Antibiotic Utilization in Deceased Organ Donors

Abstract

Antibiotic use in deceased organ donors has not been previously described. In a retrospective cohort of 440 donors, we found 427 (97%) received at least one antibiotic course, 312 (71%) received broad-spectrum antibiotics, and 61 (14%) received potentially redundant antibiotics during their terminal hospitalization, suggesting a need for stewardship.

There remains significant apprehension in the field of solid organ transplantation (SOT) about the use of donor organs that are infected or colonized with a multidrug-resistant organism (MDRO), due to the concern for an MDRO donor-derived infection (DDI) in the SOT recipient [1, 2]. One of the most important risk factors for MDRO colonization and infection, including among deceased organ donors, is prior exposure to antibiotics [3, 4]; indeed, work by our group has demonstrated that antibiotic exposures among potential organ donors are associated with up to a 13% increase in the risk of an MDRO being identified on donor culture [5]. Thus, evaluation of antibiotic exposures among potential organ donors is critical, in order to avoid nonessential antibiotic use and the associated increased risk for MDRO carriage and subsequent MDRO DDIs among SOT recipients.

To our knowledge, there are no prior studies that have described antibiotic utilization in deceased organ donors. Thus, we sought to describe and quantify antibiotic utilization among deceased organ donors, specifically during their terminal hospitalization and peri-organ procurement.

METHODS

Study Design and Setting

A retrospective cohort study was performed at 4 transplant centers in the Philadelphia region: the Hospital of the University of Pennsylvania, Temple University Hospital, Hahnemann University Hospital, and Albert Einstein Medical Center.

Study Population

The initial source population included all deceased donors who were evaluated by the local organ procurement organization (OPO)—the Gift of Life Donor Program (GLDP)—and who ultimately donated at least one organ to a recipient at one of the participating transplant centers between 1 January 2015 and 1 July 2016. Eligible donors were identified by the GLDP, which coordinates and maintains records on all local organ donation. No donors were excluded from the study. The study was approved by the institutional review board at each of the participating transplant centers.

Outcomes

For the descriptive analyses of antibiotic exposures, the following outcomes were assessed (see Supplementary Data for detailed definitions): (1) antibiotic utilization by “antibiotic class,” (2) antibiotic utilization by “antibiotic category” (narrow- vs broad- spectrum), (3) number of antibiotics administered per donor, (4) antibiotic combinations, (5) total antibiotic days of therapy (DOTs) [6], (6) total antibiotic length of therapy [6], (7) antibiotic spectrum index [7], and (8) potentially redundant antibiotic coverage.

Although it was not possible to discern the exact indication for each antibiotic given to the donors, we considered those antibiotics given within 24 hours of organ procurement to be “peri-procurement prophylaxis,” since the GLDP typically manages potential organ donors during the final 24-hour period before procurement in order to optimize organ donation.

Data Collection

Data on donors were abstracted from the GLDP medical record system. Information was collected on demographics, comorbidities, microbiological results, and medications including antibiotic administrations. Details on all antibiotics administered during the donor’s terminal hospitalization leading up to, and including, those given during organ procurement in the operating room were recorded, including antibiotic name, route of administration, and duration of therapy.

Statistical Analysis

Continuous outcomes were described using the median, interquartile range (IQR), and full range. Categorical outcomes were described using the number and proportion. In instances of missing data, complete case analysis was performed. All analyses were performed using STATA version 15.0 (StataCorp, College Station, TX).

RESULTS

Study Population

A total of 440 deceased organ donors were included in the cohort. Their baseline characteristics have been published previously [5]. In brief, the median age was 38 years (IQR, 27–52 years), and 183 (42%) were women. Sixty-four (15%) donated after circulatory death (DCD) and 84 (19%) were expanded-criteria donors (ECDs). The median length of stay for the terminal hospitalization was 3 days (IQR, 2–5; range, 1–84 days).

Antibiotic Utilization in Deceased Organ Donors

Of the 440 organ donors in the cohort, 427 (97%) received at least one course of antibiotic therapy during their terminal hospitalization and 400 (91%) received at least one antibiotic dose outside of the peri-procurement period (Table 1). The most commonly prescribed antibiotics were first-generation cephalosporins (337; 77%), fourth-generation cephalosporins (140; 32%), third-generation cephalosporins (126; 28%), and intravenous (IV) vancomycin (104; 24%). There were 312 (71%) donors who received a broad-spectrum antibiotic, with 103 (23%) receiving a broad Gram-positive (GP) agent and 299 (68%) receiving a broad Gram-negative (GN) agent.

Table 1.

