Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic treatments
Purba, Abdul
DOI:
10.33612/diss.128518764
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Publication date: 2020
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Purba, A. (2020). Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic
treatments: Focus on surgical site infection and hospitalized community-acquired pneumonia. University of Groningen. https://doi.org/10.33612/diss.128518764
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CHAPTER 3
Prevention of surgical site infections:
A systematic review of cost analyses in
the use of prophylactic antibiotics
Abdul Khairul Rizki Purba Didik Setiawan
Erik Bathoorn Maarten J. Postma Jan-Willem Dik Alex W. Friedrich
ABSTRACT
Introduction: The preoperative phase is an important period in which to prevent surgical site infections (SSIs). Prophylactic antibiotic use helps to reduce SSI rates, leading to reductions in hospitalization time and cost. In clinical practice, besides effectiveness and safety, the selection of prophylactic antibiotic agents should also consider the evidence with regard to costs and microbiological results. This review assessed the current research related to the use of antibiotics for SSI prophylaxis from an economic perspective and the underlying epidemiology of microbiological findings.
Methods: A literature search was carried out through PubMed and Embase databases from 1 January 2006 to 31 August 2017. The relevant studies which reported the use of prophylactic antibiotics, SSI rates and costs were included for analysis. The causing pathogens for SSIs were categorized by sites of the surgery. The quality of reporting on each included study was assessed with the “Consensus on Health Economic Criteria” (CHEC).
Results: We identified 20 eligible full-text studies that met our inclusion criteria which were subsequently assessed studies had a reporting quality scored on the CHEC list averaging 13.03 (8-18.5). Of the included studies, 14 were trial-based studies, and the others were model-based studies. The SSI rates ranged from 0 to 71.1% with costs amounting to US$480-22,130. Twenty-four bacteria were identified as causative agents of SSIs. Gram-negatives were the dominant causes of SSIs especially in general surgery, neurosurgery, cardiothoracic surgery, and obstetric cesarean sections.
Conclusions: Varying results were reported in the studies reviewed. Yet, information from both trial-based and model-based costing studies could be considered in the clinical implementation of proper and efficient use of prophylactic antibiotics to prevent SSIs and antimicrobial resistance. Nevertheless, the findings of economics and microbiology from the included studies have reported diverse results.
INTRODUCTION
Surgical site infections (SSIs) reflect an important complication in modern healthcare.1 As the surgical site is a potential port entry for exogenous organisms, it poses an immediate threat to the body and infections lead to prolonged wound healing.2,3 The preoperative phase is considered the most crucial period of a surgical procedure in which the goal is to reduce the bacterial load surrounding the incision area. Using antibiotics prior to surgical incision is considered to be effective in preventing SSIs, which are among the most common preventable post-surgery complications involving healthcare-associated infections (HAIs).2,4 A parenteral prophylaxis agent has been recommended recently to reduce SSI rates efficiently.3 In contrast, some preoperative procedures, such as hair removal and mechanical bowel preparation are considered today to be inefficient in reducing SSIs.5,6
In the US, SSIs were identified in approximately 1.9% of 849,659 surgical procedures in 43 states from 2006 to 2008.7 The economic burden of SSIs should be taken into account in the use of prophylactic antibiotics. In the US in 2010, more than 16 million surgical procedures were performed.8 The annual costs of SSIs amounted to approximately US$3 billion in 2012, having increased from an estimated US$1.6 billion cost attributable to SSIs in 2005.9,10 In low-and middle-income countries, SSI rates doubled from 5.6 to 11.8 in 100 surgical patients between 1995 and 2008.11 The reporting of cost and effectiveness in infectious disease presents a crucial topic, ideally supported by updated antimicrobial resistance data. Notably, economic analyses can be differentiated into trial-based – directly linked to a trial that often also already comprises part of the economic variables – and model-based studies with information gathered from various sources and integrated into a health-economic model. The aim of this study is to present recent evidence from trial-based and model-based costing studies and analyze the methodologies used in economic evaluations of prophylactic antibiotics in SSI prevention. In addition, the study comprehensively analyzes the quality of the included studies and local epidemiology of pathogen-causing SSIs.
MATERIALS AND METHODS
This review was registered in PROSPERO with number CRD42017076589. This study was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.12
Search Strategy
We searched the updated relevant evidence from PubMed and EMBASE databases. To consider changes over time in inflation rates, value of money, and patterns in microbial causes of SSIs and contemporary antimicrobial susceptibility, we initially searched a ten-year period (2006-2016) which we later updated to 31 August 2017. The search used search terms or phrases represented
in Medical Subject Headings (MeSH) with the operator ‘tiab’ for PubMed. Subsequently, the terms or phrases used in PubMed were translated to the EMBASE database by using strings and the symbols ‘ab,ti’. To refine the result, we employed a search strategy using the Boolean operator ‘OR’ within sequences of terms with close or similar meanings and ‘AND’ for one or more sequences of terms that contained completely different meanings. Whole terms and phrases for either PubMed or Embase were identified by two persons (AKRP and KS) who dealt with the search strategy.
Study Selection
Trial-based and model-based studies that examined the clinical benefits and costs related to the uses of prophylactic antibiotics for SSIs were considered eligible for inclusion in this review. Therefore, we developed criteria to identify the eligible studies which contained economic analysis and followed the defined PICO-approach (Patient or Problem, Intervention, Control, and Outcomes). Concerning the patient (P), patients undergoing all types of surgical procedures were included. There was no restriction on age or gender. For both the intervention (I) and comparison or control (C), this review included studies concerning the utilization of antibiotic prophylaxis administered intravenously, orally, or locally to prevent SSI. Other terms of post-surgical infections such as wound infections and sternal wound infections (SWIs) were included. We excluded studies mainly evaluating comparisons of the use of antiseptic, pharmaceutical care interventions or guideline adherence issues. For the outcomes (O), we included studies evaluating both SSI rates and cost. Eventually, the integrated results of searches were restricted to English full-text studies. Studies issued as commentary, editorials, research protocols or reviews were excluded.
Data Extraction
Two authors (AKRP and DS) independently assessed all included papers. Any disagreements between those authors were discussed with a third author (JWD) until the discrepancies were resolved by consensus. Fields of the extracted data included the authorship, year of publication, journal, country, type of surgery, wound categorization, gender, age, sample size, outcomes, prophylactic antibiotics, SSI rates, the timing for the prophylactic strategy, follow-up and length of stay. To address the outcome from a microbiology perspective, we extracted the pathogens based on the sites of the surgery, antimicrobial susceptibility, and their resistance rates. Furthermore, we grouped the types of SSIs based on the definitions and classifications of SSIs from the Centers for Disease Control and Prevention (CDC).13
Cost Analysis and Data Synthesis
We categorized the methodology on the health-economic analyses and outcomes for each eligible study according to four approaches.14 The first was cost-minimization analysis (CMA), which represents a straightforward method to identify the costs of different alternatives with estimated equal health outcomes of the interventions. The second was cost-effectiveness analysis (CEA) where the outcomes are expressed in a natural unit of health including the number of patients with clinical improvement of an infectious disease or life-years gained. The third was a
cost-benefit analysis (CBA), in which the interventions are made comparable in terms of benefit and cost with all aspects being expressed in financial units. The last was cost-utility analysis (CUA), which includes utility estimates potentially representing preferences for health outcomes, reporting quality-adjusted life years (QALYs) or alternatively disability-adjusted life years (DALYs). Furthermore, for the cost types, we took into account cost perspectives with components of (1) direct costs such as costs for prophylactic antibiotics, hospitalization, side-effects, and antimicrobial resistance, and (2) indirect costs including costs of loss of productivity. We made costs comparable among individual studies using currency conversions to US$ and corrections for inflation rates. We calculated inflation rates based on the 2015 annual GDP growth index in the World Data Bank for each respective country.15 If the individual article did not state the actual year for the cost analyses, we made the assumption that the year of the cost estimate was the same as the last year of data collection.
Quality Assessments
We used the Consensus on Health Economic Criteria (CHEC) list to assess the quality of reporting of the health economic outcomes, including potential bias in individual studies.16 This CHEC instrument comprises a 19-item list that relates to study design (4 items), time horizon, actual perspective, cost evaluation (5 items), outcome measurements (3 items), discounting, conclusion, generalization, conflict of interest, and ethical issues.17 These items can be conceived to reflect the minimum requirements for health economic papers. We scored one point for “yes”, indicating an item to be satisfied. Marks of “unclear” and “no” were scored half a point and zero respectively. Therefore, the minimum and maximum scores for the individual studies were in a range of 0 to 19.
RESULTS
Search Results
This review initially identified a total of 644 and 1,417 articles from PubMed and Embase respectively. A comprehensive listing of the searches in both PubMed and Embase can be found in Supplement 3.1 and Supplement 3.2. After removing duplications, we screened 1,529 titles and abstracts. Subsequently, we excluded 1,321 articles for the reasons listed in the Materials and Methods section. Eventually, we assessed 208 eligible full-text studies of which we excluded 188 because of being reviews, having incomplete data related to costs and lack of presenting on the outcomes of prophylactic antibiotic uses and SSI incidence. A total of 20 articles remained according to the inclusion criteria and were extracted systematically for further analyses.18–30 A flow chart of the search is shown in Figure 3.1.
