Appropriateness and pharmacoeconomics of surgical antimicrobial prophylaxis in open reduction internal fixation surgery practiced in a tertiary hospital compared to recommendations in the national center for disease control guidelines.

CONTEXT: Surgical site infections are frequently observed despite the availability of national guideline on surgical antimicrobial prophylaxis (SAP). These infections increase patient morbidity, mortality, and direct and indirect health-care costs. Open reduction internal fixation (ORIF) is a common orthopedic surgery for fracture. There is a paucity of Indian data on SAP in ORIF surgery. AIMS: The present study was taken up aiming at the evaluation of appropriateness and pharmacoeconomics of SAP in ORIF based on the national guidelines. SUBJECTS AND METHODS: One-year observational prospective cohort study was conducted among 412 participants, who underwent ORIF in the Department of Orthopedics in a Tertiary Care Hospital. Name, dose, route, timing, frequency, and duration of administration of prophylactic antimicrobials used were recorded. STATISTICAL ANALYSIS USED: Descriptive statistics were used wherever required.
RESULTS: The mean age of participants was 39.24 years, majority (60.92%) were male, and 49.52% had fracture of lower-limb bones. The appropriateness of preoperative SAP in terms of indication in ORIF, timing, and route of administration was 100%. Selection and dose of preoperative and postoperative antimicrobials were appropriate in only 13% of cases. Omission of intraoperative dose was appropriate in all participants. Duration of postoperative Antimicrobial agent administration was inappropriately long in all participants. None of the cases received completely appropriate regimen. Cost analysis showed the mean cost of SAP practiced in our hospital was eleven times higher than that with recommended SAP.
CONCLUSIONS: Considering the inappropriateness of SAP practiced, monitoring of guideline implementation and awareness among health-care professionals are necessary to prevent SSI and to decrease economic burden on the patients. Copyright:

INTRODUCTION

Surgical site infection (SSI) is the most prevalent (31%) health-care-associated infection.[1] CDC defines it as “infection of the incision or organ or space that occurs after surgery.”[1] Its prevalence in orthopedic implant surgeries is 1%–22%.[2] Therapeutic failure may occur in bone infections due to avascular sequestrum, making preventive measures mandatory.[3]

The WHO defines surgical antimicrobial prophylaxis (SAP) as “the prevention of infectious complications by administering an effective antimicrobial agent before exposure to contamination during surgery.”[4] India, in 2016, gave guidelines to promote rational antimicrobial use in infectious diseases including SAP.[5] There is a paucity of Indian data on SSI.[67] The present study aimed at the evaluation of SAP practiced for the prevention of SSI in open reduction internal fixation (ORIF) surgery.

SUBJECTS AND METHODS

We conducted an observational, prospective analytical cohort study in the Department of Orthopedics of a tertiary care center over a period of 1 year after obtaining Institutional Ethics Committee clearance. The objective was to compare appropriateness and pharmacoeconomics of clinically practiced SAP in ORIF surgery versus SAP recommended by the National Centre for Disease Control (NCDC) guidelines.

Sample and sample size

Participants of more than 18 years of age, irrespective of gender, with closed fracture posted for ORIF surgery were included in the study. Participants unwilling to give informed consent, with open fracture, undergoing delayed primary/secondary closure procedure, and already receiving antimicrobials were excluded from the study. For calculation of sample size required to compare appropriateness, the prevalence (P) = 22% was considered from the known orthopedic SSI prevalence range of 1%–22%.[28] We calculated minimum required sample size to be 275 so that resulting estimate will fall within 5% points of the true proportion with 95% confidence. Absolute precision was prespecified at 5%. The required sample size reached to 303 after considering 10% rate of loss to follow-up.

Study method

A total of 672 participants, posted for ORIF surgery, were screened for eligibility. Two hundred and sixty participants could not be enrolled in the study due to the presence of various exclusion criteria summarized in Figure 1. After taking informed consent from the 412 eligible participants, data were collected regarding demography (age, gender, and address), the location of fracture, and the prophylactic antimicrobials (name, dose, route, timing, frequency, and duration of administration) used. The evaluation for appropriateness of SAP was based on Indian “National treatment guidelines for antimicrobial use in infectious diseases” by NCDC-2016.[5] All the participants were followed up till postoperative day forty-five to record any incidence of superficial SSI and to assess mobilization.

Figure 1

Study design

For pharmacoeconomic cost analysis, per patient cost was calculated by multiplying acquisition price of the antimicrobial agent (AMAs) from hospital pharmacy with number of doses administered per day which was further multiplied by the duration of administration. Cost for syringes and intravenous (IV) cannula was calculated similarly. Mean per patient cost of NCDC recommended SAP was then compared with that of SAP practiced in our hospital. Prophylactic AMAs were substituted by more costly therapeutic AMAs in 12 participants who developed superficial SSI.

