Safety of high-dose doripenem in adult patients with cystic fibrosis

Abstract

Background:

High doses of β-lactam antibiotics have been advocated for acute pulmonary exacerbations caused by Pseudomonas aeruginosa in patients with cystic fibrosis (CF) secondary to high minimum inhibitory concentrations (MIC) of the infecting organisms. Some β-lactam antibiotics have increased elimination in CF patients. This case series examines the safety of high-dose doripenem (HDD), 2 g intravenously every 8 hours, which is 4 times the labeled dose, in CF patients.

Methods:

This was a retrospective, single site, chart review of all CF patients given HDD during a 3-year period. Adverse events were prospectively defined using labeled definitions within the package insert and the medical literature. A standard case report form was used to collect demographic details, antibiotic lengths of therapy and adverse events.

Results:

A total of 17 patients (9 males), with a median age of 24 years, contributed 43 unique visits and 382 HDD exposure days. Mean duration of inpatient doripenem use was 8.9 days. Concurrent antibiotics were common, with a median number of additional antibiotics per admission of three. The median number of adverse effects documented was two. The most common adverse event was anemia, which was identified in 41 of 43 visits, but was present on admission in 31 instances. One patient developed leukopenia for 1 day, but returned to normal without dose adjustment. There were three instances of Clostridium difficile infection. One patient was documented to have an allergic reaction that led to discontinuation, but was ultimately rechallenged without adverse effect. Other common adverse events were gastrointestinal in origin. No other possible adverse effects led to discontinuation of the drug.

Conclusions:

In adult patients with CF, HDD in combination with other antibiotics did not lead to adverse effects necessitating discontinuation. HDD should be considered in this selected patient population, particularly when high MIC organisms are identified.

Introduction

Chronic infection with Pseudomonas aeruginosa is a leading cause of acute pulmonary exacerbations (APEs) and hospitalizations in patients with cystic fibrosis (CF). Over 70% of adult CF patients are colonized with P. aeruginosa and are at risk for accelerated loss of pulmonary function and decreased survival [Parkins and Elborn, 2010; Gaspar et al. 2013]. Beta-lactam antibiotic therapy directed against P. aeruginosa is a critical component in the treatment of APEs in patients with CF. High doses are utilized in CF patients to overcome high minimum inhibitory concentrations (MICs) by resistant pathogens, higher volumes of distribution, shorter halflives and difficulty achieving adequate concentrations in the bronchial secretions of CF patients compared with non-CF patients [Flume et al. 2009; Zobell et al. 2013].

Carbapenems have demonstrated to be bactericidal against many Gram-negative bacteria, including P. aeruginosa. Doripenem, the newest of the carbapenems, has shown to have 2–4 fold greater in vitro activity against P. aeruginosa than either meropenem or imipenem, and up to 32-fold greater activity than other antibiotics routinely used in patients with CF [Cirillo et al. 2009; Mandell, 2009; Paterson and Depestel, 2009; Jones et al. 2006; Castanheira et al. 2009]. Regimens with doses greater than the labeled maximum dose are needed to maximize the pharmacodynamic parameters that predict efficacy in high MIC organisms, namely 50% of time above the MIC [Goyal et al. 2012; Traczewski and Brown, 2006].

In order to achieve this pharmacodynamic target, Hartford Hospital has implemented a doripenem dosing protocol that utilizes high-dose doripenem (HDD) 2000 mg intravenously (IV) every 8 hours infused over 4 hours, in patients with CF. The objective of this project was to describe the prevalence and spectrum of adverse events of the HDD dosing strategy used at Hartford Hospital, 2000 mg IV administered every 8 hours over 4 hours, to treat APEs in patients with CF. A safety analysis of HDD is particularly important in light of a report documenting the potential utility and recommendation for this doripenem dosing scheme, while simultaneously describing that no Cystic Fibrosis Foundation accredited centers had reported using it or safety analysis of it utilizing multiple doses in adults [Zobell et al. 2012].