Figure 3.1. Flow chart of search strategy on identifying eligible and included studies
General Characteristics of Included Studies
The general characteristics of the included studies are presented in Table 3.1. For the further characteristics of the 20 included studies, the most studies came from North-America18,19,21,24,30–33, followed by Asia20,22,29,34, Europe26–28,35, Africa25,36, Australia23 and South America37. The reviewed articles concerned 14 trial-based studies19–22,24–30,33,34,36 and 6 model-based studies18,23,31,35,38,39. Table 3.2 presents the baseline characteristics of the included studies. Moreover, six trial-based studies were performed as a formal randomized controlled trial (RCT) with the number of patients involved in the studies ranging between 50 and 1,196.22,25,26,29,30,36
Table 3.1. General characteristics of 20 included articles
Characteristics Included articles n(%)
Region Africa 2(10) Asia 4(20) Australia 1(5) Europe 4(20) North America 8(40) South America 1(5) Type of surgery Cardiothoracic 2(10) General 5(25) Neurosurgery 2(10) Obstetric gynaecology 2(10) Oncology 3(15) Orthopedic 6(30)
Type of economic evaluation
CBA 0
CEA 3(15)
CMA 15(75)
CUA 2(10)
Note: CMA, cost-minimization analysis; CBA, cost-benefit analysis; CEA, cost-effectiveness analysis; CUA, cost-utility analysis
Ta
ble 3.2.
Baseline char
act
eristics of included studies r
eg ar ding c ountry , type of sur gery , p ro ph
ylactic antibiotics, gender
, mean age, number of
subjects, out
co
me measur
e, stud
y design, antibiotic susc
eptibility , and p ro ph ylactic timing A ut hor , ye ar Co un tr y Ty pe o f su rge ry Pr op hy la ct ic a nt ib io tic G en der M ea n a ge (y ea rs ) N umb er of sub je ct O ut co m e m ea sure St ud y d es ign A nt ib io tic su sc ep tib ilit y Prop hy la ct ic timin g St ud y G rou p Con tro l G rou p G en er al su rg er y Ch au dh ur i e t al ., 20 06 G er ma ny Ex ci sio n o f pil oni da l sin us es M et ro ni da zo le 50 0m g i .v. Ce fu ro xi m e 1.5 g i .v. + m et ro ni da zo le 50 0m g i .v. F a nd M 27 SG : 2 5 CG : 2 5 Inf ec tio n-re lat ed w ou nd co m pli ca tio ns , to tal c os ts D ou bl e-bli nd ed RC T NA 30 m in ut es p rio r to i nc isi on a nd co nt in ue d t o d ay 5 f or m ul ti-dr ug W ils on e t a l., 20 08 Un ite d St at es El ec tive co lo re ct al su rg er y Er ta pe ne m 1g i.v . Ce fo te ta n 2 g i .v. F a nd M SG : 6 1.3 ; CG : 6 0. 2 SG : 3 38 ; CG : 3 34 SS Is, a nt ib io tic u se , an as to m ot ic l ea k of t he b ow el , c os t pe r d os e, d ire ct m ed ic al c os ts O bs er va tio nal st ud y: a na ly sis fro m P RE VE NT tria l ( Ita ni e t a l., 20 06) NA 30 m in ut es p rio r to in ci sio n M at su i e t a l., 20 14 Un ite d St at es La pa ros co pi c cho le cys t-ec to m y Ce fa zo lin so di um 1 g i .v. W ithout pr op hy la ct ic an tib io tic s F a nd M O ve r 6 5: 1 97 pa tie nt s (S G) a nd 20 2 p at ie nt s (CG ) SG : 518 ; CG : 5 19 Po st op er at ive in fe ct io ns ( SS Is, di st an t i nf ec tio ns ), ho sp ita l s ta y, an tib io tic c os ts , di re ct m ed ic al co st s RC T NA Be fo re sk in in ci sio n Si ng h e t a l., 20 14 Un ite d St at es Ab do mi na l su rg er y Tr ic lo sa n-co at ed su tu re s W ithout tri cl os an -co at ed su tu re s NA Al l a ge s in cl ud ed 1,000 in di vi dua ls Co st -s av in g o f tri cl os an -co at ed su tu re s w he n S SI -risk s w er e 5 % , 1 0% an d 15 % Mo de l-b as ed stu dy NA NA O zd em ir e t al ., 2 01 6 Tu rk ey El ec tive co lo re ct al res ec tio ns Ce fa zo lin 1g i .v. a nd m et ro ni da zo le 50 0m g i .v. plu s m et ro -ni da zo le 4g p .o. + ge nt am icin 48 0m g p .o . Ce fa zo lin 1 g i .v. a nd m et ro ni da zo le 50 0m g i .v. F a nd M SG : 58 CG : 59 SG : 45 CG :4 5 SS Is, l en gt h o f ho sp ita l s ta ys , co st-sa vi ng Re tro sp ec tive stu dy NA St ar t f ro m d ur in g an es th es ia in du ct io n t o 5 da ys p os t-op er at ion
A ut hor , ye ar Co un tr y Ty pe o f su rge ry Pr op hy la ct ic a nt ib io tic G en der M ea n a ge (y ea rs ) N umb er of sub je ct O ut co m e m ea sure St ud y d es ign A nt ib io tic su sc ep tib ilit y Prop hy la ct ic timin g St ud y G rou p Con tro l G rou p O rt hop ed ic El lio tt e t a l., 20 10 Un ite d Ki ng dom Pr im ar y hip ar th ro plas ty Cep hal os po rin Va nc om yc in or com bi na tion of v anc om yc in an d cep hal os po rin M 65 17 70 SS Is, M RS A inf ec tio n, le ng th of s ta y, m or ta lit y, ut ili ty i n Q AL Ys , co st s Mo de l-b as ed stu dy NA NA Co ur vi lle e t al ., 2 01 2 Un ite d St at es To ta l h ip an d k ne e ar th ro plas ty N as al mu pir ocin W ithout mu pir ocin NA H yp oth eti -ca l c oh or t o f 65-ye ar -ol d NA SS Is, u tili ty i n Q ALY s, c os ts Mo de l-b as ed stu dy NA NA M er ol lin i e t al ., 2 01 3 Au st ra lia To ta l h ip ar th ro plas ty An tib io tic pr op hy la xi s N o a nt ib io tic pr op hy la xi s, an tib io tic -im pre gn at ed cem en t, lami nar ai r op er at ing ro om s. NA 65 y ea rs 30 ,000 hy po th eti -ca l co hor ts SS Is, u tili ty i n Q AL Ys , le ng th o f sta y, mo rta lit y D ec isi on m od el an d c os t-effe ct ive ne ss ana ly sis NA NA Th eo lo gi s e t al ., 2 01 4 Un ite d St at es Th or ac olu m ba r ad ul t d ef or m ity re con st ruc tion In tra ve no us an tib io tic s a nd va nc om ycin po w de r 2 g In tra ve no us an tib io tic s F a nd M SG : 62 .4 ; CG : 6 0. 0 SG : 15 1 CG : 6 4 SS Is, u tili ty i n Q AL Ys , a dd -o n im pre gn at ed pr op hy la ct ic an tib io tic c os t, co st-sa vi ng Re tro sp ec tive co hor t s tu dy NA NA G ra ve s e t a l., 20 16 Un ite d St at es Pr im ar y hip rep la cem en t N o s ys te m ic an tib io tic s Sy st em ic an tib io tic s NA NA 77, 32 1 D ee p i nf ec tio ns , ut ili ty i n Q AL Ys , co st s Mo de l-b as ed stu dy NA NA Ceb al los e t al ., 2 01 7 Co lom bi a Lo w er li m b am put at ion Ce fa zo lin , ce ph al ot hin , ce fo ta xi m e, ce fo xit in , ce fu ro xi m e N on -pr op hy la ct ic an tib io tic s NA NA 10 ,000 simu la -tio ns D ec isi on a na ly tic m od el o f su pe rfi cia l a nd de ep i nf ec tio ns , he ali ng , s ep sis , re -a m pu tat io n, m or ta lit y, c os ts Mo de l-b as ed stu dy NA NA
3
A ut hor , ye ar Co un tr y Ty pe o f su rge ry Pr op hy la ct ic a nt ib io tic G en der M ea n a ge (y ea rs ) N umb er of sub je ct O ut co m e m ea sure St ud y d es ign A nt ib io tic su sc ep tib ilit y Prop hy la ct ic timin g St ud y G rou p Con tro l G rou p N eu ro su rge ry Em oh ar e e t al ., 2 01 4 Un ite d St at es Po st er io r sp in al su rg er y Ce fa zo lin i.v . a nd va nc om ycin po w de r 1 g int ra -w ou nd Ce fa zo lin i .v. F a nd M SG : 5 3. 7; CG : 5 8. 2 SG : 9 6; CG : 2 07 SS Is, i nt ra -w ou nd co st s, d ire ct c ost s Re tro sp ec tive co hor t s tu dy NA NA Le w is e t a l., 20 17 Un ite d St at es Cr an ia l s ur ge ry an d s ub dur al or su bg al ea l dr ai ns PPS As o f Ce fa zo lin a nd Va nc om yc in N on -P PS As F a nd M SG : 59 CG : 5 7 SG : 10 5 CG : 8 0 SS Is, d ire ct c os ts an d c os t s av in g Re tro sp ec tive stu dy NA NA Car di oth or ac ic su rg er y D ha dw al e t al ., 2 00 7 Un ite d Ki ng dom Co ro na ry a rt er y by pass g ra ftin g su rg er y Ri fa m pi cin 60 0m g p .o ., ge nt am icin 2m g/ kg i .v. a nd va nc om ycin 15 m g/k g i .v. Ce fu ro xi m e 1.5 g i .v. F a nd M SG : 6 2. 8; CG : 6 5. 4 SG : 8 7; CG : 9 9 SW Is, a nt ib io tic an d h osp ita l c os ts D ou bl e-bli nd ed RC T NA rif am pi ci n 1 h pr eop er at iv ely , ge nt ami ci n an d va nc om ycin af te r a ne st he sia in duc tion Jo sh i e t a l., 20 16 Un ite d Ki ng dom Ca rd ia c su rg er y in h ig h r isk o f SW I G en ta m icin -im pre gn at ed co lla ge n sp onge s W ithout ge nt am icin -im pre gn at ed co lla ge n sp onge s NA NA 12 51 SW I i nc ide nc e, m edi an po st op er at ive co st , a nn ua l ad di tio na l c os t fo r S W Is a nd th e g en ta m icin -im pre gn at ed co lla ge n s ponge s O bs er va tio nal stu dy NA NA O bs te tric g yn ec ol og ic al su rg er y Al ek w e e t a l., 20 08 N ig er ia El ec tive ce sa re an se cti on Ce ftr ia xo ne 1 g i .v. Am pi cil lin / cl ox acil lin 1g q .i.d . i. v., ge nt am icin 80 m g t .i.d . i.v . a nd m et ro ni da zo le 50 0m g t .i.d . i. v. F SG : 3 3. 53 ; CG : 3 2. 08 SG : 10 0 CG : 10 0 Inf ec tio us m or bi di ty , en do m et rit is, U TI , fe br ile m or bi dit ie s, w oun d i nf ec tio ns , du ra tio n o f ho sp ita l s ta y, an tib io tic c os ts RC T NA NA
