www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4 1

Articles

Lancet Infect Dis 2015

Published Online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4

See Online/Comment http://dx.doi.org/10.1016/S1473-3099(15)00317-5

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA (A Teillant MS); Center for Disease Dynamics, Economics & Policy, Washington, DC, USA (S Gandra MD, D Barter MS, D J Morgan MD, Prof R Laxminarayan PhD); School of Medicine and VA Maryland Healthcare System, University of Maryland, Baltimore, MD, USA (D J Morgan); Princeton Environmental Institute, Princeton, NJ, USA (Prof R Laxminarayan); and University of Strathclyde, Glasgow, UK (Prof R Laxminarayan)

Correspondence to: Prof Ramanan Laxminarayan, Center for Disease Dynamics, Economics & Policy, 1400 Eye St, Ste 500, Washington DC 20036, USA ramanan@cddep.org

Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling studyAude Teillant, Sumanth Gandra, Devra Barter, Daniel J Morgan, Ramanan Laxminarayan

SummaryBackground The declining efficacy of existing antibiotics potentially jeopardises outcomes in patients undergoing medical procedures. We investigated the potential consequences of increases in antibiotic resistance on the ten most common surgical procedures and immunosuppressing cancer chemotherapies that rely on antibiotic prophylaxis in the USA.

Methods We searched the published scientific literature and identified meta-analyses and reviews of randomised controlled trials or quasi-randomised controlled trials (allocation done on the basis of a pseudo-random sequence—eg, odd/even hospital number or date of birth, alternation) to estimate the efficacy of antibiotic prophylaxis in preventing infections and infection-related deaths after surgical procedures and immuno-suppressing cancer chemotherapy. We varied the identified effect sizes under different scenarios of reduction in the efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% reductions) and estimated the additional number of infections and infection-related deaths per year in the USA for each scenario. We estimated the percentage of pathogens causing infections after these procedures that are resistant to standard prophylactic antibiotics in the USA.

Findings We estimate that between 38·7% and 50·9% of pathogens causing surgical site infections and 26·8% of pathogens causing infections after chemotherapy are resistant to standard prophylactic antibiotics in the USA. A 30% reduction in the efficacy of antibiotic prophylaxis for these procedures would result in 120 000 additional surgical site infections and infections after chemotherapy per year in the USA (ranging from 40 000 for a 10% reduction in efficacy to 280 000 for a 70% reduction in efficacy), and 6300 infection-related deaths (range: 2100 for a 10% reduction in efficacy, to 15 000 for a 70% reduction). We estimated that every year, 13 120 infections (42%) after prostate biopsy are attributable to resistance to fluoroquinolones in the USA.

Interpretation Increasing antibiotic resistance potentially threatens the safety and efficacy of surgical procedures and immunosuppressing chemotherapy. More data are needed to establish how antibiotic prophylaxis recommendations should be modified in the context of increasing rates of resistance.

Funding DRIVE-AB Consortium.

IntroductionAntibiotics are integral to modern health care and have enabled the use of invasive surgical or immuno­suppressive medical procedures that depend on the ability to keep the body free of infection.1 Prophylactic antibiotics are used routinely as part of surgery, organ transplantation, and cancer chemotherapy to prevent infections.2,3 Increasing antibiotic resistance threatens the efficacy of these procedures and could result in adverse clinical outcomes, including increased rates of morbidity, amputation, or death.1

In 2011, in the USA, an estimated 157 500 surgical site infections were associated with inpatient surgery.4 Surgical site infections reportedly lead to a 3% mortality rate, and patients who develop such infections have a two to 11 times higher mortality rate than those who do not.5 According to the US Centers for Disease Control and Prevention (CDC), every year, about 650 000 patients with cancer receive

chemo therapy in the USA, of whom about 10% acquire an infection that necessitates a hospital visit.6

We investigated the potential consequences of increases in antibiotic resistance on the ten most com­mon surgical procedures and immunosuppressing cancer chemo therapies that rely on antibiotic pro­phylaxis in the USA. We identified meta­analyses of randomised controlled trials or quasi­randomised con­trolled trials (allocation done on the basis of a pseudorandom sequence—eg, odd/even hospital number or date of birth, alternation) that assessed the efficacy of antibiotic prophylaxis in preventing infections and infection­related deaths for these procedures. We then applied these effect sizes to estimate the number of additional infections and infection­related deaths in the USA for different scenarios of reduction in the efficacy of antibiotic prophylaxis as a consequence of increasing antibiotic resistance. Finally, we estimated the existing proportion of infections after surgery and

This version saved: 16:43, 13-Oct-15

KG

15TLID0510

THELANCETID-D-15-00510R1

S1473-3099(15)00270-4

Embargo: October 16, 2015—00:01 [GMT]

Articles

2 www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4

cancer chemotherapy caused by organisms resistant to standard prophylactic antibiotics in the USA.

MethodsSearch strategy and selection criteriaWe did literature searches in PubMed, ScienceDirect, and the Cochrane Database of Systematic Reviews to identify meta­analyses of randomised controlled trials or quasi­randomised controlled trials that assessed the efficacy of antibiotic prophylaxis on outcomes of surgical procedures and immunosuppressing cancer chemo­therapy. We searched the reference lists of relevant papers for additional, previously unidentified meta­analyses. We identified reports and clinical guidelines on antibiotic prophylaxis published by health agencies and institutions on their websites (including the National Guideline Clearinghouse from the US Department of Health and Human Services, the UK National Institute for Health and Care Excellence, the European Centre for Disease Prevention and Control, the American Society of Health­System Pharmacists, the Scottish Intercollegiate Guidelines Network, and the National Comprehensive Cancer Network). Our study is not a formal systematic review of randomised controlled trials or quasi­randomised controlled trials but rather a systematic literature review of published meta­analyses.

Search terms included (antibiotic prophylaxis* OR prophylactic antibiotic* OR antimicrobial prophylaxis*) AND (meta­analysis OR metaanalysis OR metanalysis OR review).