Methods

This study was a retrospective, observational chart review of patients aged 18 years or older admitted from 1 January 2009 to 31 December 2012. Human subjects’ protection approval was granted by Hartford Hospital’s Investigational Review Board. To be included in the study, patients had to have a documented diagnosis of CF and received an order for the HDD regimen, namely, doripenem 2000 mg IV infused every 8 hours. Eligible patients were identified from data extracted from the pharmacy inpatient verification system. Each patient needed to receive at least one dose of HDD per the medication administration record to be included in the study.

For each identified patient admission, the electronic health record was reviewed for evidence of adverse events associated with doripenem administration listed in the package insert and identified through the US Food and Drug Administration’s MedWatch program [Ortho-McNeil-Janssen Pharmaceuticals, 2009]. The adverse events investigated and associated with lab values included anemia (hemoglobin <13.7 g/dl for men and <12.2 g/dl for women), leukopenia (white blood cell count <3.0 × 10⁹/l), neutropenia (polynuclear neutrophil count <1.5 × 10⁹/l), thrombocytopenia (platelets <100 × 10⁹/l), hepatic transaminase elevation (hepatic enzymes >3× upper limit of normal) and evidence of Clostridium difficile infection (a positive laboratory test for C. difficile antigens) [Beutler and Waalen, 2006; Abboud and Kaplowitz, 2007; Benichou, 1994]. Both the electronic health record database and provider notes were reviewed to assess for the occurrence of the following events: pruritus (a documented rash and/or the use of antihistamines), rash, headache, phlebitis, nausea (reported as nausea, emesis, or the use of antiemetics), diarrhea, oral candidiasis (documented candidiasis or the use of either oral nystatin or oral clotrimazole therapy), anaphylaxis reactions, seizures, toxic epidermal necrolysis and Stevens–Johnson Syndrome. Additional information collected included height, weight, serum creatinine, length of stay, and duration of HDD therapy. The safety profile of this HDD regimen was described by determining the prevalence of these known adverse events in the study population using descriptive statistics.

Results

A total of 18 patients with CF received orders for HDD 2000 mg infused every 8 hours from 1 January 2009 to 31 December 2012. However, two patients never received HDD according to a review of the medication administration record. The remaining 16 patients met inclusion criteria and comprised the study population. The 16 patients contributed 43 unique admissions and 382 HDD exposure days. Patient demographic and admission data are summarized in Table 1.

Table 1.

Summary of patient demographic and admission data.

Characteristic	Result
Gender, n (%)	9 males (56.3%)
Ethnicity, n (%)	16 white (100%)
Age, median (IQR)	24 (21–37)
Length of stay, median (IQR)	11 (7–14)
Duration of doripenem therapy, median (IQR)	7 (4–13)
Concurrent antibiotics, median (IQR)	3 (2–4)
Serum creatinine, median (IQR)	0.5 (0.5–0.8)

IQR, interquartile range.

From the 43 patient admissions, 81 unique adverse events were discovered during the review, with a median of 2 events [interquartile range (IQR) 1–2)] per admission. Event occurrences and their associated incidence are summarized in Table 2. Anemia was the most common adverse event, occurring in 41 of the 43 admissions. However, anemia was present in 31 of the 41 admissions prior to the start of doripenem.

Table 2.

Summary of adverse event data.

Reaction	Events	Incidence
Anemia	41	95.3%
Diarrhea	11	25.6%
Nausea/vomiting/antiemetics	9	20.9%
Headache	6	14.0%
Clostridium difficile positive	3	7.0%
Oral candidiasis/oral nystatin	3	7.0%
Other	2	4.7%
Pruritus/antihistamines	2	4.7%
Rash	2	4.7%
Anaphylaxis	1	2.3%
Leukopenia	1	2.3%
Total	81

One patient had a dose reduction based on increased liver transaminases that did not meet prespecified criteria of three times the upper limit of normal. Additionally, one patient had a reported allergic reaction that occurred within 15 minutes of initiating doripenem that led to discontinuation. However, the patient was ultimately rechallenged with doripenem without adverse effect. No other treatment-related adverse events led to the discontinuation of HDD therapy. One patient developed leukopenia with a white blood cell count of 2.8 × 10⁹/l on day 4 of doripenem administration. However, none of the subsequent readings met the predefined criteria for leukopenia and HDD was not discontinued in this patient. There were no documented or reported occurrences of neutropenia, thrombocytopenia, phlebitis, seizures, Stevens–Johnson syndrome or toxic epidermal necrolysis syndrome that met the predefined criteria.