A ut hor , ye ar Co un tr y Ty pe o f su rge ry Pr op hy la ct ic a nt ib io tic G en der M ea n a ge (y ea rs ) N umb er of sub je ct O ut co m e m ea sure St ud y d es ign A nt ib io tic su sc ep tib ilit y Prop hy la ct ic timin g St ud y G rou p Con tro l G rou p Ko su s e t a l., 20 10 Tu rk ey Ce sa re an se cti on Ce ftr ia xo ne 1g i .v. a nd rif am ycin 25 0m g Ce ftr ia xo ne 1g i.v . F SG : 28 .4 ; CG : 2 6. 8 SG : 59 6; CG : 6 00 SS I r at es , c os t f or rif am yc in a nd S SI tre at m en ts RC T NA NA O nc ol ogi c s ur ge ry Pa til e t a l., 20 11 In di a H ea d a nd n ec k onc o-su rge rie s Sin gl e an tib io tic o f ce fa zo lin , o r cip ro flo xa cin , or c ef pr oz il, o r cl in da m ycin Com bi na tion an tib io tic s o f ce fa zo lin a nd m et ro ni da zo le, or cl in da m ycin an d ge nt ami ci n, or a m pi ci lli n/ cl ox acil lin , o r m ox ifl ox ac in an d m et ro ni da zo le, or cip ro flo xa cin an d m et ro ni da zo le, or c ef pr oz il a nd m et ro ni da zo le F a nd M NA 50 Po st -o pe ra tive w oun d i nf ec tio ns , co st s f or pr op hy la ct ic an tib io tic s a nd po st -o pe ra tive an tib io tic s O bs er va tio nal stu dy NA NA G ul lu og lu e t al ., 2 01 3 Tu rk ey Br ea st c an ce r su rg er y Am pi cil lin -sul ba ct am 1g i.v . W ithout pr op hy la ct ic an tib io tic s F SG : 5 8. 8; C G: 58 .2 SG : 1 87 ; CG : 18 2 SS Is, t im e t o S SI s, cul tur e r es ul ts , ad ve rs e r ea ct io ns du e t o a nt ib io tic s, m ea n S SI -re la te d co st s RC T NA NA El -M ah al la w y et a l., 2 01 3 Eg yp t Ca nc er su rg er y (b la dde r, st om ac h, c ol on , re ct um) Pe ni cil lin G s od iu m 4, 000 ,000 IU i.v . a nd ge nt am ic in 8 0 m g i .v. Cli nd am yc in 60 0m g i .v. an d a m ik acin 50 0m g i .v. F a nd M <4 0 y ea rs : 72 >4 0 y ea rs : 12 8 SG : 10 0 CG : 10 0 SS I i nc ide nc e an d c os t f or pr op hy la ct ic an tib io tic s RC T NA NA CG , c on tro l G ro up ; F , f em al e; i .v. , i nt ra ve no us ; M , m al e; M RS A, M et hi ci lli n-re sis ta nc e St ap hy lo co cc us a ur eus ; N A, n ot a va ila bl e; p .o ., p er o ra l; P PS As , p ro lo ng ed p ro ph yl ac tic s ys te m ic a nt ib io tic s; Q AL Ys , q ua lit y a dju st ed li fe y ea rs ; q .i.d ., q ua rt er i n d ie ( fo ur t im es a d ay ); R CT , r an do m iz ed c on tro l t ria l; S G , s tu dy g ro up ; S SI s, s ur gi ca l s ite i nf ec tio ns ; S W Is, s te rn al w ou nd i nf ec tio ns ; t .i.d ., t er i n d ie (th re e t im es a d ay ); U TI , u rin ar y t ra ct i nf ec tio
3
Antibiotic Prophylaxis in General Surgery
Five included studies analyzed the cost and effectiveness of antibiotic prophylaxis in general surgery.21,26,30,31,34 The types of surgery were pilonidal sinus excision26, elective colorectal surgery21,34, laparoscopic cholecystectomy30, and general abdominal surgery31. The included studies indicated that new generation antibiotics generated economic benefit in SSI prevention. An observational study reported that the use of ertapenem in elective colorectal surgery achieved cost savings of roughly US$2,200 per patient compared with cefotetan.21 The secondary costs due to selection regarding resistance were not taken into account in this study and would need to be assessed in future studies. Another study showed that triclosan-coated sutures seemed to be cost-saving and effective at reducing SSI rates from the hospital, payer, and societal perspectives.31 However, no long-term data on tissue-toxicity and possible triclosan-induced inflammatory response was included in this study. In addition, single prophylactic antibiotics and both oral or intravenous administration were demonstrated to have a positive impact on reducing SSI rates and medical costs in general surgery.26,30
Antibiotic Prophylaxis in Orthopedic surgery
Various studies modeled economic and clinical impacts from the societal and healthcare perspectives of patients undergoing total hip arthroplasty (THA), total knee arthroplasty (TKA), and lower limb amputation.18,23,35,38,39 Economic analysis on the implementation of the use of nasal mupirocin to prevent deep SSI of Staphylococcus aureus in THA and TKA showed that mupirocin was more cost-effective compared to non-preoperatively administered mupirocin with incremental cost-effectiveness ratios (ICERs) at US$380.09/QALY and US$517.16/QALY for THA and TKA respectively.18 Vancomycin has also been taken into account as an intra-wound antibiotic, with SSI rates of 3% and 11% were identified in the group with and without 2g vancomycin powder, respectively. Clinically and economically, these percentages were considered to reflect a significant impact with cost savings of US$2,762 per operative procedure at day 90 post-surgery 24. Furthermore, two studies addressed that prophylactic intervention was dominant over no prophylactic antibiotics on SSI rates and cost reductions in total hip arthroplasty and lower limb amputation.23,39
Antibiotic Prophylaxis in Neurosurgery
Two cost-minimization studies on neurosurgery concerned intra-wound vancomycin and Prolonged Prophylactic Systemic Antimicrobials (PPSAs).19,33 Firstly, a cohort study, for the purpose of reimbursement to the hospital for SSI costs, evaluated the cost savings achieved by adding intra-wound vancomycin powder as prophylactic therapy to standard intravenous cefazolin in patients who underwent spinal surgery. No SSIs were reported in patients who received intra-wound vancomycin, whereas 7 out of 207 patients who were given only cefazolin developed SSIs at a cost of US$2,879 per patient.19 Secondly, a retrospective study looked into the duration of prophylactic antibiotic use in cranial surgery and subdural or subgaleal drains. Continuous prophylactic antibiotics or PPSAs were considered costly compared with non-PPSA treatment in the operation, which saved US$93,195 per patient.33
Antibiotic Prophylaxis in Cardiothoracic Surgery
Two included RCTs and an observational study evaluated the clinical and economic impact of antibiotics for the prevention of SWIs in coronary surgery. First, one RCT study reported that the use of triple antibiotics of rifampicin gentamicin, and vancomycin for SSI prophylaxis could reduce the total cost of treatment by US$4,521 per patient compared to single prophylaxis of cefuroxime.27 Second, an observational study on Gentamicin-impregnated Collagen Sponges (GCS) to prevent SSIs in cardiac surgery noted a unit cost of GCS of roughly US$129 per patient. Nevertheless, in their cost analysis, they remarked that GCS provided no economic benefit in reducing SSI incidence in a two-year period.28
Antibiotic Prophylaxis in Obstetric and Gynecological Surgery
In obstetric and gynecological surgery, two included RCT-based studies analyzed SSI incidence and performed an economic impact analysis of ceftriaxone prophylactic in delivery through cesarean section. The first RCT compared single-dose prophylactic ceftriaxone to a triple-drug combination of ampicillin/cloxacillin, gentamicin, and metronidazole. Notwithstanding the economic benefit of a single dose of ceftriaxone compared with the combination regimen, the SSI rates were between 7% with ceftriaxone and 8% with the triple drugs.25 The second RCT was carried out on the implementation of subcutaneous rifamycin as an add-on therapy for prophylactic ceftriaxone. Twelve allocated subjects for the standard prophylactic were followed up with SSI, and in these cases, the total cost related to SSI treatment amounted to US$483 per patient. On the other hand, no patient developed SSI by the end of the follow-up period in the intervention group.29
Antibiotic Prophylaxis in Oncology Surgery
Three included studies concerned different operative procedures in oncology surgery used prophylactic antibiotics for malignancy of the breast, head-neck, bladder, stomach, colon, and rectum.20,22,36 An observational study in surgery for head and neck cancer by Patil et al.,20 conveyed that no significant difference was indicated in the total cost between single and combination antibiotics. On the other hand, an RCT study on breast cancer surgery by Gulluoglu et al.,22 presented that antibiotic prophylaxis with intravenous ampicillin-sulbactam was cost-saving and effective compared to no prophylaxis, resulting in a 9% reduction in the SSI rate and a cost reduction of US$11 per patient. Moreover, another RCT on abdominal cancer by El-Mahallawy
et al.,36 indicated cost savings with the combination of penicillin and gentamicin overusing clindamycin and amikacin. Table 3.3 compares the included studies on reporting cost analysis. In addition, the SSI rates and the cost ranges of each surgical procedure are presented in Table 3.4.
