Drug Utilization Review of Piperacillin/Tazobactam at a Tertiary Care Hospital, Pakistan

Development of bacterial resistance has become a serious problem throughout the world. Resistance may be the result of many contributing factors most common being the, the irrational widespread use of antibiotics [1]. The development of broadspectrum antibiotics such as, fourth generation cephalosporin’s, carbapenems and piperacillin/tazobactam (Piperacillin/ Tazobactam), has led to their use as an empirical therapy for many serious infections now-a-days. This widespread use of antibiotics or more precisely misuse of these agents; is high and costly [2]. Because mostly the health care provider goes for a broad spectrum-antibiotic even when a narrow spectrum-antibiotic would be enough [3]. This excessive dependence on these agents is thought to be a major underlying cause of bacterial resistance [4]. In order to overcome this growing problem, many hospitals execute a set of measures like designing and following antibiotic formulary and guidelines [5]. In our hospital, IDSA practice guidelines regarding antimicrobial agent use are followed [6,7].


Introduction
Development of bacterial resistance has become a serious problem throughout the world. Resistance may be the result of many contributing factors most common being the, the irrational widespread use of antibiotics [1]. The development of broadspectrum antibiotics such as, fourth generation cephalosporin's, carbapenems and piperacillin/tazobactam (Piperacillin/ Tazobactam), has led to their use as an empirical therapy for many serious infections now-a-days. This widespread use of antibiotics or more precisely misuse of these agents; is high and costly [2].
Because mostly the health care provider goes for a broad spectrum-antibiotic even when a narrow spectrum-antibiotic would be enough [3]. This excessive dependence on these agents is thought to be a major underlying cause of bacterial resistance [4]. In order to overcome this growing problem, many hospitals execute a set of measures like designing and following antibiotic formulary and guidelines [5]. In our hospital, IDSA practice guidelines regarding antimicrobial agent use are followed [6,7].
Some other methods which assist in strengthening the instructions of guidelines in our hospital include observation of antibiotic utilization by the infectious disease consultants/ fellows and infectious disease pharmacist, continuing education of health care providers with respect to better utilization of antimicrobial agents, application of automatic stop of medication order, and drug utilization reviews [8]. Increasing bacterial resistance and advancements in the field of infectious diseases have opened new horizons in the development of newer agents with effective as well as enhanced antibacterial spectrum.
From the time of revolutionary discovery of penicillin antibiotics which were effective against many bacterial infections caused by staphylococci and streptococci, the world is in the age of Piperacillin/Tazobactam, a β-lactam/β-lactamase inhibitor combination with a broad spectrum of antibacterial activity against Gram (+), Gram (-) aerobic and anaerobic bacteria. Piperacillin/Tazobactam is very well tolerated and effective against patients with lower respiratory tract, intra-abdominal, skin and soft tissue infections and febrile neutropenia [9].
Many years ago, Piperacillin/Tazobactam was approved by the pharmacy and therapeutic committee of our hospital and after a short period of time it became the most prescribed antibiotic combination in our hospital. In 2013, there were a total of 2080 Piperacillin/Tazobactam prescriptions. Different hospitals assess the utilization of antibiotics by estimating quantitative pharmacy data which enables to calculate the number of defined daily doses per occupied bed-days, but it doesn't provide an indication of appropriateness whether therapy was rational or irrational. So in the view of increasing number of prescriptions and mounting expenditure, this study was conducted to estimate the rationality of Piperacillin/Tazobactam utilization in our hospital.

Design and Setting
A cross sectional, retrospective study was conducted at cancer specialty hospital. The in-patient setting comprises of surgical unit, pediatric oncology unit, adult oncology unit, ICU and palliative care unit.

Data Source
The purposive sampling technique was used to select those patients who were admitted to our hospital during a period of three months and were prescribed Piperacillin/ Tazobactam as an empiric therapy. Data in the form of medical record numbers of these patients was extracted by utilizing HIS, and then medical records of randomly selected patients were retrospectively reviewed and studied. 81 prescriptions of Piperacillin/Tazobactam were reviewed for 78 patients. Only 5 patients were prescribed Piperacillin/Tazobactam as definitive therapy of documented infections and so were excluded from the study, whereas 76 prescriptions were prescribed initially as empiric therapy of suspected infection. These 76 prescriptions were thus considered subject for this study.

Criteria for appropriateness of Piperacillin/Tazobactam prescription
In order to analyze the rationality of Piperacillin/Tazobactam prescriptions, a set of criteria was established by which a prescription was regarded appropriate If: a) It was started as an empirical therapy according to IDSA guidelines.
b) It was switched to a narrow spectrum alternative antibiotic after culture and sensitivity data was obtained.
c) It was discontinued once the culture data were negative.
d) It was discontinued once the culture data showed a resistant organism.
e) The dosing, dose adjustments (if any) and indications were in accordance to a drug data base reference (Lexicomp).
If anyone of the described conditions was not met, the prescription was considered as inappropriate.

