Abstract
Background: In 2017, a national drug shortage of small volume solutions significantly affected the preparation of intravenous antibiotics. In response, a continuous infusion administration protocol for piperacillin/tazobactam (PIP/TAZ) was implemented. Objective: To compare the outcomes of continuous to prolonged infusions of PIP/TAZ in the setting of drug shortages. Methods: This study is a single-center, retrospective cohort study in a community hospital of patients 18 years and older who received intravenous PIP/TAZ through 2 different dosing strategies of intravenous antibiotics from December 2016 to January 2018. Data were collected for 2 months on patients receiving prolonged infusions of PIP/TAZ prior to November 2017 and for 2 months on patients receiving continuous infusions of PIP/TAZ after November 2017. Results: A total of 90 patients who received PIP/TAZ via either prolonged (n = 47) or continuous infusion (n = 43) were evaluated. There were no differences between the groups in mortality (3 vs 2 deaths, P = 1.00), length of therapy (6 ± 4 vs 6 ± 3 days, P = .86), or length of stay (9 ± 7 vs 8 ± 6 days, P = .47). Additionally, no differences were noted between incidences of thrombocytopenia (P = .41), Clostridioides difficile infection (P = .48), acute renal failure (P = 1.00), seizures (P = 1.0), or 30-day readmission rates (P = .27). Conclusions: Administration of continuous infusion PIP/TAZ appears to be a viable mitigation strategy during small volume fluid shortages. Future cost-effectiveness studies may provide information on the financial impact of continuous infusions during costly drug shortages.
Keywords: drug administration, continuous infusion, β-lactams, antibiotics, drug shortages, drug safety
Background
Alternative dosing strategies of time-dependent antibiotics have been the subject of many clinical investigations over the past few years. The efficacy of β-lactam antibiotics is associated with time spent above the minimum inhibitory concentration (MIC) and depends heavily on reliable dosing strategies to optimize its pharmacokinetic properties. To increase the maximum percentage of time the drug concentrations remain above the MIC within a dosing interval, the duration of administration (ie, traditional, prolonged, and continuous infusions) of β-lactam antibiotics has been widely reviewed.1-22
Prolonged infusions (PIs), usually administered over 4 hours, have been shown to achieve the target MIC more effectively than traditional dosing (ie, administration over 30 minutes). A few reports found no difference in 30-day mortality or length of stay between patients who received traditional or PI of piperacillin/tazobactam (PIP/TAZ).1,2 PI have been found to be particularly important in treating multi-drug resistance pathogens in the acute care and critical care settings where MICs of gram-negative bacteria are higher. 3 In addition to improved clinical outcomes, the safety and cost-effectiveness of PI make them a common place in today’s inpatient settings, and were subsequently implemented as the primary route of administration at North Mississippi Medical Center (NMMC) in 2011. 4
Continuous infusions (CIs) administered over 24 hours, while theoretically should improve outcomes associated with β-lactam antibiotics, are somewhat controversial in nature due to a lack of large, clinical trials in the literature. CIs have demonstrated noninferiority to traditional dosing for the treatment of intra-abdominal infections and suggest administration via CI is a cost-effective alternative.5,6 Work by Rafati and colleagues 7 demonstrated that CI of PIP/TAZ reduced the Acute Physiology and Chronic Health Evaluation (APACHE II) scores, while other studies reported improved clinical cure rates in severe sepsis and ventilator-associated pneumonia.7-9 Clinical cure and mortality rates in critically ill patients improve with extending the time of infusion with PI or CI when compared with the traditional infusion.10-12
Comparing administration of CI and PI, studies suggest that the 2 dosing strategies are equivalent.13,14 One of the first meta-analyses that investigated the clinical outcomes of the duration of administration of PIP/TAZ and carbapenems showed a reduction in mortality with PI and CI, with a more significant decrease in patients being treated for pneumonia with PIP/TAZ. 13 However, the superiority of PI and CI in comparison to traditional dosing in respect to improvement in clinical outcomes (ie, 30-day mortality) was not corroborated in a more recent meta-analysis by Yang and colleagues. 14 While results are mixed on the comparison about which administration strategy is better than the other, CI boasts a reduction in total daily dose and recourse allocation making it viable alternative during drug shortages.