Ta ble 3.3. Co mpariso ns of included studies on r epo rting of c ost index year , c ost ana lysis method, co st perspectiv e, and adjust ed c osts in US$ a t 2015 infla tio n r at e St ud y, y ea r o f pub lic at io n Co st in de x ye ar Co st an al ys is m eth od Co st pe rs pe ct iv e A dj us te d c os ts i n U S$ a t 2 01 5-in fla tio n r at e G en er al su rg er y Ch au dh ur i e t a l., 2 00 6 20 06 CM A NA To ta l c os t i n t he g ro up w ith a s in gl e-do se M et ro ni da zo le : U S$ 11 .5 3 p er p at ie nt To ta l c os t f or S SI c om pli ca tio ns : U S$ 81 3. 25 p er p at ie nt W ils on e t a l., 2 00 8 20 05 CM A NA Cos t p er d os e o f er ta pen em : U S$4 7.8 6 p er p at ien t Co st p er d os e o f c ef ot et an : U S$ 29 .7 8 p er p at ie nt D ire ct m ed ic al c os t i n t he g ro up w ith e ta pe ne m p ro ph yl ax is: U S$ 16 ,4 33 .8 9 p er p at ie nt D ire ct m ed ic al c os t i n t he g ro up w ith c ef ot et an p ro ph yl ax is: U S$ 18 ,8 12 .6 6 p er p at ie nt M at su i e t a l., 2 01 4 20 13 CM A NA Co st f or a nt ib io tic s i n t he g ro up w ith c ef az oli n: U S$ 25 .7 3 p er p at ie nt ; Co st f or a nt ib io tic s i n t he g ro up w ith ou t p ro ph yl ac tic : U S$ 8. 37 p er p at ie nt ; D ire ct m ed ic al c os t i n t he g ro up w ith c ef az oli n: U S$ 79 1.5 9 p er p at ie nt ; D ire ct m ed ic al c os t i n t he g ro up w ith ou t p ro ph yl ac tic : U S$ 85 9. 58 p er p at ie nt . Si ng h e t a l., 2 01 4 20 13 CM A H eal th ca re , pa ye r a nd so ci eta l pe rsp ec tive Fo r 1 5% S SI r isk , t ric lo sa n-co at ed s ut ur e s ave d: - US $4 ,2 32 .2 7 – 1 4, 39 4. 25 p er p at ie nt ( H osp ita l p er sp ec tive ) - US $4 ,2 56 .9 9 – 1 4, 72 5. 91 p er p at ie nt ( Pa ye r p er sp ec tive ) - US $4 1,3 30. 81 – 5 4, 84 1. 32 p er p at ie nt ( So ci et al p er sp ec tive ) O zd em ir e t a l., 2 01 6 20 16 CM A NA To tal h os pi tal c os t: - In t he g ro up w ith c ef az oli n a nd m et ro ni da zo le i nt ra ve no us ly p lu s m et ro ni da zo le a nd g en ta m ic in o ra lly : U S$ 2, 69 9 p er pa tie nt - In t he g ro up w ith c ef az oli n a nd m et ro ni da zo le i nt ra ve no us ly : U S$ 4, 41 1 p er p at ie nt O rt ho pe di c El lio tt e t a l., 2 01 0 20 05 CUA So ci eta l pe rsp ec tive To ta l c os t p er Q AL Y f or S SI -tr ea tm en ts - In t he g ro up w ith v an co m yc in p ro ph yl ac tic : U S$ 1,4 17 .7 8/ Q AL Y - In t he g ro up w ith c ep ha lo sp or in p ro ph yl ac tic : U S$ 1,4 18 .01 /Q AL Y - In t he g ro up w ith c om bi na tio n p ro ph yl ac tic : U S$ 1,4 21 .4 8/ Q AL Y Co ur vi lle e t a l., 2 01 2 20 05 CE A So ci eta l pe rsp ec tive Ave ra ge c os t p er Q AL Y: To ta l hip a rt hr op las ty : - Tr ea te d w ith m up iro ci n: U S$ 34 ,9 90. 65 /Q AL Y - Tr ea te d w ith m up iro ci n a nd s cr ee ne d p os iti ve f or S. au re us : U S$ 35, 30 8. 54 /Q AL Y - W ith ou t m up iro ci n: U S$ 35 ,3 70. 74 /Q AL Y To ta l k ne e a rt hr op la st y: - Tr ea te d w ith mu pir ocin : U S$ 41 ,3 68 .18 /Q AL Y - Tr ea te d w ith m up iro ci n a nd s cr ee ne d p os iti ve f or S. au re us : US $4 1,7 75 .92 /Q AL Y - W ith ou t mu pir ocin : U S$ 41 ,8 85 .3 4/ Q AL Y
St ud y, y ea r o f pub lic at io n Co st in de x ye ar Co st an al ys is m eth od Co st pe rs pe ct iv e A dj us te d c os ts i n U S$ a t 2 01 5-in fla tio n r at e M er ol lin i e t a l., 2 01 3 20 11 CE A H eal th ca re pe rsp ec tive IC ER non -pr op hy la ct ic c om pa re d wi th pr op hy la ct ic a nt ibi ot ic s: U S$ 9,9 17 .14 /Q AL Y-lo st Ad d-on a nt ib io tic -im pr eg na te d p ro ph yla xi s s av in g U S$ 4,1 64 .8 1/ Q AL Y-ga in ed Th eo lo gi s e t a l., 2 01 4 20 09 CM A NA Co st f or v an co m yc in p ow de r: U S$ 38 .3 0 p er o pe ra tive p ro ce du re To ta l c os t i n t he g ro up w ith v an co m yc in p ow de r: U S$ 78 ,74 5.1 8 p er o pe ra tio n To ta l c os t i n t he g ro up w ith ou t v an co m yc in p ow de r: U S$ 71 ,51 4. 31 p er o pe ra tio n Co st -s av in g u sin g v an co m yc in p ow de r: U S$ 27 6,1 74 .2 6 p er 1 00 o pe ra tive p ro ce du re s G ra ve s e t a l., 2 01 6 20 12 CUA H eal th ca re pe rsp ec tive W ith t he r ef er en ce o f n on -s ys te m ic a nt ib io tic s + p la in c em en t + c on ve nt io na l ve nt ila tio n ( T0 ), I CE Rs o f T 1 t o T8 : - T1 : U S$ 12 0, 98 9. 52 /Q AL Y - T2 : U S$ 83 ,9 04 .20 /Q AL Y - T3 : U S$ 75, 53 3. 82 /Q AL Y - T4 : US $8 8, 05 4.9 6/ Q AL Y - T5 : U S$ 95 ,76 5. 38 /Q AL Y - T6 : U S$ 44 ,615 .47 /Q ALY - T7 : U S$6 3,1 85. 