We used the following inclusion criteria: meta­analyses had to include a “treatment” group of patients receiving a

prophylactic antibiotic (either before, during, or after surgery/chemotherapy) and a “control” group of patients receiving a placebo or no antibiotic during the same period; outcomes had to include the rate of surgical site infection for surgical procedures, or infection during cancer chemotherapy (all bacterial infections, bacteraemia, bacteriuria, or pneumonia); meta­analyses had to provide level 1 evidence defined as “evidence from large, well conducted, randomized, controlled clinical trials or a meta­analysis” by the American Society of Health­System Pharmacists.2 We did not restrict studies on the basis of type of antibiotics given, route of administration, or the study publication date. When our search found several meta­analyses about the efficacy of antibiotic prophylaxis for the same type of procedure, we selected the most recent meta­analysis after ensuring that older studies were included.

In addition to reviewing published meta­analyses, we also searched the published scientific literature for randomised controlled trials published since the most recent meta­analysis by using the following search terms: (antibiotic prophylaxis* OR prophylactic antibiotic* OR antimicrobial prophylaxis*) AND (randomized controlled trial OR controlled study OR controlled trial OR randomized study OR multicenter study) AND (name of procedure). When we identified a randomised controlled trial published after a meta­analysis, we reported the results of this trial along with the results of the meta­analysis. When possible, we disaggregated infection rates by infection type, including superficial surgical site infections, deep surgical site infections, or distant infections (urinary tract infection, pneumonia, and

Research in context

Evidence before this studyIndividual studies have previously investigated the effect of increasing antibiotic resistance on a reduction in the efficacy of antibiotic prophylaxis, but a global estimate of the effect of declining antibiotic efficacy is unknown. We did two main literature searches: one to identify studies published between January, 1950, and May, 2015, that investigate the efficacy of antibiotic prophylaxis on clinical outcomes of surgical procedures and cancer chemotherapy, and one to review the existing evidence on the effect of antibiotic resistance on clinical outcomes (including infection and mortality rates) for the same procedures (studies published between January, 1990, and May, 2015). No language restrictions were applied. Besides the different meta-analyses and reviews listed for each procedure in appendix pp 11–12, we identified two main reviews that studied the efficacy of antibiotic prophylaxis in preventing infections across different surgical procedures. By contrast, the published literature about the effects of antibiotic resistance on infection rates after various medical procedures was sparse. We were able to identify studies of the effects of changes in

prophylactic regimens on infection rates for several procedures.

Added value of this studyTo our knowledge, this study provides the first estimates of the potential effect of antibiotic resistance on the efficacy of antibiotic prophylaxis for a range of surgeries and cancer treatments. By using data from the published literature on both the effects of antibiotic prophylaxis on infection rates and on the effects of antibiotic resistance on infections rates for different procedures, we were able to provide estimates of the potential effect of antibiotic resistance on clinical outcomes after major medical procedures.

Implications of all the available evidenceOur study confirms findings that increasing antibiotic resistance potentially threatens the safety and efficacy of surgical procedures and immunosuppressing chemotherapy. These results provide a basis for further studies investigating the effects of antibiotic resistance on infection rates and other clinical outcomes across a wide range of medical procedures.

Articles

www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4 3

bacteraemia). When data were available, we recorded other outcomes including all­cause mortality, infection­related mortality, or morbidity including length of hospital stay.

The annual numbers of surgeries done in the USA were obtained from the 2010 CDC National Hospital Discharge Survey7 or from the published scientific literature if unavailable in the CDC database. We estimated the annual number of chemotherapy treat­

ments for leukaemia, lymphoma, and myeloma from the National Cancer Data Base.8

Estimate of the effect of reduced antibiotic susceptibility on clinical outcomesOnce we had identified the absolute risk reduction (the difference in infection rates between antibiotic prophylaxis and control groups) from meta­analyses, we varied these effect sizes under different scenarios of reduction in the efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% reductions). Although many factors can affect the efficacy of antibiotic prophylaxis (eg, timing of injection and dose sizes according to the patient’s body­mass index), we focused on the effect of antibiotic resistance and assumed that a 100% reduction in the efficacy of antibiotic prophylaxis corresponds to infection rates in the placebo group from meta­analyses. We estimated the additional number of infections per year in the USA (I) for each scenario by applying the percentage of reduction in the efficacy of antibiotic prophylaxis (α) to the absolute risk reduction of infection between antibiotic prophylaxis and control groups (ARR) and to the annual number of procedures in the USA (N):

We used two methods to estimate the incremental infection­related deaths for different scenarios of reduction in the efficacy of antibiotic prophylaxis based on data availability. When data on the difference in mortality rates between the control and prophylaxis groups were available in the meta­analyses, we applied the percentage of reduction in the efficacy to the ARR in mortality rates and to the total number of annual procedures in the USA, in the same way as for infection rates. When these data were unavailable, we calculated the additional number of infections with a reduced efficacy of antibiotic prophylaxis and then applied mortality rates from the literature specific to the infection type for each procedure. Details about the calculations of the number of additional deaths are available in appendix pp 2–3.

Additionally, we did a literature search for studies investigating the association between a patient’s antibiotic­resistant colonisation status and the risk of surgical site infection (or infection after cancer chemo­therapy) for each of the selected medical procedures. When data for the incidence of surgical site infections in

a group of patients colonised with resistant versus susceptible bacteria were available, we calculated the number of infections attributable to antibiotic resistance by estimating the population attributable fraction (PAF). The PAF is an estimate of the proportion of cases that could hypothetically be averted by removal of exposure to a specific risk factor (in this case, antibiotic resistance). For a binary exposure (a bacterial culture either susceptible or resistant to a given antibiotic), PAF can be calculated as follows:

where p is the prevalence of exposure (resistance) in the general population and RR is the relative risk (or risk ratio) of infection in the exposed (antibiotic­resistant) versus the unexposed (susceptible) group.

Estimates of surgical site infections and infections after cancer chemotherapy with organisms resistant to standard prophylactic antibioticsFor each procedure, we estimated the proportion of surgical site infections caused by bacteria that are resistant to recommended standard prophylactic antibiotics in the USA. We combined data from the 2009–10 National Healthcare Safety Network (NHSN) of the distribution of the main infecting organisms for each procedure with NHSN data of the resistance patterns of pathogens causing surgical site infections in the USA.9 We then compared the susceptibility pattern of bacteria causing surgical site infections with the standard prophylactic antibiotics recommended in the American Society of Health­System Pharmacists clinical guidelines.2 The full details of these calculations are available in appendix pp 4–7. Because the NHSN does not report infection rates for cancer chemotherapy and transrectal prostate biopsy, we used estimates of the percentage of infections caused by pathogens resistant to recommended antibiotics for these procedures reported in the published literature.10–12 In the case of transrectal prostate biopsy, we also reported estimates of the baseline prevalence of fluoroquinolone resistance in rectal flora.12

Role of the funding sourceThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

ResultsWe identified 31 meta­analyses that met our inclusion criteria. Of these 31 meta­analyses for 31 procedures, we focused on the ten most commonly performed surgical procedures in the USA for which the benefits of antibiotic prophylaxis in reducing infection rates are

I = α × ARR × N

p (RR – 1)

1 + p (RR – 1)PAF =

See Online for appendix

Articles

4 www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4

well established and on immunosuppressing cancer chemotherapy (appendix pp 8–10).