Antibiotic Utilization in Deceased Organ Donors

	Valuesa
Donor antibiotic utilization
Received any antibiotic during terminal hospitalization or peri-organ procurement	427 (97%)
Received any antibiotic during terminal hospitalization outside of the organ procurement period	400 (91%)
Specific antibiotics administered to donors
First-generation cephalosporin	337 (77%)
Fourth-generation cephalosporin	140 (32%)
Third-generation cephalosporin	126 (28%)
Vancomycin (IV)	104 (24%)
Piperacillin-tazobactam	79 (18%)
Metronidazole	23 (5%)
Fluoroquinolone	20 (5%)
Clindamycin	13 (3%)
Penicillins	11 (3%)
Extended-spectrum penicillins	10 (2%)
Macrolide	7 (2%)
Aztreonam	5 (1%)
Aminoglycoside	3 (1%)
Tetracycline	2 (1%)
Carbapenem	2 (1%)
TMP-SMX	1 (0.2%)
Echinocandin	1 (0.2%)
Erythromycin	1 (0.2%)
Antibiotic categories and spectrum
Narrow GP antibioticsb	341 (78%)
Narrow GN antibioticsc	48 (11%)
Broad GP antibioticsd	103 (23%)
Broad GN antibioticse	299 (68%)
Antibiotic spectrum index (cumulative over terminal hospitalization) (median, IQR, range), points	9 (5–13, 0–31)
Antibiotic combinations
First-generation cephalosporin plus fourth-generation cephalosporin	71 (16%)
First-generation cephalosporin plus third-generation cephalosporin	67 (15%)
First-generation cephalosporin plus piperacillin-tazobactam plus IV vancomycin	15 (3%)
First-generation cephalosporin plus piperacillin-tazobactam	10 (2%)
Number of antibiotics per donor (median, IQR, range)	2 (1–2, 0–5)
Total antibiotic days of therapy per donor (median, IQR, range)	4 (3–7, 1–34)
Total antibiotic length of therapy per donor (median, IQR, range), days	3 (2–4, 1–18)
Antibiotic days by antibiotic category (median, IQR, range)
Days of narrow GP antibioticsb	2 (2–2, 1–17)
Days of narrow GN antibioticsc	4 (3–5, 1–10)
Days of broad GP antibioticsd	3 (2–4, 1–17)
Days of broad GN antibioticse	2 (2–3, 1–10)
Potentially redundant antibiotic utilization
Any potentially redundant antibiotic coverage during terminal hospitalization or peri-organ procurement	63 (14%)
Any potentially redundant GP coverage	29 (7%)
Days of potentially redundant GP coverage (median, IQR, range)	2 (1–2, 1–17)
Timing of initiation of potentially redundant GP coverage (median, IQR, range), days prior to organ procurement	1 (1–2, 1–16)
Any potentially redundant GN coverage	43 (10%)
Days of potentially redundant GN coverage (median, IQR, range)	2 (1–3, 1–8)
Timing of initiation of potentially redundant GN coverage (median, IQR, range), days prior to organ procurement	2 (1–3, 1–8)

Abbreviations: GN, Gram-negative; GP, Gram-positive; IQR, interquartile range; IV, intravenous; TMP-SMX, trimethoprim-sulfamethoxazole.

^aData are presented as n (%) except where noted.

^bNarrow GP antibiotics included cefazolin and nafcillin.

^cNarrow GN antibiotics included ceftriaxone, cefotaxime, ampicillin/sulbactam, and amoxicillin/clavulanate.

^dBroad GP antibiotics included vancomycin.

^eBroad GN antibiotics included fourth-generation cephalosporins, ceftazidime, piperacillin-tazobactam, meropenem, aztreonam, fluoroquinolones, and aminoglycosides.

The median number of unique antibiotics per donor was 2 (IQR, 1–2; range, 0–5). The most common antibiotic combinations were first-generation cephalosporin plus fourth-generation cephalosporin (71; 16%) and first-generation cephalosporin plus third-generation cephalosporin (67; 15%).

The median number of total antibiotic DOTs was 4 (IQR, 3–7; range, 1–34), and the median length of therapy was 3 days (IQR, 2–4; range, 1–18 days). The median cumulative antibiotic spectrum index over the donors’ terminal hospitalizations was 9 (IQR, 5–13; range, 0–31), and 258 (61%) donors received an antibiotic on every day of their terminal hospitalization.

Potentially Redundant Antibiotic Utilization in Deceased Organ Donors

A total of 63 (14%) donors received potentially redundant antibiotics (Table 1), with 29 (7%) receiving potentially redundant GP coverage and 43 (10%) receiving potentially redundant GN coverage. Nine donors (2%) had instances of both potentially redundant GP and GN coverage during their terminal hospitalization. Thirty-five (8%) donors received potentially redundant antibiotics outside of the peri-procurement period. The median duration of potentially redundant GP coverage was 2 days (IQR, 1–2; range, 1–17 days); the most common combination was a first-generation cephalosporin (eg, cefazolin) plus IV vancomycin (23; 5%). Potentially redundant GP coverage was started a median of one day prior to organ procurement (IQR, 1–2; range, 1–16 days). Outside of the first-generation cephalosporin plus IV vancomycin combination, there were 6 (1%) donors who received potentially redundant GP coverage for a median of 2 days prior to organ procurement (IQR, 2–3; range, 2–3 days). The median duration of potentially redundant GN coverage was 2 days (IQR, 1–3; range, 1–8 days); the most common combinations were a third-generation cephalosporin plus fourth-generation cephalosporin (9; 2%), a fourth-generation cephalosporin plus piperacillin-tazobactam (7; 2%), and piperacillin-tazobactam plus ceftazidime (6; 1%). Potentially redundant GN coverage was started a median of 2 days prior to organ procurement (IQR, 1–3; range, 0–11 days).