13 /Q AL Y - T8 : U S$ 21 ,3 02 /Q AL Y Ce ba llo s e t a l., 2 01 7 20 14 CE A H eal th ca re pe rsp ec tive In cr em en ta l c os t b et w ee n n on -p ro ph yl ac tic a nd p ro ph yl ac tic g ro up : U S$ 1,2 45 .8 3 p er p at ie nt N eu ro su rge ry Em oh ar e e t a l., 2 01 4 20 12 CM A NA Co st f or i nt ra -w ou nd v an co m yc in : U S$ 12 .4 6 p er p at ie nt D ire ct m ed ic al c os t i n t he g ro up w ith ou t i nt ra -w ou nd v an co m yc in : U S$ 2, 87 9. 02 p er p at ie nt Le w is e t a l., 2 01 7 20 15 CM A NA Th e d ire ct c os t f or P PS As : U S$ 88 7.5 0 p er p at ie nt Co st -s av in g f or N on -P PS As : U S$ 93 ,19 4. 63 p er p at ie nt Ca rdi ot hor ac ic su rg er y D ha dw al e t a l., 2 00 7 20 04 CM A NA Co st for pr op hy la ct ic a nt ibi ot ic s: - In t he g ro up w ith a s in gl e p ro ph yl ac tic a nt ib io tic : U S$ 54 0.1 8 p er p at ie nt - In t he g ro up w ith c om bi na tio n p ro ph yl ac tic a nt ib io tic s: U S$ 42 5. 95 p er p at ie nt To tal h os pi tal c os ts : - In t he g ro up w ith a s in gl e p ro ph yl ac tic a nt ib io tic : U S$ 22 ,13 0. 53 p er p at ie nt - In t he g ro up w ith c om bi na tio n p ro ph yl ac tic a nt ib io tic s: U S$ 17 ,6 09 .2 4 p er p at ie nt
3
St ud y, y ea r o f pub lic at io n Co st in de x ye ar Co st an al ys is m eth od Co st pe rs pe ct iv e A dj us te d c os ts i n U S$ a t 2 01 5-in fla tio n r at e Jo sh i e t a l., 2 01 6 20 13 CM A NA M ed ia n c os t w ith ou t S SI : U S$ 15 ,5 02 .7 2 p er p at ie nt M ed ia n a dd iti on al c os t f or S SI t re at m en ts : U S$ 7,8 35 .5 9 p er p at ie nt Co st f or t he G CS : U S$ 12 8. 96 p er p at ie nt To ta l a nn ua l a dd iti on al c os ts i n r ed uc in g S SI i nc id en ce b y 5 0% - w ith ou t G CS : U S$ 70 ,5 23 .9 0 p er p at ie nt - w ith G CS : U S$ 11 5,9 24 .5 9 p er p at ie nt O bs te tric g yn ec ol og ic al sur ge ry El lio tt e t a l., 2 01 0 20 08 CM A NA Co st s f or a nt ib io tic s: - In t he g ro up w ith a s in gl e p ro ph yl ac tic a nt ib io tic : U S$ 10. 61 p er p at ie nt - In t he g ro up w ith c om bi na tio n p ro ph yl ac tic a nt ib io tic s: U S$ 16 .5 2 p er p at ie nt Co ur vi lle e t a l., 2 01 2 20 07 CM A NA Th e p ric e o f r ifa m yc in : U S$ 1.5 8 p er p at ie nt M ea n c os t f or S SI t re at m en ts : U S$ 48 2. 59 p er p at ie nt O nc ol ogi c s ur ge ry Pa til e t a l., 2 01 1 20 07 CM A NA Co st s i n t he g ro up w ith a s in gl e a nt ib io tic : - Pr op hy la ct ic a nt ib io tic c os ts : U S$ 7.2 2 p er p at ie nt - Po st -s ur gi ca l a nt ib io tic c os ts : U S$ 79 .76 p er p at ie nt - To ta l a nt ib io tic s c os ts : U S$ 86 p er p at ie nt Co st s i n t he g ro up w ith a c om bi na tio n o f p ro ph yl ac tic a nt ib io tic s: - Pr op hy la ct ic a nt ib io tic c os ts : U S$ 12 .13 p er p at ie nt - Po st -s ur gi ca l a nt ib io tic s c os ts : U S$ 82 .7 9 p er p at ie nt - To ta l a nt ib io tic s c os ts : U S$ 94 .92 p er p at ie nt G ul lu og lu e t a l., 2 01 3 20 10 CM A NA Co st s f or S SI t re at m en ts : - In t he g ro up w ith p ro ph yl ac tic a nt ib io tic s: U S$ 9.1 8 p er p at ie nt - In t he g ro up w ith ou t p ro ph yl ac tic a nt ib io tic s: U S$ 21 .93 p er p at ie nt El -M ah al la w y e t a l., 20 13 20 13 CM A NA D ire ct c os t i n t he g ro up w ith p en ic illi n G s od iu m a nd g en ta m ic in : U S$ 3. 26 p er p at ie nt D ire ct c os t i n t he g ro up w ith c lin da m yc in a nd a m ik ac in : U S$ 17 .3 9 p er p at ie nt CM A, c os t m in im iz at io n a na ly sis ; G CS , G en ta m ic in c ol la ge n sp on ge s; I CE R, i nc re m en ta l c os t-effe ct ive ne ss r at io ; N A, n ot a va ila bl e; P PS As , p ro lo ng ed p ro ph yl ax is s ys te m ic a nt im ic ro bia ls; T 1, sy st em ic a nt ib io tic s + p la in c em en t + c on ve nt io na l ve nt ila tio n; T 2, n on -s ys te m ic a nt ib io tic s + p la in c em en t + l am in ar a irfl ow ; T 3, s ys te m ic a nt ib io tic s + p la in c em en t + l am in ar a irfl ow ; T 4, n on -sy st em ic a nt ib io tic s + a nt ib io tic -im pr eg na te d c em en t + c on ve nt io na l ve nt ila tio n; T5 , s ys te m ic a nt ib io tic s + a nt ib io tic -im pr eg na te d c em en t + c on ve nt io na l ve nt ila tio n; T 6, s ys te m ic a nt ib io tic + an tib io tic -im pr eg na te d c em en t + l am in ar ai rfl ow ; T 7, sy st em ic a nt ib io tic s + an tib io tic -im pr eg na te d ce m en t + ve nt ila tio n + bo dy e xh au st s ui t; T8 , s ys te m ic a nt ib io tic s + a nt ib io tic -im pr eg na te d ce m en t + l am in ar ve nt ila tio n + b od y e xh au st s ui t; T H A, t ot al h ip a rt hr op la st y; T KA , t ot al k ne e a rt hr op la st y; U S$ , t he U ni te d S ta te s D ol la rs .
