Study setting

This prospective observational study was performed at a 1500 bedded tertiary care teaching hospital in Gujarat state, India in the inpatient department of Obstetrics at S.S.G. Hospital, Baroda. It is a state government-funded hospital, so the cost of treatment is borne by the state government.

Study population

Cases were all patients admitted in wards of Obstetrics department who underwent cesarean section at S.S.G. Hospital, Baroda, during the period of July 2019 to March 2020, irrespective of indication for cesarean, type of operation (elective or emergency), their parity, or amniotic membrane status, who satisfied the criteria of incisional surgical site infection(ISSI) according to CDC guidelines¹³, and had given written informed consent.

ISSI was identified by using the following criteria, either singly or in combination according to CDC guidelines [13].

Date of event occurs within 30 days after the cesarean section (where day 1 = the procedure date) AND involves only skin and subcutaneous tissue of the incision AND patient has at least one of the following:

1. purulent drainage from the superficial incision.
2. organism(s) identified from an aseptically-obtained specimen from the superficial incision or subcutaneous tissue by a culture or nonculture based microbiologic testing method which is performed for purposes of clinical diagnosis or treatment.
3. superficial incision that is deliberately opened by a surgeon, physician or physician designee and culture or non-culture based testing of the superficial incision or subcutaneous tissue is not performed AND patient has at least one of the following signs or symptoms: localized pain or tenderness; localized swelling; erythema; or heat.
4. diagnosis of a superficial Incisional SSI by a physician or physician designee.

In order to calculate differential costs, ISSI patients were compared to matched control patients. Controls were selected randomly among the patients who underwent cesarean section during the same period but did not develop infection. They were individually matched to cases on key attributes such as age, and co morbidities including ASA score.

Data collection procedure

All patients operated for cesarean section at the study institute were screened and data was collected of patients who developed ISSI and their matching controls. Demographic and clinical details of such patients were obtained from the case records of the patient. The laboratory reports, as well as microbiology report of specimen (e.g. wound swab, pus or tissue) obtained from patients, were screened on daily basis. All such patients were followed up on daily basis until they were discharged from the hospital and the duration of hospital stay was noted.

Outcome and economic analysis were limited to ISSIs occurring during admission or on readmission, with the latter aggregated with those of the original admission to form a single patient episode. Only the first episode of the ISSI was included in the study.

Various cost included in the study

The costs of illness considered in the study included direct as well as indirect costs. The intangible cost has not been taken into consideration in the study.

The direct cost of treatment included the cost of antimicrobial agents and other concomitant medication used, cost per bed days, and cost of diagnostics procedure during hospitalization.

The indirect cost of treatment included travel cost to the hospital, boarding, and lodging as well as loss of productivity.

Data/Definition used for the calculation of various costs included in the study

1. Direct cost:

1.1 Direct medical cost

The cost of the antimicrobials and other concomitant medication used during hospitalization was obtained from the purchase department of our hospital setting.

1.2 Direct non-medical cost

For calculation of cost per inpatient stay (I.e. cost per bed-day) which included the human resource, capital cost, and material cost were taken into consideration based on the study by Chatterjee S et al [14] and appropriate inflation rate for 2019–2020 was applied.

1.3 Diagnostic cost: included the cost of lab investigations carried out during inpatient stay including microbiological investigations. As the cost of treatment, as well as diagnostics, is borne by the hospital, only the material cost has been calculated here.

2. Indirect cost:

Indirect cost is the money spent for purposes other than treatment but indirectly related to treatment like travel, boarding, and lodging and loss of income due to absence from work due to the illness.

2.1 Travel cost: As patients used different modes of travel, to reach the institute, which included, on foot, use of private/personal vehicle, or public transport. To maintain uniformity, we calculated the charge/km as decided for reimbursement policy by the Government of India [15]. For the patients who developed ISSI, during their hospital admission, as well as for the control group, only one-time travel costs to and from the place of residence were calculated. However, for the patients who were readmitted for ISSI, travel cost for the patient and one accompanying person was calculated as per the number of follow up visits including the readmission.