The safety and efficacy of dosing strategies are particularly important in the setting of drug shortages when prescribers may be forced to rely on published data not included in the Food and Drug Administration–approved drug monographs. This became particularly important when Hurricane Maria pummeled the island of Puerto Rico in 2017, resulting in the disruption of global pharmaceutical supply chains. The impact was significant, causing an economical imbalance of supply and demand for small volume parenteral solutions (SVPs). SVPs have a wide range of use and are typically needed with compounding intravenous medications, especially antibiotics. Hospitals quickly adjusted and implemented alternatives to SVPs, that is, administration via intravenous push. Marsh and colleagues 15 recently demonstrated that intravenous push administration of β-lactam antibiotics provide a safe alternative to mitigate the critical drug shortage of SVPs.
In addition to the implementation of IVP administration of antibiotics, NMMC implemented a CI protocol for select β-lactam antibiotics (eg, cefepime, ceftazidime, nafcillin, ceftolozone/tazobactam, and PIP/TAZ) as a plan to conserve SVPs. The addition of IVP administration resulted in selective use of the CI with the most widely used antibiotics that were given via CI were PIP/TAZ and cefepime. Prior to the drug shortage, cefepime and PIP/TAZ were administered via different strategies (ie, traditional vs prolonged, respectively) and, thus, were not compared together in this study. The main objective of this study was to compare the outcomes of continuous and prolonged infusions of PIP/TAZ as a way to mitigate SVPs shortages.
Methods
Study Design
This study was a retrospective, cohort study performed at NMMC, a 650-bed regional referral center in North Mississippi. This study was exempt from review by the NMMC Institutional Review Board. Dosing guidelines and the implementation of pharmacy consult services were developed by the antimicrobial stewardship team and approved by the Pharmacy and Therapeutics (P&T) Committee in November 2017. An auto-substitution was approved for pharmacists to adjust PIP/TAZ to the equivalent CI dose at the time of verification and through consult services.
Patients were divided into 2 phases: pre-implementation and post-implementation. The pre-implementation phase, or prolonged infusion phase, consisted of patients who received PIP/TAZ from December 1, 2016, to January 31, 2017. PIs are defined in this study as administration of PIP/TAZ over 4 hours. The post-implementation phase, or the CI phase, consisted of patients who received PIP/TAZ from December 2, 2017, to January 31, 2018. CIs were administered over a 24-hour period.
Patients were identified through queries of Sunrise Clinical Manager and Premier Healthcare Database systems. Patients were included if they were 18 years or older and had received either PI or CI PIP/TAZ therapy for at least 24 hours. Patients were excluded from the study if they required dialysis prior to admission, had a history of seizures or thrombocytopenia, were pregnant, had a history of anaphylaxis to β-lactam antibiotics, had an absolute neutrophil count of <500 mm3, existing thrombocytopenia (ie, platelet count <150 000), or if they had an interruption of antibiotic therapy for more than 12 hours.
Implementation
Initiatives to mitigate the SVP shortage had to move quickly as supply was already limited by previous issues encountered in the SVP supply chain. Once the pharmacy workgroup developed an implementation plan to shift away from the use of SVPs as much as possible, virtual P&T Committee meetings were conducted to gain approval for the recommended plan. Once approved, changes were made where needed to the electronic medical record and intravenous infusion pump dose error reduction system settings. Dosing conversions at NMMC (Table 1) were developed from previous pharmacokinetic studies suggesting the benefits of including both a loading and continuous infusion doses.16-21 Previous preparation of PI PIP/TAZ antibiotic infusions required the use of 100 mL normal saline to be prepared every 8 to 12 hours. Conversely, CI were prepared in the central pharmacy with 500 mL normal saline once daily. Preselected orders items were created in the electronic medical record to allow for ordering of intravenous push and CI infusion dosing options.
Table 1.
NMMC Piperacillin/Tazobactam Dosing Conversion Table.
| Renal adjustments | LD | PI | CI |
|---|---|---|---|
| >40 mL/min | 3.375 g in 100 mL over 30 minutes | 3.375-4.5 g Q8h in 100 mL over 4 hours a | 13.5 g in 500 mL over 24 hours |
| 20-40 mL/min | 9 g in 500 mL over 24 hours | ||
| <20 mL/min/iHD | 3.375 g Q12h in 100 mL over 4 hours | Use prolonged dosing |
Abbreviations: NMMC, North Mississippi Medical Center; LD, loading dose; PI, prolonged infusion; CI, continuous infusion; iHD, intermittent hemodialysis.
Dosing based on indication and suspected pathogen.
At NMMC, pharmacists review and verify orders entered by providers. The NMMC Department of Pharmacy opted to not change physician workflow related to prescribing of affected medications. Physicians were educated to enter orders as they normally would before the shortage, and pharmacists changed orders where needed to fit the new model of drug delivery as approved by the NMMC P&T Committee as part of their process for reviewing and verifying orders. Additionally, the decision was made to not make sweeping changes to order sets.