Ta ble 3.4. Co mpariso n of select ed studies o n r epo
rting of SSI classifica
tio n, SSI r at e, sta tistica l significanc
e, timing SSI identified, and length of
ho spita liz atio n St ud y, y ea r o f pub lic at io n SS I cla ss ific at io n SSI ra te * St at is tic al si gn ifi can ce Timin g S SI id en tifi ed Le ng th o f ho sp ita liz at io n (d ay s) G en er al su rg er y Ch au dh ur i e t a l., 20 06 Su per fic ial M et ro ni da zo le : 1 1(4 4%) Ce fu ro xi m e a nd m et ro ni da zo le : 3 (1 2% ) p v alu e: 0. 9, < 0. 00 01 a nd <0. 03 a t w ee k 1 , 2 a nd 4 re sp ec tive ly W ee k 1 ,2 , a nd 4 NA W ils on e t a l., 2 00 8 Su per fic ial , de ep , o rg an sp ace Er ta pen em : 6 2( 18 .3 % ) Ce fo te ta n: 1 04 (3 1.1 % ) CI 95 % a bs olu te di ffe re nc e: -1 9.5-6.5 We ek 4 Er ta pe ne m : 9 ; Ce fo te ta n: 11 .6 M at su i e t a l., 2 01 4 NA Ce fa zo lin : 4 (0. 8% ) W ithout pr op hy la ct ic a nt ibi ot ic : 1 9( 3. 7% ) p v alu e: 0. 00 1 D ay 1 a nd o r d ay 2 p os to pe ra tive Ce fa zo lin : 3 .6 9 N o a nt ib iot ic : 4. 07 Si ng h e t a l., 2 01 4 Su pe rfi cia l a nd de ep SS I An a ss um pt io n o f S SI -ri sk f or t he t ric lo sa n c oa te d s ut ur es t re at m en t: 5 -2 0% NA 30 -9 0 d ay s NA O zd em ir e t a l.,2 01 6 Su per fic ial , de ep a nd or ga n sp ac e Co m bi na tio n o f i nt ra ve no us p ro ph yl ax is ( ce fa zo lin a nd m et ro ni da zo le ) a nd o ra l pr op hy la xi s ( m et ro ni da zo le a nd g en ta m ic in ): 1 6( 35 .6 % ) In tra ve no us p ro ph yl ax is o nl y ( m et ro ni da zo le a nd g en ta m ic in ): 3 2(7 1.1 % ) p v alu e< 0. 00 1 30 d ay s In tra ve no us o nl y: 1 4. 2 Com bi na tion of in tra ve no us a nd o ra l pr op hy la xi s: 8 .1 O rt hop ae di c El lio tt e t a l., 2 01 0 Su pe rfi cia l a nd de ep /jo int Va nc om yc in g ro up : 2 (0. 4% ) i nf ec te d b y M RS A a nd 4 1( 9.1 % ) i nf ec te d b y o th er s Ce ph al osp or in g ro up : 7 (1 .6 % ) i nf ec te d b y M RS A a nd 3 2(7 .4 % ) i nf ec te d b y o th er s NA 30 d ay s NA Co ur vi lle e t a l., 20 12 D eep Pr ob ab ili ty a m on g M up iro ci n-tre at ed c ar rie rs : 1 .3 % Pr ob abi lit y a m ong non -M upi ro ci n a nd non -c ar rie rs : 0 .5 8% NA Ti m e horiz on : 1 y ea r NA M er ol lin i e t a l., 20 13 D eep In cr em en tal S SI in ci den ce : - In n on -p ro ph yl ac tic a nti bi oti c g ro up o ver th e p ro ph yl ac tic g ro up : 2 30 ca se s - In a dd -o n a nti bi oti c-im pr eg na te d c em en t o ver a nti bi oti c p ro ph yl ax is: pr ev en te d 4 6 c as es NA Ti m e horiz on : 3 0 yea rs NA Th eo lo gi s e t a l., 20 14 NA In tra ve no us a nt ib io tic s a nd v an co m yc in p ow de r: 4 (2 .6 % ) In tra ve no us a nt ib io tic o nl y: 7 (1 0. 9% ) p v alu e: 0. 01 90 d ay s NA
3
St ud y, y ea r o f pub lic at io n SS I cla ss ific at io n SSI ra te * St at is tic al si gn ifi can ce Timin g S SI id en tifi ed Le ng th o f ho sp ita liz at io n (d ay s) G ra ve s e t a l., 2 01 6 D eep T0 : 1 88 7 c as es T1 : 8 70 c as es T2 : 6 70 c as es T3 : 7 21 c as es T4 : 95 0 c as es T5 : 4 06 c as es T6 : 6 66 c as es T7 : 9 05 c as es T8 : 1 12 6 c as es CI 95% : T0 : 12 53 -2 62 1 T1: 3 45 -1 65 5 T2 : 9 0-19 37 T3 : 1 92 -15 89 T4 : 2 86 -2 05 9 T5 : 9 0-96 4 T6 : 1 01 -2 01 7 T7 : 7 7-24 99 T8 : 1 43 -2 82 7 Ti m e horiz on : 30 d ay s f or non -im pl an t a nd 1 ye ar f or i m pl an t pr oc ed ur es NA Ceb al los e t al ., 2 01 6 Su pe rfi cia l a nd de ep Pr op hy la cti c a nti bi oti c: 6 2( 16 .2 % ) N on -pr op hy la ct ic a nt ibi ot ic : 4 4( 38 .3 % ) NA NA NA N eu ro su rge ry Em oh ar e e t a l., 20 14 Su per fic ial (s tu dy g ro up : 5 ( 5% ); c on tro l gr ou p: 5 (2% )); D ee p ( st ud y gr ou p: 0 ; co nt ro l gr oup :7( 3% )) Ce fa zo lin a nd v an co m yc in : 0 o ut o f 9 6 Ce fa zo lin : 7 (3 .4 % ) NA 20 -2 2 m on th s NA Le w is e t a l., 2 01 7 Su pe rfi cia l a nd de ep PP SA s: 2( 1.9 %) N on -P PS As : 1 (1 .3 % ) D ee p S SI : p =1 .0 0 Su pe rfi cia l S SI : p = 0. 77 90 d ay s PPS As a nd n on -P PS As : 5 Ca rdi ot hor ac ic su rg er y D ha dw al e t a l., 20 07 Su per fic ial , de ep , o rg an sp ace Ri fa m pi cin + g en ta m icin + v an co m ycin : 8( 9. 2% ) Ce fu ro xi m e: 2 5(2 5. 3% ) NA D ay 9 0 Tr ip le a nt ib io tic s: 9 .1 Sin gl e a nt ib io tic : 1 2 Jo sh i e t a l., 2 01 6 D ee p a nd su per fic ia l st er na l w ou nd inf ec tio n 18 (1 .4 % ) d ia gn os ed a s S W I i n a t w o-ye ar p er io d NA NA W ar ds : 5 ( no n-SW I) a nd 12 .7 (S W I) IC U: 2 .5 ( no n-SW I) a nd 3 (S W I)
St ud y, y ea r o f pub lic at io n SS I cla ss ific at io n SSI ra te * St at is tic al si gn ifi can ce Timin g S SI id en tifi ed Le ng th o f ho sp ita liz at io n (d ay s) O bs te tric g yn ec ol og ic al sur ge ry Al ek w e e t a l., 2 00 8 D eep Ce ftr ia xo ne : 7 (7 % ) Am pli co x + g en ta m ic in + m et ro ni da zo le : 8 (8 % ) p v alu e: 0. 78 8 D ay 3 Si ng le a nt ib io tic : 6 .3 3; Tr ip le a nt ib iot ic s: 6 .2 2 Ko su s e t a l., 2 01 0 Su pe rfi cia l a nd de ep Ce ftr ia xo ne + r ifa m yc in S V: 0 o ut o f 5 96 Ce ftr ia xo ne : 1 2( 2%) p v alu e < 0. 05 D ay 2 , 5 , 4 0 7 O nc ol og ic su rg er y Pa til e t a l., 2 01 1 NA Sin gl e a nt ib io tic : 1 1( 47 .8 % ) Com bi na tion of a nt ibi ot ic s: 7 (2 5% ) NA NA Si ng le a nt ib io tic : 3 6 Com bi na tion of an tib iot ic s: 3 3 G ul lu og lu e t a l., 20 13 Su per fic ial Am pi ci lli n/ su lb ac ta m : 9 (4 .8 % ) N on -p ro ph yl ac tic a nti bi oti cs : 25 (1 3. 7% ) NA D ay 3 0 NA El -M ah al la w y e t al ., 2 013 NA Pe ni ci lli n G s od iu m + g en ta m ic in : 1 1( 11 % ) Cl in da m ycin + a m ik acin : 8( 8% ) p v alu e: 0. 47 NA NA *t he p rov id ed p er ce nt ag es w er e t he p er ce nt ag es w ith in t he g ro up CI , c on fid en t in te rv al ; I CU , i nt en sive ca re un it; i.v ., in tr ave no us ; L oS , l en gt h of st ay ; N A, no t av ai la bl e; PPS As , p ro lo ng ed pr op hy la xi s sy st em ic an tim ic ro bia ls; SW I, st er na l w ou nd in fe ct io n; T0 , N o s ys te m ic a nt ib io tic s + p la in c em en t + c on ve nt io na l ve nt ila tio n; T 1, s ys te m ic a nt ib io tic s + p la in c em en t + c on ve nt io na l ve nt ila tio n; T 2, n on -s ys te m ic a nt ib io tic s + p la in c em en t + l am in ar ai rfl ow ; T 3, sy st em ic an tib io tic s + pl ai n ce m en t + la m in ar ai rfl ow ; T 4, no n-sy st em ic an tib io tic s + an tib io tic -im pr eg na te d ce m en t + co nve nt io na l ve nt ila tio n; T5 , s ys te m ic an tib io tic s + an tib io tic -im pr eg na te d c em en t + c on ve nt io na l ve nt ila tio n; T 6, s ys te m ic a nt ib io tic + a nt ib io tic -im pr eg na te d c em en t + l am in ar a irfl ow ; T 7, s ys te m ic a nt ib io tic s + a nt ib io tic -im pr eg na te d c em en t + ve nt ila tio n + b od y e xh au st s ui t; T8 , s ys te m ic a nt ib io tic s + a nt ib io tic -im pr eg na te d c em en t + l am in ar ve nt ila tio n + b od y e xh au st s ui t
3
Timing of Antibiotic Prophylactic Interventions
The starting time of antibiotics in prophylactic administrations was different ranging from an hour before the surgical procedure to the time of skin incision. Five studies explicitly stated the time of starting the prophylactic antibiotics.21,26,27,30,34 Chaudhuri et al.,26 and Wilson et al.,21 reported the administration of the agents 30 minutes preoperatively for cefuroxime, metronidazole, and cefotetan. Rifampicin in the study conducted by Dhadwal et al.,26 was administered orally an hour before incision, followed by vancomycin post-induction of anesthesia. Additionally, intravenous cefazolin sodium was injected before skin incision. Elongation of antibiotic prophylaxis was also expounded in the studies, for instance, being explicitly analyzed by Alekwe et al.,25 Chauduri et al.,26 Dhadwal et al.27
Reports of the Microorganisms Causing SSI
From 7 included studies, this review generated a list of 24 bacteria that were reported as causing SSIs at the site of surgery on the cranium, thorax, abdomen, and thoracolumbar spine.22,24,27,29,33,34,36 The predominant species that have been reported to be found for SSIs were gram-negative bacteria. The most common pathogen reported among studies was Escherichia coli isolates, accounting for 6.7-50% of incidence in general surgery, orthopedic, cardiothoracic surgery and cesarean section.24,27,29,34 More importantly, Staphylococcus aureus was the second most prevalent which was dominant among gram-positive bacteria causing SSIs.22,27,34,36 Anaerobic bacteria were also reported, with an isolated case of Bacteroides fragilis as a rare bacteria, accounting for approximately 13% of the SSI causes among cesarean section procedures.29 We compiled the results of the pattern of bacterial causation of SSIs in Table 3.5.