Concurrent antibiotics were common, with half of all patients receiving at least three per admission. Most concomitant antibiotics were initiated at the same time doripenem was initiated. Table 3 summarizes the concurrent antibiotic data.

Table 3.

Concurrent antibiotic orders.

Antibiotic	Number of admissions with concurrent order
Azithromycin	23
Tobramycin	21
Minocycline	12
Aztreonam	11
Ceftazidime	10
Voriconazole	10
Levofloxacin	8
Piperacillin-tazobactam	7
Trimethoprim-sulfamethoxazole	7
Ciprofloxacin	5
Vancomycin	5
Fluconazole	4
Amikacin	3
Cefazolin	2
Cefepime	2
Linezolid	2
Meropenem	2
Tigecycline	2

Discussion

To the best of our knowledge, this is the first case series in adults to evaluate the safety of administering doripenem 2 g IV every 8 hours for multiple doses in adult CF patients. Although the rate of adverse events in this study was high, the patients’ baseline disease states likely contributed significantly, and ultimately, the medication and dose were well tolerated. This is evident in that only one patient had a dose reduction of medication attributed to an adverse effect of HDD, which was secondary to an elevation in liver transaminases that were not above three times the upper limit of normal.

Two serious dose-dependent complications exist with carbapenem therapy: central nervous system toxicity, including seizures; and various blood dyscrasias including neutropenia, anemia and thrombocytopenia [Norrby, 2000; Miller et al. 2011; Lagacé-Wiens and Rubinstein, 2012]. Rates of seizures with carbapenem therapy are reported to be <2% with standard dosing [Nicolau, 2008]. This study utilized a significantly higher dose of doripenem in this patient population with no reports of seizures. The rate of anemia in our study population was high, 95% of patient admissions utilizing HDD had anemia by the end of therapy, although 31 of 44 admissions the patient had anemia before beginning therapy. Anemia can be common in patients with CF and its prevalence has been reported to be >50% in adult patients [von Drygalski and Biller, 2008]. Anemia can arise from a multitude of reasons including spinocerebellar degeneration or hemolytic anemia because of vitamin E deficiency, iron deficiency anemia and anemia of chronic disease. Other hematological adverse events were rare.

Gastrointestinal adverse events were common in this population with diarrhea and nausea/emesis reported in 25.6% and 20.9% of admissions, respectively. Similar to anemia, these symptoms are common in the CF population resulting from pancreatic insufficiency which develops in up to 90% of patients with CF [O’Sullivan and Freedman, 2009].

Cirillo and colleagues examined the pharmacokinetics and safety of HDD in adult CF patients (n = 10) compared with healthy controls (n = 24). The study subjects received either a single dose of 1 g or 2 g. One patient did experience nausea and hypertension during the infusion that resulted in that patient being withdrawn. Seven treatment emergent adverse events were report in four patients, all of which were rated as mild to moderate [Cirillo et al. 2012]. Similar to our results, HDD in this population appeared to be tolerated. Higher doses of doripenem have also been utilized in pediatric patients. Zobell and colleagues described a case series of pediatric CF patients who received high doses of doripenem as a result of a national meropenem shortage. Patients received between 75 and 90 mg/kg/day of the drug in 3 divided doses utilizing an infusion of 1 hour. Possible adverse reactions to the drug were mild in nature and did not require discontinuation [Zobell et al. 2014].

The causality of the relationship between the incidences of the adverse events identified and HDD in this study cannot be determined due to the retrospective design, concurrent antibiotics administered, and the underlying disease state of patients.

Conclusion

Based on this case series results, we conclude that HDD, in combination with other antibiotics, did not lead to adverse events necessitating discontinuation of therapy. HDD should be considered in adult patients with CF, particularly when organisms with high MICs to doripenem are identified and therapeutic alternatives are not available.