Statistical analysis

Data were entered in Microsoft Excel, 2010. The analysis was done using descriptive methods such as percentage and mean wherever required. Microsoft Word and Excel were used for statistical calculation and to generate tables and figures.

RESULTS

We have evaluated appropriateness and pharmacoeconomics of SAP in ORIF in this observational study. Table 1 summarizes the demographic and clinical characteristics of all eligibly enrolled study participants. The mean age of study participants was 39.24 years and majority (60.92%) were male. Fracture(s) of lower-limb bones (49.52%) were the most commonly encountered fracture followed by that of upper-limb bones (33.98%).

Table 1

Demographic and clinical characteristics of study participants

Characteristics	Study participants (n=412)
Gender, n (%)
Female	161 (39.08)
Male	251 (60.92)
Mean age±SD (years)	39.24±14.13
Location of fracture
Clavicle, n=60 (14.56%)	Right	Left
-	28	32
Upper-limb bone, n=140 (33.98%)	Right	Left
Humerus	24	16
Ulna	4	0
Radius	32	24
Ulna + radius	24	8
Metacarpal	8	0
Lower-limb bones, n=204 (49.52%)	Right	Left
Femur	38	30
Tibia	50	22
Fibula	0	4
Tibia + fibula	25	17
Metatarsal	5	13
Vertebra, n=8 (1.94%)
Thoracic	4
Lumbar	4

SD=Standard deviation

Figure 2 shows the analysis for appropriateness of antimicrobials administered for perioperative SAP. The use of the prophylactic antimicrobials was appropriate in all of the study participants; however, selection of agent and dose of AMA administered was appropriate in only 54 participants (13%). Timing, route of administration, and frequency of preoperative antimicrobial administration as well as the omission of intraoperative dose were appropriate in all. However, all of the enrolled participants received AMA for longer than recommended duration postoperatively.

Figure 2

Appropriateness of prophylactic antimicrobial agent used based on national center for disease control criteria (n= 412)

We studied the pattern of AMAs used for SAP up to postoperative day 11 for pharmacoeconomic analysis [Table 2]. Three different IV AMAs were used for preoperative SAP, namely, cefuroxime (n = 54; 13.11%), cefoperazone + sulbactam (n = 354; 85.92%), and ceftriaxone (n = 4; 0.97%). All the participants received additional IV amikacin postoperatively on the day of surgery, and for the next 4 days, except 12 participants of cefoperazone + sulbactam group in whom these prophylactic AMAs were replaced by IV piperacillin + tazobactam (n = 8) and linezolid (n = 4) subsequent to the development of superficial SSI. Remaining participants on IV cefoperazone + sulbactam were switched to oral cefixime (n = 342), while those on IV cefuroxime and ceftriaxone were switched to oral cefuroxime (n = 58) for the next 7 days.

Table 2

Pattern of perioperative prophylactic antimicrobials (n=400)*

AMA	Preoperative (n)	Postoperative days 0-4# (n)	Postoperative days 5-11 (n)
Cefuroxime	54	54	58
Cefoperazone + sulbactam	342	342	0
Ceftriaxone	4	4	0
Cefixime	0	0	342

*In remaining 12 participants out of 412, who developed SSI, prophylactic cefoperazone + sulbactam was replaced by therapeutic antimicrobials (piperacillin + tazobactam (n=8) and linezolid (n=4)), #All the participants received additional amikacin except cefixime group. SSI=Surgical site infection, AMA=Antimicrobial agent

Table 3 represents the cost analysis of NCDC recommended AMAs and the AMAs practiced in our hospital. Mean per patient direct health-care cost was eleven times higher with the SAP regimens practiced in our hospital than with the NCDC recommended SAP.

Table 3

Cost analysis: patient’s perspective (n=412)

Per patient direct cost (Rs.)	Recommended AMA* (n=0)		Practiced AMA#,! (n=412)
	Cefazolin (n=0)	Cefuroxime (n=0)	I (n=54)	II (n=342)	III (n=4)	IV (n=8)	V (n=4)
AMA	156	597	3707	4035	2446	5483	6811
Syringes + IV cannula	15	15	55	55	55	125	125
Total	171	612	3762	4090	1940	5608	6936
Mean	391.5		4467.2

*Price of generic drug was used for recommended AMAs as none of the participants received AMAs as per recommendation; #I=Cefuroxime and amikacin, II=Cefoperazone + sulbactam and amikacin and cefixime, III=Ceftriaxone and amikacin and cefuroxime, IV=Cefoperazone + sulbactam and piperacillin + tazobactam, V=Cefoperazone + sulbactam and linezolid; !Brands used: Cefuroxime – Kritum; Amikacin – Trasocin, Cefoperazone + sulbactam – Vapbacto; Ceftriaxone – Gramocef; Piperacillin + tazobactam – Sinibec; Linezolid – Lizofast. IV=Intravenous, AMAs=Antimicrobial agent