Quality Assessments of the Included Studies
The range of CHEC scores in the included studies was from a low of 8 to a high of 18.5.27,38 The quality assessment scores of studies regarding general surgery ranged from 10 to 12.21,26,30,31,34 Among studies on orthopedic surgery and neurosurgery, the quality ranged between 12 and 18.5.18,19,23,24,33,35,38,39 Two cardiothoracic studies scored 8 and 11.5 points for CHEC items.27,28 Two obstetric and gynecological studies were scored at 10.5 and 11.25,29 Furthermore, two oncologic surgery studies obtained quality scores of 9.5 and 12.5.20,22,36 From the CHEC items, related to incremental analysis concerns mostly and sensitivity analysis. The quality assessments of each article are reported in Table 3.6.
Table 3.5. Characteristics of pathogens, prophylactic antibiotic, mean cost and SSI incidence in
each surgical procedure
Type of surgery,
reference Pathogen (%) Prophylactic antibiotic Mean cost, US$* SSI incidence, %
General surgery
(Chaudhuri et al., 2006; Matsui et al., 2014; Ozdemir et al., 2016; Singh et al., 2014; Wilson et al., 2008)
- Colorectal surgery - Excision of pilonidal sinuses - Laparoscopic cholecystectomy Escherichia coli (25) Klebsiella pneumonia (50) Staphylococcus aureus (25) Cefazolin Cefotetan Ertapenem Gentamicin Metronidazole Triclosan. 791.59 – 54,841.32 0.8-71.1 Orthopedic
(Ceballos et al., 2017; Courville et al., 2012; Elliott et al., 2010; Graves et al., 2016; Merollini et al., 2013; Theologis et al., 2014)
- Deformity reconstruction - Hip arthroplasty - Hip replacement - Knee arthroplasty - Lower limb amputation
Citrobacter freundii (6.7) Corynebacterium afermentan (6.7) Corynebacterium jeikeium (6.7) Enterobacter cloacae (6.7) Escherichia coli (6.7) MRSA (39.9) Proteus mirabilis (13.3) Pseudomonas mirabilis (13.3) Staphylococcus epidermidis (6.7) Cefazolin Cefotaxime Cefoxitin Cefuroxime Cephalotin Mupirocin Vancomycin 1,245.83 – 120,989.52 0.5-38.3 Neurosurgery
(Emohare et al., 2014; Lewis et al., 2016) - Cranial surgery - Posterior spinal surgery - Subdural and subgaleal drains Enterobacteriacea (33.3) Klebsiella pneumonia (33.3) Propionibacterium acnes (33.3) Cefazolin Vancomycin 887.79 – 2,879.02 0-3.4 Cardiothoracic surgery
(Dhadwal et al., 2007; Joshi et al., 2016) - Cardiac surgery
- Coronary artery bypass Staphylococcus aureus (8.7)Bacteroides fragilis (4.3) Enterobacter cloacae (2.9) Enterobacteriaceae (30.4) Enterococcus faecalis (14.5) Escherichia coli (24.6) Klebsiella pneumonia (3.0) Pseudomonas aeruginosa (7.2) Proteus mirabilis (3.0) Serratia marcescens (1.4) Gentamicin Rifampicin Vancomycin 7,835.59 – 22,130.53 1.4-25.3
Obstetric gynecological surgery
(Alekwe et al., 2008; Kosus et al., 2010)
- Cesarean section Bacteroides fragilis (12.5) Escherichia coli (50) Enterococci (25) Streptococci spp.s Group B (12.5) Ampicillin Ceftriaxone Gentamicin Metronidazole Rifamycin 482.59 0-8 Oncologic surgery
(El-Mahallawy et al., 2013; Gulluoglu et al., 2013; Patil et al., 2011) - Bladder cancer surgery
- Breast cancer surgery - Head and neck
onco-surgeries
- Rectal cancer surgery
- Stomach cancer surgery Acinectobacter haemolyticus (2.7) Staphylococcus aureus (32.4) Streptococci (16.2) Staphylococcus epidermidis (35.1)
Various gram negatives (13.6)
Amikacin Ampicillin Cefazolin Cefprozil Ciprofloxacin Clindamycin Gentamicin Metronidazole Moxifloxacin Penicillin G Not adequately informed 4.8-47.8
*Adjusted mean cost in US$ at 2015-inflation rate
DISCUSSION
Guidance for the reporting of economic and clinical studies in the specific field of infectious disease and antibiotic use is urgently needed. Choosing the use of prophylactic antibiotics especially for SSIs should take into account the local epidemiological data of the pathogens and antimicrobial susceptibility. The microbial etiology of SSIs and antibiotic resistance are often missing from reports of the mid-and long-term economic impact of antibiotic use. For the economic part, the minimum requirements of the established CHEC checklist can assist in the reporting of economic studies. Also, a different checklist from the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement has been performed to assess the quality of the economic study.17,40 However, the CHEERS checklist only considers the completeness of reporting and does not evaluate the quality. Another checklist which was developed by Caro et
al.,41 was merely to conceptualize model-based studies. Hence, the CHEC checklist seems most applicable and appropriate for quality assessment in this review.
The diversity in the definition of SSIs in terms of the period to identify the SSIs potentially generates under-reporting of the diseases’ occurrence. Despite the definition from the CDC 13, other definitions were addressed by Peel and Taylor,42 from the Surgical Infections Society Study Group (SIGS) and Ayliffe et al.,43 from the National Prevalence Survey (NPS) which considered grouping wound infection based on the cause of infection, the time of appearance, and the severity of infection. For the time of the appearance of infection, they divided this into three categories, namely early, intermediate, and late based on whether the infection appeared in a 30-day period, in a period of between 1 and 3 months, and over 3 months post-surgery, respectively. By these definitions, the cost is accurately predicted especially for the potentially extensive financial burden of late-occurrence SSIs. Twelve included studies (60%) defined the time for the appearance of SSIs within diverse follow-up intervals for trial-based studies and time horizons for model-based studies.
Obviously, the clinical outcome depends not only on prophylactic antibiotics which is prior to surgical procedures but also whether minimal intervention is concerned comprising limited tissue damage, which has the effect of accelerating wound healing.44 Other influential issues that were identified for the costs of the management of surgical patients include surgical techniques, skilled surgeons being available, types of diseases, and the for-profit or not-profit nature of healthcare system services involved.45,46 The desired economic impacts of the proper use of prophylactic antibiotics in SSIs prevention are shorter lengths of stay, lower resistance rates, and ultimately, the reduction of costs. Some evidence showed a positive relationship between the infection rate and length of stay, and the reason given was that inpatients are at a high risk of nosocomial infection with often antibiotic- and multi-resistant microorganisms.47–51 Costs for a day of hospital stay and re-hospitalizations, especially in the short-term, are virtually however fully fixed.52 An illustrative example concerns a prospective study with a hospital perspective that included direct medical costs by calculation based on the length of hospital stay in nosocomial infections after head and neck cancer surgery.53 Of the included studies, 9 (45%) comprised length of hospitalization in their evaluation. Moreover, costs due to antimicrobial resistance, included as indicating the secondary costs for
Ta
ble 3.6.