We found two randomised controlled trials for abdominal hysterectomy and pacemaker implantation that were published after the meta­analyses. Because the RRs of these randomised controlled trials had overlapping CIs with RRs in the meta­analyses and the differences were not statistically significant, we considered only the original meta­analyses to ascertain effect size.

The overall surgical site infection rate for patients receiving prophylactic antibiotics for the ten surgeries reported in meta­analyses was 4·2%, compared with 11·1% for patients not receiving prophylactic antibiotics. Appendix pp 11–12 shows the RR of infection for the ten common surgical procedures plus blood cancer chemotherapy (for leukaemia, myeloma, and lymphoma). The relative risk reduction (RRR) of infection with antibiotic prophylaxis ranged from 35% for cancer chemotherapy to as high as 86% for pacemaker implantation (appendix pp 11–12).

The 290 randomised controlled trials included in the meta­analyses were done between 1968 and 2011. 148 (51%) of the 290 randomised controlled trials originated from the European Union, 79 (27%) the USA, nine (3%) Canada, and 54 (19%) from other countries. Studies were clinically heterogeneous in terms of the type of surgeries done, patient profile, and antibiotics given.

RRs can mask wide differences in the baseline infection rates and ARR between treatment and control groups. The baseline risk of infection without antibiotic prophylaxis varied greatly, from 2·9% for hip fracture surgery to 39% for colorectal surgery, corresponding to an ARR of 1·8% for hip fracture surgery and 26% for colorectal surgery for control patients compared with those who receive antibiotic prophylaxis (figure 1, table 1).

The proportion of surgical site infections caused by pathogens that were resistant to recommended standard prophylactic antibiotics ranges from 38·7% after caesarean section and hysterectomy to 50–90% after transrectal prostate biopsy (table 2). 47·7% of surgical site infections after spinal surgery, total hip replacement, and hip fracture surgery were caused by pathogens at least partly resistant to standard prophylactic antibiotics (table 2). The proportion of infections caused by pathogens that were resistant to standard prophylactic antibiotics is 26·8% for infections after cancer chemotherapy. We were unable to estimate the proportion of resistant pathogens after abortions because NHSN does not report resistance to doxycycline, which is the standard prophylactic antibiotic used for abortions. We were unable to estimate the prevalence of resistant bacteria colonising the patient’s flora for other procedures.

We calculated that a 30% reduction in the efficacy of antibiotic prophylaxis by comparison with effect sizes observed in randomised controlled trials done between 1968 and 2011 for the ten major surgeries and blood cancer chemotherapy would result in 120 000 additional infections per year in the USA (ranging from 40 000 for a 10% reduction in efficacy to 280 000 for a 70% reduction in efficacy; figure 2). Additional infections are attributable to procedures that are done frequently with low rates of infection such as caesarean section (21 862 additional wound infections for a 30% reduction in prophylaxis efficacy) and transrectal prostate biopsy (17 100 additional urinary tract infections for a 30% reduction in prophylaxis efficacy), and less frequent procedures with high rates of infection such as colorectal surgery (22 500 additional wound infections for a 30% reduction in prophylaxis efficacy; figure 2).

By preventing surgical site infections, antibiotic prophylaxis also reduces mortality. A 30% reduction in the efficacy of antibiotic prophylaxis could result in 6367 additional infection­related deaths per year in the USA for the seven procedures for which mortality data were available (ranging from 2100 additional deaths for a 10% reduction in efficacy to 15 000 for a 70% reduction in efficacy; figure 3). Most of the additional deaths would occur for patients undergoing colorectal surgery (4586 additional deaths for a 30% reduction in prophylaxis efficacy), blood cancer chemotherapy (683 additional deaths for a 30% reduction in prophylaxis efficacy), and total hip replacement (376 additional deaths for a 30% reduction in prophylaxis efficacy). We were unable to obtain data for infection­related mortality rates for caesarean section, hysterectomy, surgical abortion, and pacemaker implantation.

Data for the association between patients’ antibiotic­resistant colonisation status and infection rates were available only for transrectal prostate biopsy. In a retrospective study of 2673 men undergoing rectal culture before transrectal prostate biopsy, the overall infection rate after transrectal prostate biopsy was 2·6%, and the overall

Figure 1: Absolute risk reduction (ARR) of infection with antibiotic prophylaxis in common surgical procedures and blood cancer chemotherapy in the USAThe ARR of infections refers to: all surgical site infections for total hip replacement, pacemaker implantation, spinal surgery, and hysterectomy; wound infections for colorectal surgery, caesarean section, and appendectomy; deep surgical site infections for hip fractures; urinary tract infections for transrectal prostate biopsy; upper genital tract infection for abortion; and clinically documented infections for cancer chemotherapy. Cancer chemotherapy includes chemotherapy for leukaemia, lymphoma, and myeloma. Error bars are 95% CIs.