Outcomes
Primary outcomes of the study included comparison of length of stay, length of antibiotic therapy, and mortality rate. Secondary outcomes included incidence of thrombocytopenia (as defined as a platelet count <150 000), incidence of acute renal failure (as defined by an increase in serum creatinine [SCr] ≥0.3 or an increase in SCr ≥1.5 times the assumed baseline SCr within 48 hours), incidence of Clostridioides difficile (as defined by a positive polymerase chain reaction), incidence of 30-day hospital readmission, and incidence of seizure post-administration of PIP/TAZ.
Statistical Analysis
To achieve a power of 0.8 and an α of 0.05, a sample size of 130 participants (65 in each group) was estimated to demonstrate a statistical significance in the primary endpoint. Normal distribution was determined by the Shapiro-Wilk test. For continuous data that were not normally distributed, a Mann-Whitney U test was performed. Normally distributed continuous data were analyzed with an independent-samples Student’s t test. A 2-sided P <.05 was considered statistically significant. Categorical data were analyzed by using a 2-tail Fisher’s exact test. Statistical analysis was performed using IBM SPSS 26 (IBM Corporation).
Results
A total of 209 patients who received PIP/TAZ during the pre- and post-implementation phases were reviewed, of which 119 patients were excluded from the study (Figure 1). The primary reason for exclusion was due to patients receiving antibiotics for less than 24 hours due to the discontinuation of empiric therapy by the Stewardship team (n = 35) followed by patients experiencing thrombocytopenia at baseline (n = 22). Additionally, a number of patients were excluded if PIP/TAZ was ordered but administration was not documented (n = 17) and if the patients in the CI group received more than one loading dose (n = 8) or did not receive a loading dose (n = 7). A total of 90 patients were included in the study with 47 patients in the PI group and 43 patients in the CI group.
Figure 1.
Flow diagram depicting the selection of patients based on inclusion and exclusion criteria.
Demographic and baseline characteristics were similar for the patients receiving the 2 dosing strategies (Table 2). The mean age was 61 years, average body mass index of 30 ± 9 kg/m2, and the majority identified as Caucasian race (72%). Overall, approximately 53% of patients were male; however, a slight difference was observed for the distribution of men and women with slightly less subjects in the prolonged group (43%) as compared with the CI group (65%; P = .04). Documented source of infections did not differ between the 2 groups (P = .12). The overall main source of infection was primarily pulmonary with 50% of patients presenting with a suspected infection of the lungs, followed by skin/soft tissues (22%), intraabdominal (12%), urinary tract (10%), and empiric therapy (5%). Overall, patients most commonly (54%) received one antibiotic in addition to PIP/TAZ with no difference between the groups (P = .90). The overall median patient severity of illness score was 3 (interquartile range = 2-4).
Table 2.
Demographics and Baseline Characteristics.
| Overall (n = 90) | PI (n = 47) | CI (n = 43) | P | |
|---|---|---|---|---|
| Age (years) a | 61 ± 17 | 63 ± 18 | 60 ± 15 | .49 |
| Weight (kg) a | 91 ± 29 | 91 ± 32 | 90 ± 28 | .86 |
| Body mass index (kg/m2) a | 30 ± 9 | 31 ± 10 | 29 ± 9 | .53 |
| Gender (% male) | 53% | 43% | 65% | .04 |
| Race (% Caucasian) | 72% | 72% | 72% | 1.00 |
| Serum creatinine (mg/dL) a | 1.1 ± 0.5 | 1.1 ± 0.6 | 1.1 ± 0.4 | .82 |
| WBC (×1000 cm3) a | 13.1 ± 6.3 | 12.2 ± 6.1 | 14.1 ± 6.4 | .16 |
| Temperature (°F) a | 98.4 ± 1.5 | 98.6 ± 1.8 | 98.3 ± 1.2 | .31 |
| Heart rate (beats per minute) a | 90 ± 18 | 87 ± 20 | 94 ± 15 | .04 |
