quinolones, trimethoprim/sulfamethoxazole) but susceptible to ertapenem. Ertapenem has been used at our institution (a 656 bed, NCI designated Comprehensive Cancer Center, devoted exclusively to the care of cancer patients) for all the indications mentioned above since its approval by the FDA. However, it has not been formally studied in this patient population and published clinical data regarding the indications, for the safety, and the efficacy of ertapenem usage in cancer patients are scarce. To fill this void, we have reviewed, and report herein, our clinical experience of ertapenem usage in cancer patients treated at our institution.
board (IRB) of the University of Texas MD Anderson Cancer Center. We queried the institutional pharmacy database and the infectious disease consultative services patient lists in order to identify unique patients hospitalized between January 2007 and March 2013 that were treated with ertapenem as a single agent (monotherapy) for at least 72 h. Electronic medical records of these patients were then reviewed in order to collect information regarding patient demographics including age, sex, type of underlying malignancy and hematopoietic stem cell transplantation status, potential risk factors for infection such as active chemotherapy, graft vs host disease, neutropenia, diabetes, and renal insufficiency. We also determined the indications for ertapenem use, the type and source of infection, response, and the duration of therapy. Patients were followed for 30 days after the discontinuation of ertapenem in order to document adverse events and relapsed or recurrent infections. For this analysis, patients were considered to have undergone de-escalation if a switch to ertapenem was made after initial therapy with some other broad-spectrum agent/ regimen (primarily in order to comply with the recommendations of our antimicrobial stewardship program) while still requiring >48 h of hospitalization. Many patients were also switched from another agent/regimen to ertapenem in order to facilitate imminent discharge from the hospital. In patients with microbiologically documented infections, deescalation or a switch to ertapenem to facilitate discharge was done only after determining that the organisms isolated were susceptible to ertapenem. We excluded patients who had received ertapenem for surgical prophylaxis during the study period, as this experience has been reported elsewhere [20]. We also excluded patients who received ertapenem in combination with other agents as it is not possible to determine the exact impact or role of ertapenem therapy in this setting. Statistical analysis We summarized the baseline demographic data including relevant statistical data for categorical variables. One-way analysis of variance, Chi-squared test, and Fisher’s exact test were used to assess the demographic and clinical differences between the groups. Significance was based on two-tailed analysis with alpha = 0.05, using SPSS software version 21 (IBM Corporation, Chicago, IL, USA).
Results Materials and methods
Patient characteristics
For this retrospective study, we obtained approval and a waiver of informed consent from the institutional review
Table 1 shows demographics and general characteristics of the 97 study patients. The mean age of the patients was
13
Ertapenem usage in cancer patients… Table 1 General characteristics of 97 patients with cancer treated with ertapenem Characteristic
n = 97
Age, median (range) Sex male Solid organ malignancy Leukemia Lymphoma Multiple myeloma receiving active chemotherapy Hematopoietic stem cell transplant Absolute neutrophil count
ORIGINAL PAPER
Ertapenem usage in cancer patients with and without neutropenia: a report on 97 cases from a comprehensive cancer center L. Nesher1 · F. P. Tverdek1 · S. N. Mahajan1 · R. F. Chemaly1 · Kenneth V. I. Rolston1
Received: 9 March 2015 / Accepted: 21 April 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Ertapenem is being increasingly utilized in cancer patients, but published data regarding its usage are limited. Our objective was to describe the various indications for ertapenem therapy and its safety and efficacy in cancer patients. Methods We conducted a retrospective cohort study of cancer patients who received monotherapy with ertapenem for at least 72 h, between January 2007 and February 2013. Results Among 97 unique patients who received ertapenem monotherapy, the most common indications were: (1) To facilitate discharge from the hospital of stable patients still requiring antimicrobial therapy (46 %). (2) Primary therapy of various documented infections (bacteremia, pneumonia, urinary tract infection, skin and skin structure infection) with ertapenem (28 %). (3) De-escalation from a different broad-spectrum agent or regimen to ertapenem within the hospital setting in patients not ready for discharge (25 %). The median age of the 97 patients studied was 59 years (range 9–87 years) with 52 % being men. Most patients had underlying hematologic malignancies (54 %), and 7 % were recipients of hematopoietic stem cell transplantation. Twenty-nine patients (30 %) were neutropenic, 26 % were diabetic, and 6 % had chronic lung disease. Primary ertapenem monotherapy was successful in all patients, de-escalation in 95.8 % of patients, and the strategy of discharge on outpatient therapy with ertapenem in 95.6 % of patients. Patients failing de-escalation * Kenneth V. I. Rolston [email protected] 1
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (Unit 1460), Houston, TX 77030, USA
or early discharge responded to alternative regimens. We documented no significant ertapenem associated toxicity or adverse events. Conclusions Ertapenem appears to be safe and effective for several indications in cancer patients. Keywords Ertapenem · De-escalation · Neutropenia · Cancer patients
Introduction Patients with cancer develop bacterial infections frequently, especially, but not exclusively during episodes of neutropenia [1, 2]. Many recent epidemiologic surveys have shown that ~40–60% of these infections are caused by Grampositive organisms, ~20–25% by Gram-negative organisms, and ~20–25% are polymicrobial [3–6]. Due to the presence of a multitude of immunologic deficits in cancer patients, infections can develop and progress quite rapidly. Consequently, empiric therapy with broad-spectrum antimicrobial agents (e.g. the carbapenems, extended spectrum cephalosporins, and piperacillin/tazobactam), either alone, or in combination with agents such as the aminoglycosides or vancomycin, is recommended in this setting by various societies including the Infectious Diseases Society of America (IDSA), and the National Comprehensive Cancer Network (NCCN) [7, 8]. The duration of broad-spectrum therapy remains controversial, especially in patients with prolonged neutropenia. Some experts recommend continuation of broad-spectrum coverage until recovery from neutropenia (defined as an absolute neutrophil count of >500/mm3 for 2 consecutive days) in all patients. Others favor discontinuation of the broad-spectrum regimen when clinical, radiographic, and microbiologic
13
L.Nesher et al.