0

Hip fractu

re surgery

Pacemaker implantatio

n

Surgical aborti

on

Spinal surgery

Total hip re

placement

Caesarean secti

on

Transrecta

l prosta

te biopsy

Appendectomy

Cancer chemotherapy

Abdominal hyste

rectomy

Colorectal su

rgery

5

10

ARR

of in

fect

ion

(%)

15

20

25

30

Articles

www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4 5

prevalence of fluoroquinolone­resistant bacteria in rectal cultures was 20·5%.12 Patients with fluoroquinolone­resistant rectal cultures receiving fluoroquinolone prophylaxis had an 8·2% infection rate compared with 1·8% in those with a negative culture also receiving fluoroquinolone prophylaxis (odds ratio 4·71, 95% CI 2·75–8·07, p<0·001).12 In a recent review,14 similar results were reported, with higher infection rates after transrectal

prostate biopsy in patients with fluoroquinolone­resistant rectal cultures (7·1%) than in those with fluoroquinolone­sensitive rectal cultures (1·1%). We used the RR of infection in patients with fluoroquinolone­resistant rectal cultures relative to fluoroquinolone­sensitive cultures and the overall prevalence of fluoroquinolone resistance in rectal cultures from Liss and colleagues’ study12 to calculate the proportion of post­biopsy infections attributable to

Procedures (n) per year in USA

Type of infection, ARR in infection rates (95% CI) Mortality rate of infected patients

Caesarean section 1 325 000 Wound infections, 5·5% (5·2–6·2) ND

Transrectal prostate biopsy 1 000 000 Urinary tract infections, 5·7% (4·4–8·0) 3·4%

Spinal surgery* 796 000 Wound infections, 3·7% (2·6–6·2) 2·5%

Surgical abortion 765 600 Upper genital tract infections, 3·6% (2·1–4·9) ND

Hysterectomy† 498 000 Serious surgical site infections, 12·1% (10·7–13·7) ND

Pacemaker implantation 370 000 Infective complications, 3·1% (2·8–3·8) ND

Total hip replacement 332 000 Surgical site infections, 5·4% (4·9–6·3) 7·0%

Appendectomy 305 000 Deep surgical site infections, 1·0% (0·7–1·6); superficial surgical site infections, 7·9% (7·0–8·9)

2·3% after deep surgical site infections

Colorectal surgery 288 458 Wound infections, 26·0% (23·9–29·0) ARR 5·3%‡

Hip fracture 258 000 Deep surgical site infections, 1·8% (1·4–2·6); superficial surgical site infections, 1·6% (0·6–2·8)

12·5% after deep surgical site infections

Cancer chemotherapy§

(leukaemia, lymphoma, myeloma)

99 109 Clinically documented infections, 10·2% (7·9–13·6) ARR 2·3%‡

ARR=absolute risk reduction. ND=no data. *Data include excision of intervertebral disc and spinal fusion. †Data include abdominal, vaginal, and laparoscopic hysterectomy. We assumed that the ARR of infection established in abdominal hysterectomy also applies to vaginal and laparoscopic hysterectomy. ‡ARR in mortality rates between the placebo and prophylactic antibiotic groups. §The annual number of patients receiving chemotherapy for leukaemia, lymphoma, and myeloma in the USA was estimated based on data for treatment patterns for each type of blood cancer.7 Overall, we estimated that about 63·0% of all patients with blood cancer would receive chemotherapy.

Table 1: Number of procedures per year in the USA and associated infection and mortality rates

Standard prophylactic antibiotic

Main infecting organisms (proportions of total infections)

Proportion of infections caused by pathogens resistant to standard prophylactic antibiotics

Resistance data source (patients, location, year)

Caesarean section, hysterectomy

Cefazolin Staphylococcus aureus (19·7%), Escherichia coli (12·9%), coagulase-negative staphylococci (7·1%), Enterococcus faecalis (8·3%), Streptococcus spp (7·6%)

38·7% NHSN data for 16 019 surgical site infections, USA, 2009–105

Transrectal prostate biopsy

Fluoroquinolone E coli (91·0%), Pseudomonas aeruginosa (9·0%)13 Clinical isolates: 50·0–90·0%; pre-biopsy rectal cultures: 20·5%

Various (review);7 data from 2673 men in five countries8

Spinal surgery, total hip replacement, hip fracture surgery

Cefazolin S aureus (47·1%), coagulase-negative staphylococci (11·0%), Streptococcus spp (5·6%), E faecalis (4·6%), P aeruginosa (4·4%)

47·7% NHSN data for 16 019 surgical site infections, USA, 2009–105

Pacemaker implantation

Cefazolin S aureus (30·7%), coagulase-negative staphylococci (13·4%), P aeruginosa (7·9%), E coli (6·4%), Klebsiella pneumoniae/Klebsiella oxytoca (5·9%)

50·9% NHSN data for 16 019 surgical site infections, USA, 2009–105

Appendectomy, colorectal surgery

Cefazolin and metronidazole

E coli (18·6%), S aureus (11·5%), E faecalis (9·3%), Enterococcus spp (5·9%), P aeruginosa (5·6%)

43·2% NHSN data for 16 019 surgical site infections, USA, 2009–105

Cancer chemotherapy

Fluoroquinolone Meticillin-resistant S aureus (11·3%), multidrug-resistant E coli (8·0%), vancomycin-resistant enterococci (4·2%), multidrug-resistant P aeruginosa (3·3%)

26·8% Data from 622 patients with bacteraemia at the University of Texas Cancer Center, 2005–066

NHSN=National Healthcare Safety Network.

Table 2: Proportion of surgical site infections and infections after cancer chemotherapy caused by pathogens resistant to standard prophylactic antibiotics in the USA

Articles

6 www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4

fluoroquinolone resistance. We estimated that 42% of post­biopsy infections today are attributable to resistance to fluoroquinolones, corresponding to 13 120 post­biopsy infections attributable to fluoroquinolone resistance every year in the USA (figure 4).

In a scenario in which resistance to fluoroquinolones were to increase to 100%, the proportion of post­biopsy infections attributable to resistance would rise to 78%, to give a total of 64 000 post­biopsy infections attributable to this type of antibiotic resistance (figure 4). This number is similar to our estimated 57 000 additional infections without antibiotic prophylaxis (figure 2) based on historical data. Also, the estimates of the present number of post­biopsy infections in a situation of a fluoroquinolone resistance prevalence of 20·5% are similar based on relative risk from Liss and colleagues12 (13 120 infections) and based on relative risks in previous randomised controlled trials (11 685 infections; see figure 2).

DiscussionIn addition to making the treatment of patients with infections difficult, antibiotic resistance also limits the efficacy of antibiotic prophylaxis, leading to worse outcomes in patients undergoing surgical procedures or receiving immunosuppressive cancer chemotherapy. The published literature supports the important role of antibiotics for these patients. A 30% reduction in the efficacy of antibiotic prophylaxis by comparison with effect sizes recorded in randomised controlled trials done between 1968 and 2011 for the ten major surgical procedures and blood cancer chemotherapy would probably result in 120 000 additional infections per year in the USA (40 000 for a 10% reduction in efficacy, and 280 000 for a 70% reduction in efficacy), and 6300 infection­related deaths (2100 and 15 000 for a 10% or a 70% reduction in efficacy, respectively).