| Respiratory rate (breaths per minute) a | 20 ± 3 | 20 ± 4 | 19 ± 3 | .06 |
| Mean arterial pressure (mm Hg) a | 89 ± 16 | 86 ± 16 | 93 ± 16 | .06 |
| Expected total daily dose, n (%) a | <.0001 | |||
| 13.5 g | 1 (2) | 39 (91) | ||
| 9-10.125 g | 13 (28) | 4 (9) | ||
| 6.75 g | 30 (64) | 0 | ||
| 4.5 g | 3 (6) | 0 | ||
| Achieved total daily dose (g) b | 7.7 ± 1.9 | 12.9 ± 1.4 | <.0001 | |
| Co-administered antibiotics, n (%) | .90 | |||
| None | 18 (20) | 10 (21) | 8 (19) | |
| 1 | 49 (54) | 24 (51) | 25(58) | |
| 2 | 20 (22) | 11 (23) | 9 (21) | |
| 3 | 3 (3) | 2 (4) | 1 (2) | |
| Primary source of infection, n (%) | .12 | |||
| Intraabdominal | 11 (12) | 7 (15) | 4 (9) | |
| Lung | 45 (50) | 20 (43) | 25 (58) | |
| Urinary tract | 9 (10) | 6 (13) | 3 (7) | |
| Skin/soft tissue | 20 (22) | 9 (19) | 11 (26) | |
| Blood steam/empiric | 5 (6) | 5 (11) | 0 | |
| Severity of illness index, n (%) c | 3 (2-4) | 3 (2-4) | 3 (2-4) | .93 |
| Low | 6 (6.7) | 3 (6.4) | 3 (6.9) | |
| Moderate | 25 (27.8) | 11 (23.4) | 14 (32.6) | |
| Major | 31 (34.4) | 16 (34.0) | 15 (34.9) | |
| Extreme | 24 (26.7) | 13 (27.7) | 11 (25.6) |
Abbreviations: PI, prolonged infusion; CI, continuous infusion; WBC, white blood cell.
Mean ± standard deviation.
Expected total daily doses were dependent on dose and dosing frequency (eg, an expected TDD of 10.125 g was based off a 3.375 g Q8h dosing regimen).
Data reported as median (interquartile range). Severity of illness index based on Diagnosis-Related Group and are rated on a scale of 1 (low) to 4 (extreme) illness.
Overall, patients in the CI group received a larger total daily dose than those in the prolonged group (12.9 ± 1.4 g vs 7.9 ± 1.9 g, P < .0001). On average, patients in the study received antibiotic therapy for 6 ± 4 days and stayed in the hospital for 8 ± 6 days. No difference was noted in either length of therapy (P = .86) or length of stay (P = .47). A total of 5 deaths were noted within this study. Mortality did not differ between 3 deaths in the PI group and 2 deaths in the CI group (P = 1.00).
A review of the secondary outcomes to assess the safety of the 2 dosing strategies revealed no statistical difference (Table 3). Overall, there were 6 instances of thrombocytopenia with a lower incidence reported in the PI group (4.3%) than in the CI group (9.3%). Only one instance of a newly diagnosed Clostridioides difficile infections within the CI group was reported. Five patients (5.5%) developed acute renal failure with similar incidences between the PI (6.4%) and CI (4.7%) groups. There were no seizures reported in either treatment group. Additionally, hospital readmissions within 30 days were similar between the 2 treatment groups. Out of 8 total readmissions, 6 (12.8%) were reported in the PI group and 2 (4.7%) in the CI group (P = .53).
Table 3.
Piperacillin/Tazobactam Outcomes.
| Outcomes | Overall (n = 90) | PI (n = 47) | CI (n = 43) | P |
|---|---|---|---|---|
| Length of therapy (days) a | 5.9 ± 3.5 | 5.8 ± 4.0 | 6.0 ± 3.0 | .86 |
| Length of stay (days) a | 8.3 ± 6.3 | 8.8 ± 7.0 | 7.8 ± 5.6 | .47 |
| Deaths, n (%) | 5 (5.5) | 3 (6.4) | 2 (4.7) | 1.00 |
| Thrombocytopenia, n (%) b | 6 (6.7) | 2 (4.3) | 4 (9.3) | .41 |
| Clostridioides difficile , n (%) c | 1 (1.1) | 0 (0) | 1 (2.3) | .48 |
| Acute renal failure, n (%) d | 5 (5.5) | 3 (6.4) | 2 (4.7) | 1.00 |
| Seizure, n (%) | 0 (0) | 0 (0) | 0 (0) | 1.00 |
| 30-day readmission, n (%) | 8 (8.9) | 6 (12.8) | 2 (4.7) | .27 |
Abbreviations: PI, prolonged infusion; CI, continuous infusion.
Reported as mean ± standard deviation.
Defined by a decrease in platelet count to <150 000/µL.
Determined by receipt of a positive Clostridioides difficile polymerase chain reaction test.
Defined by an increase in serum creatinine ≥0.3 within 48 hours or increase serum creatinine ≥1.5 times baseline.