DISCUSSION

In this study, we found that nearly all deceased organ donors received at least one antibiotic course during their terminal hospitalization and/or peri-organ procurement. Although first-generation cephalosporins were the most frequently utilized antibiotic, approximately 71% received a broad-spectrum agent, with 68% receiving a broad GN agent and 23% receiving a broad GP agent.

Of particular note, we found that 14% of the donors received potentially redundant antibiotic courses. Although providers may have been broadening or narrowing antibiotics on the day of overlap, the majority had potentially redundant antibiotics administered for more than one consecutive day (median of 2 days), suggesting this was not typically the reason for redundancy. Rather, this antibiotic use was likely driven by other factors, including: (1) potential organ donors are at the end of life, when there is often minimal stewardship [8]; (2) antibiotic prescription decisions are being made by several stakeholders including intensive care unit physicians, OPOs, and receiving transplant centers; and (3) OPOs, including the GLDP, have standardized antibiotic prophylaxis regimens for donors that do not take into account other antibiotics that are being administered concurrently. Indeed, the majority of potentially redundant antibiotic coverage in our study occurred in the final 24 to 48 hours prior to organ procurement, suggesting that the redundant antibiotics were added as part of a peri-procurement prophylaxis protocol. Such protocols merit further study, as there is no evidence to our knowledge that donor peri-procurement prophylaxis improves SOT recipient outcomes and, on the contrary, may actually increase the risk for donor MDRO colonization and thus recipient MDRO DDIs [3–5, 9, 10].

There are several limitations to this study. First, since documentation of medical decision making for potential donors is limited, it was difficult to ascertain the specific indication for each antibiotic prescription and to determine, in cases of potentially redundant antibiotics, whether it was the result of a deliberate change in the care plan, a medical error, or limited awareness of antibiotic spectrum. Second, “redundant antibiotics” is a crude measure of antibiotic disorganization, since there is not uniformity among experts as to exactly which antibiotics are equally effective for each infectious syndrome or pathogen. We nonetheless chose to use this measure in an attempt to capture the overlapping agents used in this population. Similarly, classifying antibiotics as “narrow” or “broad” is overly simplistic and not uniformly defined by experts. Third, this was a retrospective study from one region of the United States that evaluated donors managed by a single OPO and lacks a comparison group. And fourth, we did not report daily defined doses due to a lack of precise dosing data.

In conclusion, our study identified widespread use of broad-spectrum antibiotics and many instances of potentially redundant antibiotic prescription among deceased organ donors. Since brief antibiotic exposures may increase the risk for donor MDRO colonization and subsequent MDRO DDIs in the recipient, the organ donor population is an important future target of antibiotic stewardship interventions.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial support. This work was supported by the Transplant Foundation’s Innovative Research Grant Program, an affiliate of the Gift of Life Donor Program (Donation and Transplantation Grant to J. A. A.); the Antibacterial Resistance Leadership Group (grant number 5 UM 1AI104681–05 with a subaward fellowship grant to J. A. A.); the National Institutes of Health (grant numbers K24-AI080942 to E. L., K01-AI137317 to J. A. A.); and by a Centers for Disease Control and Prevention (CDC) Cooperative Agreement FOA#CK16–004—Epicenters for the Prevention of Healthcare Associated Infections (to E. L.).

Potential conflicts of interest. E A. B.: Receives research support from Merck, Takeda, and Hologic; is a member of a Data and Safety Monitoring Board (DSMB) for Amplyx; and is a member of Scientific Advisory Committees for Merck and Takeda. None of these associations are relevant to this article. J. A. A.: Receives honoraria for committee participation from the Antibacterial Resistance Leadership Group; is co-chair of the Multidrug-Resistant Organism (MDRO) Working Group (unpaid) for the American Society of Transplantation; receives travel support from the National Institutes of Health (NIH) (grant number K01-AI137317 to J. A. A.). J. H.: Affiliated with the University of Pennsylvania during the conduct of this project; is now employed by, and holds shares in, the GlaxoSmithKline group of companies. This association is not relevant to this article. E. L.: Member of a DSMB for Merck; receives consulting fees as a consultant for Shionogi; reports grants/contracts from NIH (T32–AI055435, R01–AI139240, R01–AI39188, IM1-AI104681), the Centers for Disease Control and Prevention (CDC) (CDC–75D30121C10, CDC–U54CK-000163, CDC–U54CK000485), and the Agency for Healthcare Research and Quality (AHRQ) (R01–HS023794); reports payments/honoraria from AHRQ (AHRQ Patient Safety Summit) and CDC (CDC Diagnostic Stewardship Summit). None of these associations are relevant to this article. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.