Our estimates suggest that currently recommended antibiotic prophylactic regimens might have insufficient activity against the most commonly reported pathogens

Figure 2: Number of additional infections per year in the USA under four scenarios of decreased efficacy of antibiotic prophylaxisWe assessed 10%, 30%, 70%, and 100% reductions in antibiotic efficacy by comparison with effect sizes in randomised controlled trials done between 1968 and 2011. Cancer chemotherapy includes chemotherapy for leukaemia, lymphoma, and myeloma. *The present situation estimate for transrectal prostate biopsy is calculated based on the overall prevalence of fluoroquinolone resistance of 20·5%, and under the assumption that placebo group infection rates apply to fluoroquinolone-resistant cultures and antibiotic prophylaxis group infection rates apply to fluoroquinolone-sensitive cultures.

0

Number of additional infections per year

80 000

Hip fracture surgery

Cancer chemotherapy

Pacemaker implantation

Total hip replacement

Appendectomy

Surgical abortion

Spinal surgery

Transrectal prostate biopsy

Hysterectomy

Caesarean section

Colorectal surgery

Additional infections for a 10%reduction in efficacyAdditional infections for a 30%reduction in efficacy

Additional infections for a 70%reduction in efficacy

Additional infections for a 100%reduction in efficacy

Present situation estimate*

10 000 20 000 30 000 40 000 50 000 60 000 70 000

Figure 3: Number of additional deaths per year in the USA under four scenarios of decreased efficacy of antibiotic prophylaxisWe assessed 10%, 30%, 70%, and 100% decreased antibiotic efficacy by comparison with effect sizes in randomised controlled trials done between 1968 and 2011.

Number of additional deaths per year

Total hip replacement

Transrectal prostate biopsyAdditional deaths for a 10%reduction in efficacyAdditional deaths for a 30%reduction in efficacy

Additional deaths for a 70%reduction in efficacy

Additional deaths for a 100%reduction in efficacyAppendectomy

0 2000 4000 6000 8000 10 000 12 000 14 000 16 000 18 000

Hip fracture surgery

Spinal surgery

Cancer chemotherapy

Colorectal surgery

Figure 4: Number of post-biopsy infections per year attributable to fluoroquinolone resistance in the USAFluoroquinolone resistance refers to resistant rectal cultures.

0Present situation

estimate(20·5% fluoroquinolone

resistance)

100% fluoroquinoloneresistance scenario

10 000

20 000

30 000

40 000

50 000

60 000

70 000

80 000

90 000

Num

ber o

f pos

t-bi

opsy

infe

ctio

ns p

er ye

ar

Total number of post-biopsyinfections per yearNumber of post-biopsyinfections attributable tofluoroquinolone resistance

Articles

www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4 7

that cause infections after surgeries and cancer chemotherapy (table 2). This very high proportion of resistant pathogens might be partly explained by the disproportionate effect of prophylactic antibiotics on susceptible pathogens, leaving a residual subset of resistant pathogens, or by the emergence of resistant pathogens replacing a proportion of susceptible pathogens.15 For example, a substantially higher prevalence of fluoroquinolone resistance has been reported in rectal cultures obtained after fluoroquinolone­based prophylaxis (20·4%) than in those obtained before prophylaxis (12·8%).14

To quantify the consequences of rising antibiotic resistance on prophylactic antibiotic efficacy is com­plicated. The effect of an increasing prevalence of antibiotic­resistant bacteria, both in the hospital environ­ment and in patients’ bacterial flora, on infection rates is unclear because surgical site infection rates are affected by various factors, such as compliance with infection control measures or appropriate timing of administration of prophylactic antibiotics.16 The effect of antibiotic resistance on rates of surgical site infection has not been investigated widely. We were only able to find data about the correlation between resistance rates in rectal cultures and surgical site infection rates for transrectal prostate biopsy.12,14 In patients undergoing this procedure, increases in rates of infection­related hospital admissions have been reported in the USA17 and in Canada.18 The main risk factor for infection after transrectal prostate biopsy is rectal colonisation with fluoroquinolone­resistant bacteria.11 Colonisation with antibiotic­resistant bacteria has been associated with increased postoperative infection rates in patients undergoing prostate biopsy, and in those receiving a liver transplant.19 However, in patients with cancer, the results of studies investigating the link between colonisation with resistant bacteria and infections are conflicting.20–22 Because of this paucity of data regarding the relation between resistance and reduced efficacy of prophylaxis, we were unable to project changes in infection rates attributable to resistance for procedures besides transrectal prostate biopsy. Consequently, we considered different scenarios of reduced efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% decrease), which are not tied to specific levels of resistance, except in the case of transrectal prostate biopsy.

Procedures associated with increased risk of surgical site infections caused by Gram­negative organisms are of major concern because of the increasing prevalence of multidrug­resistant strains and absence of development of new antibiotics targeting these organisms. 2009–10 NHSN data show that a significant proportion of Gram­negative organisms isolated from surgical site infections are resistant to third­generation cephalosporins (28% for Enterobacter species, 13% for Klebsiella species, and 11% for E coli) and carbapenems, which are last­resort antibiotics for infections with Gram­negative organisms

(8% for Klebsiella species, 2·4% Enterobacter species, and 2% for E coli).9 Increased resistance rates in Gram­negative pathogens are also a concern for patients with chemotherapy­induced neutropenia, who are at risk of bacteraemia caused by Gram­negative organisms typically derived from their gastrointestinal tract. One study showed a rise in fluoroquinolone­resistant E coli bacteraemia from 28% in 1999 to 60% in 2008 in a US centre (University of Texas MD Anderson Cancer Center, Houston, TX, USA) where fluoroquinolones were used widely as prophylaxis.23 A review of resistance patterns in bacteraemia isolates from patients with cancer undergoing chemotherapy in different countries reported an increase in detection of quinolone­resistant Gram­negative bacteria, with rates of fluoroquinolone resistance in E coli isolates ranging from 16% in Sweden to 68% in Japan.24