Discussion
The purpose of our study was to evaluate the efficacy and safety of 2 different PIP/TAZ administration strategies in the setting of drug shortages. In comparison with PI of PIP/TAZ, clinical and safety outcomes of PIP/TAZ when administered via CI were similar and may provide a reasonable alternative option in lieu of SVPs.
Unlike previous studies that boasted a reduction in total daily dose, patients in the CI arm received average total daily doses of PIP/TAZ that were significantly larger than in the PI group. Expected doses and frequencies for patients in the PI group appear less aggressive with the majority of patients prescribed a regimen that would provide an expected total daily dose of 6.75 g (64%), followed by 28% of PI patients receiving a target total daily dose of 9 to 10.125 g. Alternatively, 91% of patients in the CI received an expected total daily dose of 13.5 g. Larger doses were expected in the CI group due to the patients receiving a loading dose in addition to the infusion dose at the beginning of therapy. Differences noted between the average total daily doses may shed light on a slight trend toward an increase in 30-day hospital readmission within the PI group potentially suggesting subtherapeutic therapy. Changes in prescribing habits may also have contributed to the difference in total daily doses, but could not be validated through this study.
The large-volume, CI administration protocol was implemented throughout NMMC with the exclusion of the emergency room. Subsequently, the study population was not limited to critically ill patients and included patients on general medicine floors. The APACHE II score could not be determined for all patients; therefore, the Severity of Illness (SOI) score was utilized to provide a general classification of patient severity. Unlike the APACHE II score, which is a real-time tool to predict hospital mortality of patients in the intensive care unit, SOI indices are assigned at discharge to reflect the burden of illness. SOI scores/indices range from 1 (minimal burden) to 4 (extreme burden). Patients in this study were assigned a median SOI score of 3 (interquartile range, 2-4) indicating the need for a higher level of dependency and care.
Overall, no statistical differences noted between the prolonged and continuous dosing strategies for PIP/TAZ suggest that CI administration may be considered a safe and effective strategy for treating patients in the event of shortages of SVPs. The results presented here, while did not meet statistical power, are consistent with previously performed studies that suggest CI administration is safe and effective when compared with prolonged and intermittent infusions. Additionally, despite the absence of statistical differences, data trends suggest that CI may contribute to an increase in thrombocytopenia, while PI may have some effect on the incidence of 30-day readmissions; however, further studies are needed to provide concrete associations. Outcomes of previous studies that reviewed the use of CI PIP/TAZ in the critically ill and those with a greater risk of multi-drug resistant pathogens were also observed in both non-critical and critically ill patients included in this study.5,7,8,10-13 This report, however, is the first to review its use as an alternative in the setting of drug shortages and provides reason to investigate the use of CI PIP/TAZ further.
With larger concentrations of PIP/TAZ expected when given via CI administration, safety measures were reviewed. PIP/TAZ has been reported to have neurotoxic effects when drug levels accumulate in critically ill patients which manifests in seizure activity. One small observational study by Quinton and colleagues 22 suggested that a serum concentration of PIP/TAZ above 157 mg/L (odds ratio = 26.58, 95% confidence interval = 3.08-229.32, P = .0028) is a risk factor neurotoxicity in the critically ill patient. Serum concentrations of PIP/TAZ when given via the CI have not been regularly reported in the literature. Unfortunately, in this study PIP/TAZ serum levels were not obtained but no seizure occurred in either group.
The current study is not without limitations. First and foremost, while the results provide a review of the outcomes and safety of dosing strategies for PIP/TAZ, they do not provide conclusive evidence to support CI over PI PIP/TAZ because the study did not achieve the appropriate power. The retrospective study design is associated with documentation issues such as proper characterization of patient severity and clinical outcomes related to culture growth or pathogen-specific information. Patient outcomes also may have been affected by concurrent antibiotic therapy. Additionally, CI has some notable disadvantages that may prevent the full adoption of CI into practice, such as requiring a dedicated line for administration. This may have been more feasible in this study as the population was not restricted to the critical care population that may also require additional dedicated lines. A simple comparison of the costs associated with PI and CI dosing strategies suggests that while drug acquisition was slightly higher in the CI group, cost savings may be offset by preparation and administration time consumption among hospital personnel.
Conclusions
Larger studies are needed to fully ascertain which administration strategy is superior. Based on the observations reported in the current study, it appears that administration of PIP/TAZ via CI seems to be both safe and potentially cost-effective in the event of SVP drug shortages.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Emily Tschumper 
https://orcid.org/0000-0001-8447-6062
Kim McCrory
https://orcid.org/0000-0003-2631-8204
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