Qua
lity assessment of each individua
l stud y ac co rding t o C onsensus o n Hea lth E co no mic Crit eria ( CHEC ) N o. Item s Cha udh uri l et a Wils on e t al Mat sui e t al Sin gh e t al Ozd emir et al Elli ott e t al Cou rvi llel et a Mer olli ni e t al The olo gis l et a Gra ves e t al Ceb allo s et a l Emohar e e t a l Lew is e t al Dha dwal et al Jos hi e t al Ale kw e et a l Kos us e t al Patil e t al Gul luo glu l et a El-M ahal law y l et a 1 Is t he st ud y p opu la tio n c le ar ly d esc rib ed ? Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 2 Ar e c om pe tin g a lte rn at ive s c le ar ly d es cr ib ed ? Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 3 Is a w el l-d efi ne d r es ea rc h q ue st io n p os ed i n a ns w er ab le fo rm ? N Y Y Y Y Y Y Y Y Y Y Y Y N Y N Y Y Y Y 4 Is t he e co no m ic s tu dy d es ig n a pp ro pr ia te t o t he s ta te d ob je ct iv e? Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 5 Is t he c ho se n t im e horiz on a ppr opri at e t o i nc lu de re le va nt co st s a nd c on se que nc es ? N N N Y Y Y Y Y Y Y Y Y Y N Y N N Y N N 6 Is t he a ct ua l p er sp ec tive c ho se n a pp ro pr ia te ? N N N Y N Y Y Y N Y Y N N N N N N N N N 7 Ar e a ll i m po rt an t a nd r el ev an t c os ts f or e ac h a lte rn at ive id en tifie d? Y N Y Y N Y Y Y Y Y Y Y Y N Y N Y N N Y 8 Ar e a ll c os ts m ea su re d a pp ro pr ia te ly i n p hy sic al u ni ts ? U Y Y Y N Y Y Y Y Y Y U Y U Y U Y N N Y 9 Ar e c os ts v al ue d a ppr opri at ely ? U U U Y N Y Y Y U Y Y U U U U U U U U U 10 Ar e a ll i m po rt an t a nd r el ev an t o ut co m es f or e ac h al ter na tiv e i den tifi ed ? Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 11 Ar e a ll out com es m ea su re d a ppr opri at ely ? Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 12 Ar e out com es v al ue d a ppr opri at ely ? U U U Y Y U Y U U U Y U U U U U U U U Y 13 Is a n i nc re m en ta l a na ly sis o f c os ts a nd o ut co m es o f al ter na tiv es p er fo rm ed ? N N N U N Y U Y N Y Y N N N N N N N N N 14 Ar e a ll f ut ur e c os ts a nd o ut co m es d isc ou nt ed appr opri at ely ? U U Y Y N Y Y Y U Y Y U U U U U U U U N 15 Ar e a ll i m po rt an t v ar ia bl es , w ho se v alu es a re u nc er ta in , appr opri at ely su bj ec te d t o s en sit iv ity a na lys is? N N N Y N U Y Y N Y Y N N N N N N N N N 16 D o t he c on clu sio ns f ol lo w f ro m t he d at a r ep or te d? Y Y N Y Y Y Y Y Y Y Y Y Y N Y Y Y Y Y Y 17 D oe s t he s tu dy d isc us s t he g en er ali za bi lit y o f t he r es ul ts to o th er s et tin gs a nd p at ie nt /c lie nt g ro up s? N Y Y Y Y Y Y Y Y Y Y N Y N N Y N N N Y 18 D oe s t he a rt ic le i nd ic at e t ha t t he re i s n o p ot en tia l c on fli ct of i nt er es t o f s tu dy r es ea rc he r(s ) a nd f un de r(s )? N N N Y Y N Y Y N Y U Y Y Y N Y N Y N N 19 Ar e e th ic al a nd d ist rib ut io na l i ss ue s d isc us se d appr opri at ely ? Y N Y N Y N N N N Y N N N N N Y N N Y Y To ta l sc or e 10 10 .5 12 17. 5 12 16 17. 5 17. 5 12 .5 18 .5 17. 5 12 13 .5 8 11 .5 11 10 .5 10 .5 9. 5 12 .5 N =n o, w ith n o p oi nt s; U =U nc le ar , u nc le ar w ith h al f a p oi nt ; Y =Y es , w ith o ne p oi nt .
3
advanced medications to overcome the resistance rates, can be expected to eventually become variable costs.52 The timing administration of prophylactic antibiotics is essential to evaluate the clinical effectiveness, resistance, and costs. A previous RCT in London stated that the administration of prophylactic antibiotics within two hours prior to incision had the lowest risk of SSIs.54 Regarding the frequency of the drug administration, one included study showed that prolonged prophylactic use after 24 hours post-surgery did not show any benefit in cost and SSI prevention.33
With regards to new antibiotics, the pricing process has a significant influence on the calculation of the economic outcomes, and thus bias potentially may come from trial-based economic studies that are sponsored by the pharmaceutical industry. The industry can affect the way in which results are reported.55,56 Disclosure of either funding contributions or conflicts of interest in all the works and the findings of each study is a recommended strategy to identify potential bias.57 Half of the included studies explicitly included a statement of conflict of interest. It is essential to adjust the costs for antibiotics especially for patented drugs that could decrease significantly in price when the patent period expires. Only 7(35%) included studies reported the costs of the antibiotics including the price of a single dose.
In economic evaluation, the outcome parameters are holistic including costs, clinical effectiveness, and utility. Hence, a narrow or restricted perspective fosters the omission of some essential costs and outcomes. Half of the included studies did not explicitly state the perspective, hence here may be cost measurement omission bias.58 For both trial and model-based studies, the societal perspective has a broader view and its use is recommended in economic evaluation.59 The included study by Singh et al.,60 showed that the societal perspective had a 10 times higher cost compared with healthcare and payer perspectives since not only direct costs but also productivity loss is considered comprehensively in a societal perspective.14 Of the included studies only 3(15%) took into account the societal perspective with DALY and QALY as utility units. Most of the included studies (75%) performed CMA as the method to analyze the costs for SSIs. Obviously, CMA was used and implemented to address the costs due to the presence of SSIs such as in two studies in cesarean section and orthopedics which reported the median cost for SSIs at US$4,091 and US$108,782, respectively.61,62 High burden of post-surgical procedures with SSIs were also present for nosocomial pneumonia. The additional direct medical cost was considered to increase from EUR19,000 for SSIs to EUR35,000 for post-surgical complications.53 Furthermore, in clinical outcome measurements, there is some evidence that systemic prophylactic antibiotics have a significant impact on minimizing the incidence of SSIs and medical costs in high-risk patients, especially in major surgical procedures including oncologic surgery63, cardiothoracic64, cesarean section65, and orthopedic surgery66. To achieve high efficacy, a current strategy is a prophylactic combination added locally to the standard prophylaxis, especially in deep surgical sites, for instance, using intra-wound vancomycin67 or gentamicin68. A meta-analysis showed that implantable gentamicin-collagen reduced either superficial or deep wound infection effectively, even though the mortality rate was not significantly different.69 The use of a local or intra-wound antibiotic as an add-on treatment can be predicted as more effective since the site-target concentration of antibiotics with local treatment is higher than that without local antibiotics. In contrast, Eklund et al.,70
stated that there was no statistically significant difference in SSI rates between an add-on local gentamicin group and the group without local prophylaxis.
The scope of cost analysis is critical when evaluating the relevant costs and the patient’s expectations on clinical outcomes and safety. To achieve successful treatments especially in the use of antibiotics, antimicrobial susceptibility and the pattern of pathogens causing SSIs should be taken into account. Under-reported unsusceptible antibiotics in the group of high SSI rates can potentially produce bias especially in the interpretation of the treatment outcomes. Therefore, failure in clinical improvement from surgical wounds should consider the local epidemiology susceptibility of antibiotics. None of the included studies reported on antimicrobial susceptibility. Notably, regarding SSIs the importance of correct and early diagnosis cannot be stressed enough. Here, microbiological diagnostics are paramount in decisions for specific antibiotic treatment. Treating infection in the most effective method with the correct antibiotics is important with respect to the treatment, but also with respect to the development of antibiotic resistance.71 An integrated stewardship program, such as the AID stewardship (Antibiotic, Infection Prevention, and Diagnostic Stewardship) is crucial since it targets all different aspects of infection management. This theragnostic approach involves a combination of diagnostics and therapeutics considering the interdisciplinary staff in the complexity of infection management. The role of diagnostic stewardship is especially gaining momentum right now to achieve a personalized approach in infection management.72–74 Therefore, this review comprehensively takes into account all stewardship aspects on each surgical procedure in terms of the effectiveness of prophylactic therapeutics, diagnostics to determine SSIs’ pathogens, patient safety, antibiotic resistance, the timing of prophylaxis and further impact on costs.
We are aware that this review has limitations. Notably, the study may be less representative of other important procedures such as urological, ophthalmological, organ transplantations, implantable devices, and dental surgery. Nearly 15% of 441 patients undergoing kidney transplantation in a hospital in the US developed SSIs. In the 2013 annual report, almost 18,000 patients have carried out kidney transplantation procedures 75. It indicated a high number of potential SSIs coming from the procedures and obviously, a need exists to perform an analysis on the cost and effectiveness of the use of prophylactic antibiotics. Of 208 eligible studies, only 3 studies referred to SSIs in urology; nevertheless, these studies did not meet the further inclusion criteria. Using different definitions to determine the infections potentially leads to underreporting of SSIs and the location or types of SSIs, even in community health services. Of the included studies, only one reported incidence of the SSIs based on the types.19 The reporting of updated data related to microbiological results is fruitful, even though it may be more difficult to determine the definite cause of SSI at particular sites of the incision from the results. None of the included studies considered procedures in children or pediatric surgery which has a higher risk of SSIs and different pathogen patterns. Moreover, because of major differences in the incidence of antibiotic resistance between the US and Europe, outcome studies need to be interpreted with caution. Finally, this review used the CHEC as a rigorous method to assess the quality of the articles and can be used as a baseline for guidelines for further economic evaluations.16