Although several antibiotics are available to treat Gram­positive organisms that cause surgical site infections, antibiotic resistance complicates the prophylactic regimen. For example, prophylactic administration of vancomycin alone instead of β­lactam agents in various surgical procedures for preventing surgical site infections caused by meticillin­resistant Staphylococcus aureus increases the risk of meticillin­susceptible S aureus infections.25 For vancomycin­resistant enterococci—a cause of surgical site infections after abdominal and transplant surgeries, and bacteraemia in patients with cancer—therapeutic options are scarce.26 According to 2009–10 NSHN data, Enterococcus faecium, which is mostly (62%) vancomycin resistant, accounts for 5·6% of surgical site infections that occur after abdominal surgeries in the USA.9

Although surgical site infections caused by bacteria resistant to recommended standard prophylactic agents have increased,23,27,28 insufficient data exist to support or discourage the use of broader spectrum regimens for surgical procedures or cancer chemotherapy.15,29,30 Expansion of the range of prophylactic antibiotic regimens either in all patients or a subset of high­risk patients must be weighed against the potential increase in selective antimicrobial pressure and expansion of antimicrobial resistance. New strategies such as a targeted approach to prophylaxis based on preoperative screening for colonisation of resistant bacteria (eg, rectal swab before prostate biopsy or screening of nasal meticillin­resistant S aureus before pacemaker implantation) have been proposed.14,15 Targeted antibiotic prophylaxis that uses rectal swab cultures has been associated with a reduced incidence of post­biopsy infections.14,31,32 However, the feasibility and cost­effectiveness of such strategies still need to be assessed.14 As emphasised in a recent survey study in the USA,13 several opportunities exist to implement improved prophylaxis regimens for transrectal prostate biopsy, including culture­guided prophylaxis and appropriate duration of prophylaxis.

Articles

8 www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4

This report has several limitations. First, the definition of reported infections was not uniform across the meta­analyses. For some surgical procedures, infections reported were disaggregated by infection type (superficial surgical site infection, deep surgical site infection, sepsis, urinary tract infections, and so on), whereas other studies reported only aggregated numbers (eg, for total hip replacement, spinal surgery, or pacemaker implantation). Second, not all the meta­analyses included an analysis of the overall risk of bias, and, although infection rates vary substantially between low­risk and high­risk patients, the meta­analyses did not report infection rates disaggregated by patient risk level.

Third, as mentioned previously, the meta­analyses we reported include randomised controlled trials done in clinical settings that were heterogeneous in terms of the type of surgeries done, type of cancers included, patient profiles, antibiotics given, and time and place when the trials were done, which might not be entirely applicable to present­day hospital settings in the USA. Most of the randomised controlled trials included were done outside the USA (in the European Union, Canada, and other countries), which could limit the applicability of our findings to US settings, although substantial variability exists even within the trials that were done in the USA.

Fourth, the clinical trials reported in the meta­analyses were done over a long period (1968–2011), and many pre­date the 21st century. In the context of rising resistance levels and the availability of newer antibiotic regimens, the results of such studies might no longer be applicable to hospital settings in which infection control standards might have since improved. Fifth, infection control practices will probably continue to improve in response to increasing resistance, which could lower the effect of resistance on surgical infections. Thus, overall our estimates of attributable burden might overstate the effect of resistance on infection rates.

Sixth, estimates of surgical site infections caused by resistant organisms were based on the assumption that the proportions of organisms resistant to standard surgical prophylaxis are believed to be the same for various surgical procedures. When the resistance rates for specific organisms (coagulase­negative staphylococci, Streptococcus spp, and Proteus spp) isolated from surgical site infections were not available from NHSN data, we considered the proportion resistant to standard surgical prophylaxis to be similar to aggregated resistance percentages for standard prophylaxis drugs obtained from various infection sites from nationally representative studies (appendix pp 4–7).

We also acknowledge that antibiotic prophylaxis might not be 100% effective, since organisms endogenously resistant to prophylactic antibiotics could cause infections and are included in these estimates. Furthermore, the proportion of resistant organisms does not account for all patients receiving prophylaxis; therefore, the resistance percentage in those who developed infections

could be high. Finally, because data for mortality rates after each procedure were sparse and were derived from individual studies, the applicability of these data to specific situations might be low. Since we did not use specific mortality rates after resistant infections, and mortality rates attributable to resistant infections tend to be higher than for susceptible infections,3,33 we might underestimate the number of additional deaths.

As suggested by Smith and Coast,1 the reduction in the ability to safely undertake common surgical procedures and cancer chemotherapy could lead to a fall in the frequency of such procedures, yielding an indirect increase in non­infectious morbidity and mortality. More data are needed to assess the degree of antibiotic resistance in pathogens that cause surgical site infections or infections after cancer treatments in different settings, and to study infection rates after these medical procedures. Increasing resistance rates after surgical procedures and cancer chemotherapy would lead physicians to use alternative or last­resort prophylaxis regimens. In general, these regimens are less supported by data than currently used regimens and their use would contribute further to an increase in resistance. Clinical studies are needed to ascertain how antibiotic prophylaxis recommendations should be modified in a situation of increasing resistance. We urgently need national and international strategies to limit the growing threat of antimicrobial resistance and to develop new antibiotics, especially against multidrug­resistant Gram­negative pathogens.ContributorsAT and RL designed the study. AT, SG, and DB did the literature search and gathered the data. AT, SG, DB, DJM, and RL analysed and interpreted the data and wrote the report.

Declaration of interestsDJM has been a research consultant for Welch Allyn and 3M; has received personal fees from Welch Allyn; grants from VA Health Services Research and Development Service (number CRE 12­307) and the Agency for Healthcare Research and Quality (number K08 HS18111); and expenses from the Infectious Diseases Society of America, the American Society for Microbiology, and the Society for Healthcare Epidemiology of America to organise or present at national meetings outside the submitted work. AT was supported by the Science and Technology Directorate, Department of Homeland Security, contract HSHQDC­12­C­00058 to Princeton University. SG and DB were supported by the Global Antibiotic Resistance Partnership, which is supported by the Bill & Melinda Gates Foundation. We declare no other competing interests.

AcknowledgmentsThis research was supported by the DRIVE­AB Consortium, which is supported by the IMI Joint Undertaking under the DRIVE­AB grant agreement number 115618, the resources of which are composed of financial contribution from the European Union’s 7th Framework Programme and the European Federation of Pharmaceutical Industries and Associations companies’ in­kind contribution.