2.2 Boarding and lodging cost: As almost all patients in the study were from the low socioeconomic background, could not afford the boarding and lodging facility for the accompanying person, during the period of hospital stay, on their own, and as many of them accepted the free boarding lodging services offered to them by different organizations, it was not possible to uniformly calculate the amount spent on the same. So to get an estimation of the same, we opted to use the average per day boarding & lodging cost calculated by another study conducted for a tertiary care teaching hospital, from the same tier of the city in which our city belongs [16].

2.3 Loss of productivity cost: We applied the wages / per day index for the loss of productivity cost for the accompanying person based on the Director of Labour, labour and employment department, Government of Gujarat website. (https://col.gujarat.gov.in/news.htm) [17].

The total cost of illness included the sum of direct as well as indirect costs.

Data analysis

Statistical analyses was performed using the Graphpad Prism software (version 9.1.0(221)). The data are expressed as mean ± standard deviation (SD) or number (%). Cost data were also expressed in range (min-max). An unpaired two-tailed t-test was used for comparison of data between two groups. P<0.05 was considered as statistically significant.

For analysis of difference between proportions, fisher exact test (two tailed) was performed. P<0.05 was considered statistically significant.

The cost data were obtained and calculated in Indian rupees and later were converted to US dollar. Conversion rate 1 US $ = 74.88 INR was applied as on the day of analysis i.e. 9^th april 2021 (Reserve Bank of India,India’s central bank [Internet]. Available from: https://www.rbi.org.in/Scripts/BS_DisplayReferenceRate.aspx. last assessed on 09-04-2021).

Antimicrobial exposure

As a routine practice of the institute, microbiological diagnostic testing is done for all the patients, suspected to have SSI.

Out of 114 patients with ISSI, in 52 (46%) patients one or more microorganisms were isolated from their clinical specimen. In five specimens more than one type of microorganism was isolated. The most common organism isolated was Acinetobacter spp. (37%) followed by Klebsiella spp. (25%) and E. coli spp. (21%). In one patient the microbiology testing was done twice due to no response to treatment.

In total 52 clinical specimens, 57 microorganisms were isolated and they were tested against a total of 27 different antimicrobial agents (AMAs) for their sensitivity. Each isolate was tested against an average of 7.63±0.90 AMAs, out of which it was resistant to 5.23±1.52 AMAs. The majority of the microorganisms showed > 50% resistance to most of the antimicrobials tested except for high-end or reserved AMAs (i.e. Meropenem; Colistin, Linezolid, Polymixin-B, and Tigecycline).

All 114 patients who developed ISSI, were given three or more AMAs during their course of treatment. Out of which 57% were prescribed four AMAs, 25% were prescribed 5 AMAs, and 13% were prescribed six or more than six AMAs during their course of treatment.

Days of therapy (DOT) and Length of therapy (LOT) are commonly used antimicrobial usage metrics [18]. DOT is defined as the number of days that a patient receives an antimicrobial agent (regardless of dose). Any dose of an antibiotic that is received during a 24- hour period represents 1 DOT. The DOT for a given patient on multiple antibiotics will be the sum of DOT for each antibiotic that the patient is receiving [18].

LOT is defined as the number of days that a patient receives systemic antimicrobial agents, irrespective of the number of different drugs. Therefore, LOT will be lower than or equal to DOT because each antibiotic received is its own DOT [18].

The ratio of DOT/LOT may be useful as a benchmarking proxy for the frequency of combination antibiotic therapy vs. monotherapy. That is, ratio = 1, identifies monotherapy; ratio > 1 identifies combination therapy.

In the ISSI group, the Mean DOT (Days of therapy) of AMA was 28 ± 6.19 days with a range of 18 to 48 days. In contrast, the mean DOT of AMA therapy for the control group was 10.33 ±3.82 (P<0.0001).

Mean LOT (Length of therapy) of AMA in the ISSI group was 15.14 ± 2.93 days with a range of 10 to 25 days. While in the control group it was 4 ±0.91 (P<0.0001).