DISCUSSION

Various guidelines have been given to promote appropriate use of antimicrobials for SAP including international guideline by the WHO and several national guidelines such as NCDC, American Society of Health-care Pharmacists (ASHP), National Institute for Health and Care Excellence, and Scottish Intercollegiate Guidelines Network.[59101112] Formulation of these guidelines is one of the steps toward decreasing the incidence of SSI and containment of antimicrobial resistance. Our national guideline, given by NCDC, recommends single preoperative dose of IV cefazolin 2 g or cefuroxime 1.5 g to be given within 60 min before surgical incision and thereafter twice a day up to 24 h of ORIF surgery.[5]

NCDC approves the use of SAP in ORIF surgery. Besides clean-contaminated and contaminated surgical wounds, practice of SAP is well documented in clean surgeries involving the use of implants.[13] ORIF, though a clean surgery, uses implants for fixation of fracture reduction which mandates SAP.[14] Hence, the use of prophylactic antimicrobials was appropriate in all of the participants.

Selection of the AMA and the dose administered was appropriate in only 54 participants (13%) who received 1.5 g cefuroxime. Remaining 87% cases received third-generation cephalosporins (cefoperazone + sulbactam or ceftriaxone). This is alarming as the injudicious use of newer generation AMAs unless indicated, results in increased cost of treatment as well as the rate of AMA resistance among nosocomial pathogens.[15]

NCDC recommends a single preoperative dose to be given by IV route which was followed in all of the study participants. IV route is preferred due to the reliability of achieving adequate serum concentration at the time of surgical incision.[16]

Timing of preoperative dose administration was appropriately within 60 min before the surgical incision in all of the participants. With too early administration, serum level of AMA will fall below minimum inhibitory concentration toward the end of surgery, while too late administration will not be adequate enough for protection at the time of surgical incision.[16] Vancomycin and fluoroquinolones are the exceptions which should be administered within 120 min before surgical incision due to the longer infusion time required.[10]

As suggested by NCDC, the omission of intraoperative dose was appropriate in all of the cases depending on the AMA chosen for preoperative SAP. The ASHP guidelines recommend intraoperative dosing specifically when the duration of surgery exceeds two half-lives of the AMA administered preoperatively.[10]

The 24 h limit for postoperative administration was not followed in any of the participants. The possible reason behind this inappropriate practice may be the anticipation of the high rate of SSI among hospital inpatients.[17] The long duration of AMA use will further add to the increased cost and risk of development of resistant strains.

During the postoperative phase, addition of IV amikacin was irrational considering the Gram-positive nature of Staphylococcus aureus, the most common causative pathogen of SSI.[18]

Overall none of the participants received SAP in complete accordance with our national guidelines. This particular pattern of appropriate timing and frequency of preoperative dose, omission of intraoperative dose along with inappropriately high use of third-generation cephalosporin for longer than recommended duration, was seen in a previous study conducted by Khan et al.[19]

For pharmacoeconomic analysis, the incidence of superficial SSI as well as cost of the hospital stay, treatment of SSI, and adverse events among study participants could not be compared due to the lack of comparison group as none of the patients received SAP in complete accordance with the NCDC guidelines. For the same reason, we conducted cost analysis instead of cost-effectiveness analysis. This analysis showed that the SAP practiced in our hospital was more costly than the SAP recommended by our national NCDC guidelines. Inappropriate selection of more costly third-generation cephalosporin instead of NCDC recommended first and second generation along with inappropriately longer duration of administration resulted in eleven times higher economic burden on the study participants.

To the best of our knowledge, this study is first of its kind to correlate the use of prophylactic antimicrobials and the economic burden in ORIF surgery. Our study provides data to the hospital for the formulation of evidence-based strategies to monitor the implementation of the national guidelines. We believe it is a big strength of our study in the view of recent WHO report mentioning SSI to be more prevalent in low- and middle-income countries; however, data from these areas are scarce.[9] Sample size of our study was adequate. Few limitations of the present study were also there. The duration of follow-up was not long enough to record the incidence of deep SSI. CDC recommends 90-day follow-up period to detect deep SSI in open reduction of fracture; however, for superficial SSI, it is 30 days.[1] We could not perform cost-effectiveness analysis. Furthermore, the study was conducted in only one of the department of our hospital. In the future, conduct of similar multidepartment/hospital studies along with awareness sessions for health-care professionals and assessment of post-session improvement will generate further systematic data for formulation of valid strategies to facilitate implementation of national guidelines on appropriate SAP.

CONCLUSIONS

SAP practiced in our hospital was not completely appropriate in any of the study participants resulting in eleven times higher economic burden on them. Besides economic burden, inappropriate SAP results in resistance among pathogens which is of serious concern.[2520] Hence, spreading awareness among health-care professionals and continuous monitoring of the NCDC guidelines implementation is crucial to promote rational antimicrobial use to decrease the incidence of preventable SSI, economic burden, and AMA resistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.