References1 Smith R, Coast J. The true cost of antimicrobial resistance. BMJ 2013;

346: f1493.2 Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice

guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013; 70: 195–283.

3 Bow EJ. There should be no ESKAPE for febrile neutropenic cancer patients: the dearth of effective antibacterial drugs threatens anticancer efficacy. J Antimicrob Chemother 2013; 68: 492–95.

Articles

www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00270-4 9

4 Magill SS, Edwards JR, Bamberg W, et al. Multistate point­prevalence survey of health care­associated infections. N Engl J Med 2014; 370: 1198–208.

5 Awad SS. Adherence to surgical care improvement project measures and post­operative surgical site infections. Surg Infect 2012; 13: 234–37.

6 Centers for Disease Control and Prevention. Preventing infections in cancer patients. http://www.cdc.gov/cancer/preventinfections/patients.htm (accessed June 26, 2015).

7 Centers for Disease Control and Prevention. Number of all­listed procedures for discharges from short­stay hospitals, by procedure category and age: United States, 2010. 2010. http://www.cdc.gov/nchs/data/nhds/4procedures/2010pro4_numberprocedureage.pdf (accessed July 16, 2014).

8 DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014; 64: 252–71.

9 Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial­resistant pathogens associated with healthcare­associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010. Infect Control Hosp Epidemiol 2013; 34: 1–14.

10 Rangaraj G, Granwehr BP, Jiang Y, Hachem R, Raad I. Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug­resistant organisms. Cancer 2010; 116: 967–73.

11 Wagenlehner FME, Pilatz A, Waliszewski P, Weidner W, Johansen TEB. Reducing infection rates after prostate biopsy. Nat Rev Urol 2014; 11: 80–86.

12 Liss MA, Taylor SA, Batura D, et al. Fluoroquinolone resistant rectal colonization predicts risk of infectious complications after transrectal prostate biopsy. J Urol 2014; 192: 1673–78.

13 Johnson JR, Polgreen PM, Beekmann SE. Transrectal prostate biopsy­associated prophylaxis and infectious complications: report of a query to the emerging infections network of the Infectious Diseases Society of America. Open Forum Infect Dis 2015; 2: ofv002.

14 Roberts MJ, Williamson DA, Hadway P, Doi SAR, Gardiner RA, Paterson DL. Baseline prevalence of antimicrobial resistance and subsequent infection following prostate biopsy using empirical or altered prophylaxis: a bias­adjusted meta­analysis. Int J Antimicrob Agents 2014; 43: 301–09.

15 Berríos­Torres SI, Yi SH, Bratzler DW, et al. Activity of commonly used antimicrobial prophylaxis regimens against pathogens causing coronary artery bypass graft and arthroplasty surgical site infections in the United States, 2006–2009. Infect Control Hosp Epidemiol 2014; 35: 231–39.

16 Bratzler DW, Hunt DR. The surgical infection prevention and surgical care improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis 2006; 43: 322–30.

17 Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER­Medicare. J Urol 2011; 186: 1830–34.

18 Nam RK, Saskin R, Lee Y, et al. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2013; 189: S12–17.

19 Kirby A, Santoni N. Antibiotic resistance in Enterobacteriaceae: what impact on the efficacy of antibiotic prophylaxis in colorectal surgery? J Hosp Infect 2015; 89: 259–63.

20 Vehreschild MJGT, Hamprecht A, Peterson L, et al. A multicentre cohort study on colonization and infection with ESBL­producing Enterobacteriaceae in high­risk patients with haematological malignancies. J Antimicrob Chemother 2014; 69: 3387–92.

21 Liss BJ, Vehreschild JJ, Cornely OA, et al. Intestinal colonisation and blood stream infections due to vancomycin­resistant enterococci (VRE) and extended­spectrum β­lactamase­producing Enterobacteriaceae (ESBLE) in patients with haematological and oncological malignancies. Infection 2012; 40: 613–19.

22 Arnan M, Gudiol C, Calatayud L, et al. Risk factors for, and clinical relevance of, faecal extended­spectrum β­lactamase producing Escherichia coli (ESBL­EC) carriage in neutropenic patients with haematological malignancies. Eur J Clin Microbiol Infect Dis 2010; 30: 355–60.

23 Mihu CN, Rhomberg PR, Jones RN, Coyle E, Prince RA, Rolston KV. Escherichia coli resistance to quinolones at a comprehensive cancer center. Diagn Microbiol Infect Dis 2010; 67: 266–69.

24 Montassier E, Batard E, Gastinne T, Potel G, de La Cochetière MF. Recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance. Eur J Clin Microbiol Infect Dis 2013; 32: 841–50.

25 Bull AL, Worth LJ, Richards MJ. Impact of vancomycin surgical antibiotic prophylaxis on the development of methicillin­sensitive Staphylococcus aureus surgical site infections: report from Australian Surveillance Data (VICNISS). Ann Surg 2012; 256: 1089–92.

26 Kamboj M, Chung D, Seo SK, et al. The changing epidemiology of vancomycin­resistant Enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Biol Blood Marrow Transplant 2010; 16: 1576–81.

27 Feliciano J, Teper E, Ferrandino M, et al. The incidence of fluoroquinolone resistant infections after prostate biopsy—are fluoroquinolones still effective prophylaxis? J Urol 2008; 179: 952–55.

28 Patel M, Kumar RA, Stamm AM, Hoesley CJ, Moser SA, Waites KB. USA300 genotype community­associated methicillin­resistant Staphylococcus aureus as a cause of surgical site infections. J Clin Microbiol 2007; 45: 3431–33.

29 Saleh A, Khanna A, Chagin KM, Klika AK, Johnston D, Barsoum WK. Glycopeptides versus β­lactams for the prevention of surgical site infections in cardiovascular and orthopedic surgery: a meta­analysis. Ann Surg 2015; 261: 72–80.

30 Crawford T, Rodvold KA, Solomkin JS. Vancomycin for surgical prophylaxis? Clin Infect Dis 2012; 54: 1474–79.

31 Taylor AK, Zembower TR, Nadler RB, et al. Targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated with reduced incidence of postoperative infectious complications and cost of care. J Urol 2012; 187: 1275–79.

32 Duplessis CA, Bavaro M, Simons MP, et al. Rectal cultures before transrectal ultrasound­guided prostate biopsy reduce post­prostatic biopsy infection rates. Urology 2012; 79: 556–61.