Cost of illness due to ISSI

Direct cost

1.1 Cost of antimicrobial prescribing:

The total cost of antimicrobial prescribing in patients with ISSI was significantly higher compared to the control group. While for the patients in the control group, the average number of AMAs prescribed was restricted to 2.58± 0.52 AMAs, prescribed for four days as surgical antimicrobial prophylaxis, however, for patients with ISSI, it was 4.41±0.95 AMAs, prescribed for 15.14± 2.93 days. Which resulted in nearly 10 days of additional AMA exposure and 11 times higher cost of antimicrobial treatment. (P<0.0001). The average cost of AMA in the control group was 2.80±0.86 $, with a range of 1.83–3.98 $, (INR 209.75±64.27 with a range of 137.16 to 297.60); while the same cost in patients with ISSI was 30.75 ±20.02 $ with the range of 6.54–119.36 $ (INR 2302.46± 1498.65 with the range of 489.96 to 8937.36) (Table 2).

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Table 2. Cost of treatment (in USD) in control and cases with post cesarean ISSI.

https://doi.org/10.1371/journal.pone.0269530.t002

1.2 Cost of concomitant medication:

The average cost of the concomitant treatment in patients with ISSI was 2.18 ± 2.15 $ (INR 218.08±161.30) which was significantly higher compared to control (0.83 ± 0.77 $ or INR 61.98± 57.49). (P<0.0001) (Table 2).

1.3. Hospital cost per bed days:

As the patients with ISSI had nearly four times higher total length of hospitalization, the average total cost per bed days in patients with ISSI was 181.40 ±13 $, (INR 582.68± 2704.59), which was significantly higher compared to 57.63 ± 7.04 $ (INR 4314.667 ±526.93) for control patients. (P<0.0001) (Table 2).

1.4. Diagnostic cost:

Average diagnostic cost per patient was 2.48±0.43 $ (INR 185.70± 32.14) in patients with ISSI compared to 0.85±0.08 $ (INR 63.89± 6.01) in control patients (Table 2).

2. Indirect cost:

2.1 Travel cost:

Only one time to and from travel costs were calculated for the control as well as patients who had their episode of ISSI while in the hospital, and an actual number of follow-up visits were considered for readmissions. Mean travel cost in the ISSI group was 6.81 ± 5.01 $ compared to 4.88± 2.73 $ in the control group, (P<0.001)

2.2 Cost of lodging and boarding for the patient’s relatives:

The cost of lodging and boarding was calculated based on the study performed in the similar tier of city in India. Due to the longer length of hospital stay, the parallel cost of lodging and boarding in patients with ISSI was significantly higher compared to the control group (P<0.0001) (Table 2).

2.3 Cost to loss of wages:

72.80% of the women were working as semiskilled laborers before they underwent cesarean section at our hospital. However, as per the local custom, postpartum women would otherwise take at least a few days of work-leave, their loss of wages has not been considered here.

All our patients were from poor socio-economic background, who could not afford a care taker for the new borns. And moreover, as per the local Indian custom, for the initial few months, usually the new born baby is taken care of by the close first or second degree female relative of either spouse. So that cost has also not been taken into consideration.

So cost to loss of wages of only the accompanying person have been calculated. The average loss of productivity of the accompanying person among patients with ISSI was 76.28 ± 15.19 $ (INR 5711.78± 1137.33) compared to 24.23 ± 2.96 (INR 1814.4± 221.58) for the control group (Table 2).

In our study, the total cost of treatment for patients with ISSI was 41,521 USD (INR 31,06,010), which was 2.91 i.e. almost three times higher than the equally sized control group. With per patient average total cost of treatment in the ISSI group was 363.89 ± 86.32 $ with a range of 222.96–769.40 $ (INR 27,246.43±6463) compared to 124.90 ±14.56 $ (INR 9351.84± 1090.40) in the control group (Table 2).

At our settings, the direct and indirect cost of treatment for all the patients, except for the financial impact caused by loss of productivity, as well as the travel cost, was borne by the government-funded hospital.

Subgroup analysis based on the presence of Co morbidities was initially planned, but couldn’t be done because 1) the number of patients with pre-eclampsia was too small and 2) almost all the patients with ISSI had anemia, and the same for the controls who were matched on several characteristics including anemia.