Data collection and Analysis
The medical record numbers of patients prescribed with Piperacillin/Tazobactam were retrieved from HIS, a computer based hospital wide information system. Patient data related to the demographics, diagnosis and type of Piperacillin/ Tazobactam therapy prescribed (empiric/definitive) was gathered. The relevant data was transferred to a SPSS version 16 which was then used to analyze the data by applying Pearson chi-square test.   Table 2 describes the rational use of Piperacillin/Tazobactam keeping in view the criteria set to identify whether the usage was rational. Culture susceptibility and sensitivity work up was carried out for 45/76(59.2%) cases. Out of these 45 cases culture sensitivity test was returned positive for 40/45(88.9%) and negative for 5/45(11.11) cases. The most frequent organisms encountered were GNB including E.coli, Klebsiella.pneumoniae, Pseudomonas.aerugnosa, Acinetobacter species and related organisms. Culture sensitivity data revealed that organisms resistant to Piperacillin/Tazobactam were found in 8/40 cases (20 %) and sensitive to Piperacillin/Tazobactam as well as other alternative narrow spectrum antibiotics in 24/40 cases (60 %).

Results
However, it was inferred from the result that in 8/40(20%) cases, culture isolates sensitive not only to Piperacillin/ Tazobactam but also to other broad-spectrum antibiotics (meropenem, imipenem, cefepime).12/24 prescriptions (50%) were de-escalated to a narrow spectrum antibiotic after culture sensitivity reports were received and reviewed. On the other hand in 12/24 cases (50%), organisms were sensitive to a narrow spectrum antibiotic, even then therapy was not changed, thus reflecting an irrational usage of the antibiotic. From 5/45 cases which were negative for cultures, in 4/5 (80%) prescriptions Piperacillin/Tazobactam was stopped and only 1/5 prescription (20%) was continued with Piperacillin/Tazobactam. About 39/76 prescriptions (51.31%) were evaluated on the basis of criteria of dose, dosing adjustments and right indications. Result depicted that 26/39 orders (66.66%) were found to meet the criteria for rational use whereas 13/39 prescriptions (33.33%) were irrational (P=0.000). Dosing and dose adjustments were done in a perfect way in all patients. Patients were distributed in different wards/units. The units in which most of the irrational prescriptions were ordered include palliative care unit (83.83 %) and ICU (37.5%). Table 3 summarizes the distribution of patients in different units with respect to the rational use of Piperacillin/Tazobactam.

Discussion
Irrational utilization of Piperacillin/Tazobactam as compared to other broad-spectrum antibiotics, which increases the chances of emergence of resistant species [10], is a major contributing factor in the rise of resistance in gram-negative organisms as shown in a study. The increase in the number of empiric prescriptions and the up trending resistance, prompted us to conduct a study at our hospital. This study illustrate the statistically significant results (P=0.001) in case of rational and irrational prescription.
Table1 for Piperacillin/Tazobactam as empiric therapy Figure 1 (Part: B).It is also revealed from the results Table 2, that according to the standard dosing, dose adjustments and indication, 26/39 orders (66.66 %) were found to meet the criteria for rational use whereas 13/39 prescriptions (33.33 %) were irrational (P=0.000) Figure 1 (Part: F).
As discussed earlier, number of bacterial cultures out of the positive ones for particular organism sensitive to Piperacillin/ Tazobactam as well as other alternative narrow spectrum antibiotics were 24/40 (60%), out of these about 50% cases were possible to be switched to a narrow spectrum antibiotic but were continued with Piperacillin/Tazobactam. Moreover one subject grew a culture resistant to Piperacillin/Tazobactam, but the drug was continued.
Such findings may be attributed to lack of knowledge or negligence of the physician regarding culture results or antibiotic sensitivity profile [11], and it is clear and evident that modification of empiric therapy in accordance with the culture results will surely help in minimizing the cost, reducing the resistance, decreasing the trend of super-infections and improving the patient's quality of life [12].
The choice of any antibacterial agent depends not only on the identity of bacterial strain but also on the documented efficacy of drug in that particular infection, so most of the institutions are compelled to develop/follow a set of guideline which instruct about the empiric usage of the antibiotics. In our hospital, IDSA guidelines are followed. In addition to these guidelines, expert opinions from infectious diseases consultants, infectious diseases pharmacist and microbiologists are appreciated in about all clinical scenarios.
However a considerable number of irrational empirical prescriptions in the study are depicting either a lack of communication, education and implementation of these guidelines or uncertainty in the differential diagnosis, lack of confidence and experience of the attending physician and complex co-morbidities. Retrospective study being the major limitation, certain other limitations of this study include the lack of follow up for patients like those not switched to narrow spectrum antibiotic where it was possible or continued with Piperacillin/Tazobactam despite cultures were negative. The study also lacks comparison with any other published work due to lack of international data on Piperacillin/Tazobactam worldwide.

Conclusion
In appropriate Piperacillin-Tazobactam use has been observed at our hospital as evident by significant number of inappropriate empiric prescriptions regardless of the results of the microbial cultures and antibiogram pattern. Further prospective studies should be carried out to evaluate the cause of irrational prescribing.

Recommendation
We recommend: a) To disseminate facility-specific criteria/guidelines via HIS, brochures and pamphlets. b) To promote CME of the health care providers with a special emphasis on selection of appropriate empirical antibiotic therapy and modification once culture results are available. c) To regularize constant surveillance for monitoring of the resistance patterns of important nosocomial bugs. d) To improve the utilization of Piperacillin/Tazobactam and patient outcome by applying method of preauthorization and prospective audit and feedback interventions by ASP team.