evidence of infection has resolved, even if neutropenia persists. Regardless of which approach is adopted, antimicrobial usage in neutropenic cancer patients is frequent and often prolonged. This practice, albeit necessary in these high-risk patients, has been associated with the emergence of resistant pathogens due to selection pressures, particularly among organisms such as Enterococcus species, and Gram-negative bacilli such as Pseudomonas aeruginosa [9, 10]. This problem has been magnified by the fact that the pipeline for the development of novel agents with activity against resistant bacteria remains relatively dry [11–14]. Judicious use of currently available antimicrobial agents (referred to as antimicrobial stewardship) is of paramount importance, and national guidelines recommend strategies such as de-escalation of broad-spectrum regimens as soon as clinically feasible [15]. Ertapenem, a Group 1 carbapenem, has a narrower spectrum of activity than Group 2 carbapenems (imipenem, meropenem, doripenem) and other frequently used broadspectrum agents, and may exert less selective pressure. At least one study has documented that more than 5 years of ertapenem use was not associated with the selection of resistant isolates [16]. Most Gram-negative pathogens isolated from cancer patients treated at The University of Texas MD Anderson Cancer Center with the exception of P. aeruginosa, Acinetobacter species and S. maltophilia, are susceptible to ertapenem [17]. It is uniformly active against quinolone-resistant Escherichia coli, which have become frequent pathogens in cancer patients at institutions such as ours, due to the high volume of quinolone usage for antibacterial prophylaxis [18, 19]. Additionally, once a day dosing of ertapenem increases convenience of administration in the outpatient/clinic setting and may facilitate early discharge of stable patients from the hospital, particularly those unable to take oral medications, those in whom parenteral therapy is preferred, and those with an infection caused by organisms resistant to oral agents (e.g. quinolones, trimethoprim/sulfamethoxazole) but susceptible to ertapenem. Ertapenem has been used at our institution (a 656 bed, NCI designated Comprehensive Cancer Center, devoted exclusively to the care of cancer patients) for all the indications mentioned above since its approval by the FDA. However, it has not been formally studied in this patient population and published clinical data regarding the indications, for the safety, and the efficacy of ertapenem usage in cancer patients are scarce. To fill this void, we have reviewed, and report herein, our clinical experience of ertapenem usage in cancer patients treated at our institution.
board (IRB) of the University of Texas MD Anderson Cancer Center. We queried the institutional pharmacy database and the infectious disease consultative services patient lists in order to identify unique patients hospitalized between January 2007 and March 2013 that were treated with ertapenem as a single agent (monotherapy) for at least 72 h. Electronic medical records of these patients were then reviewed in order to collect information regarding patient demographics including age, sex, type of underlying malignancy and hematopoietic stem cell transplantation status, potential risk factors for infection such as active chemotherapy, graft vs host disease, neutropenia, diabetes, and renal insufficiency. We also determined the indications for ertapenem use, the type and source of infection, response, and the duration of therapy. Patients were followed for 30 days after the discontinuation of ertapenem in order to document adverse events and relapsed or recurrent infections. For this analysis, patients were considered to have undergone de-escalation if a switch to ertapenem was made after initial therapy with some other broad-spectrum agent/ regimen (primarily in order to comply with the recommendations of our antimicrobial stewardship program) while still requiring >48 h of hospitalization. Many patients were also switched from another agent/regimen to ertapenem in order to facilitate imminent discharge from the hospital. In patients with microbiologically documented infections, deescalation or a switch to ertapenem to facilitate discharge was done only after determining that the organisms isolated were susceptible to ertapenem. We excluded patients who had received ertapenem for surgical prophylaxis during the study period, as this experience has been reported elsewhere [20]. We also excluded patients who received ertapenem in combination with other agents as it is not possible to determine the exact impact or role of ertapenem therapy in this setting. Statistical analysis We summarized the baseline demographic data including relevant statistical data for categorical variables. One-way analysis of variance, Chi-squared test, and Fisher’s exact test were used to assess the demographic and clinical differences between the groups. Significance was based on two-tailed analysis with alpha = 0.05, using SPSS software version 21 (IBM Corporation, Chicago, IL, USA).
Results Materials and methods
Patient characteristics
For this retrospective study, we obtained approval and a waiver of informed consent from the institutional review
Table 1 shows demographics and general characteristics of the 97 study patients. The mean age of the patients was
13
Ertapenem usage in cancer patients… Table 1 General characteristics of 97 patients with cancer treated with ertapenem Characteristic
n = 97
Age, median (range) Sex male Solid organ malignancy Leukemia Lymphoma Multiple myeloma receiving active chemotherapy Hematopoietic stem cell transplant Absolute neutrophil count