33 Engemann JJ, Carmeli Y, Cosgrove SE, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis 2003; 36: 592–98.

Comment

www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00317-5 1

Antibiotic resistance threatens the efficacy of prophylaxisThe slow-motion catastrophe of antibiotic resistance has gained substantial attention as common bacterial infections become increasingly difficult to treat. In The Lancet Infectious Diseases, Aude Teillant and colleagues1 report an original approach to the issue. They used published data to model the effects of antibiotic resistance on antibacterial prophylaxis in patients under going surgery or cancer chemotherapy.

Many researchers, clinicians, and media reports have focused on the poor treatment outcomes of antibiotic-resistant infections, supported by data showing that antibiotic-resistant infections are more difficult to cure and more likely to be fatal than are those that are susceptible to antibiotics.2 However, the effect of antibiotic resistance on the efficacy of prophylactic regimens has been studied less thoroughly. Use of antibiotic prophylaxis is standard practice for many surgical procedures and some chemotherapy regimens because good evidence shows that it prevents infection and mortality.3,4 For example, for every 75 colorectal surgeries done, prophylaxis can prevent around 20 surgical site infections and one death.4 The efficacy of prophylaxis is clearly affected by antibiotic resistance. Studies in men undergoing transrectal prostate biopsy show that pre-operative gut colonisation with resistant bacteria substantially reduces the efficacy of antibacterial prophylaxis, leading to post-operative infection.5 Similarly, some studies of antibiotic prophylaxis in patients with cancer have shown a high rate of breakthrough infections with resistant organisms.6

Teillant and colleagues provide an important and novel perspective by estimating the possible effect of the waning efficacy of prophylaxis on the risk of developing otherwise preventable infections. They conclude that a 30% reduction in the efficacy of surgical and oncological prophylaxis would be disastrous, resulting in an additional 120 000 surgical site infections and 6300 infection-related deaths in the USA every year. Their study has some limitations: point estimates of surplus infections are provided without confidence intervals, so the actual number of infections could differ somewhat from the estimate. Furthermore, the authors assumed that estimates of prophylactic efficacy in controlled trials translate directly to effectiveness in

clinical practice, but research study populations differ from the patient populations routinely treated in our hospitals so this assumption might be invalid.7 However, these limitations concern only the magnitude of the problem, not its overall importance.

The inescapable conclusion is that the spread of antibiotic resistance will meaningfully increase the risk of infection in patients undergoing surgery and cancer chemotherapy, and that these infections will often be caused by bacteria that are difficult or impossible to treat. When this occurs, prophylaxis regimens might be changed in an attempt to keep surgical and cancer treatment safe. Indeed, interest is increasing in personalised antibiotic prophylaxis based on pre-operative culture or rapid resistance tests.5,8–10 However, although modified regimens might provide short-term benefits, they will contribute to the problem of resistance in the long term. In patients with cancer, complete cessation of prophylaxis might be the only way to reduce the incidence of resistant infections as efficacy wanes.

Once the reality of routine failure of prophylaxis hits, it will be too late; we need to address the problem of antibiotic resistance now. However, the spectre of the “post-antimicrobial era” was raised long ago, and we already knew what to do then: develop new classes of antimicrobial drugs, reduce antibiotic exposure in animals and human beings, and prevent diseases through the use of vaccines and infection control.11 Despite this knowledge, most countries still have no coordinated strategy to reduce antimicrobial resistance,12 the new drug pipeline is drying up,2 and only a small amount of progress has been made towards reducing the use of antibiotics in livestock.13

The most direct action that clinicians can take is to improve antibiotic prescribing in human beings through support of antimicrobial stewardship. Anti microbial stewardship uses systemic interventions such as clinician education, guideline development, and form ulary restriction to optimise antibiotic use. How ever, attempts to improve prescribing have often been met with scepticism, manipulation, or even outright hostility.14 To improve stewardship outcomes, we need more research that focuses on understanding impediments to appropriate antibiotic prescribing, strategies that

Lancet Infect Dis 2015

Published Online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00317-5

See Online/Articles http://dx.doi.org/10.1016/S1473-3099(15)00270-4

THELANCETID-D-15-01054 0510S1473-3099(15)00317-5Embargo: October 16, 2015—00:01 [GMT]

KG

Comment

2 www.thelancet.com/infection Published online October 16, 2015 http://dx.doi.org/10.1016/S1473-3099(15)00317-5

3 Gafter-Gvili A, Fraser A, Paul M, et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev 2012; 1: CD004386.

4 Nelson RL, Gladman E, Barbateskovic M. Antimicrobial prophylaxis for colorectal surgery. Cochrane Database Syst Rev 2014; 5: CD001181.

5 Roberts MJ, Williamson DA, Hadway P, Doi SA, Gardiner RA, Paterson DL. Baseline prevalence of antimicrobial resistance and subsequent infection following prostate biopsy using empirical or altered prophylaxis: a bias-adjusted meta-analysis. Int J Antimicrob Agents 2014; 43: 301–09.

6 De Rosa FG, Motta I, Audisio E, et al. Epidemiology of bloodstream infections in patients with acute myeloid leukemia undergoing levofloxacin prophylaxis. BMC Infect Dis 2013; 13: 563.

7 Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. London: The Cochrane Collaboration, 2011.

8 R-GNOSIS project. Resistance in Gram-negative organisms: studying intervention strategies. 2012. http://www.r-gnosis.eu/ (accessed Aug 19, 2015).

9 Horakova M, Lubuska L, Kolar M, et al. Individualized prophylaxis in patients with esophageal replacement because of cancer. Surg Infect 2015; published online Aug 3. DOI:10.1089/sur.2014.132.

10 Kirby A, Bretsztajn L, Santoni N, Patel H, Burke D, Horner C. Microbiological prediction of surgical site infection risk after colorectal surgery: a feasibility study. J Hosp Infect 2015; 90: 271–72.

11 Cohen ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science 1992; 257: 1050–55.

12 WHO. Worldwide country situation analysis: response to antimicrobial resistance. Geneva: World Health Organization, 2015.

13 Food and Drug Administration. Guidance for industry: new animal drugs and new animal drug combination products administered in or on medicated feed or drinking water of food-producing animals: recommendations for drug sponsors for voluntarily aligning product use conditions with GFI #209. Rockville, MD: Food and Drug Administration, 2013.

14 Szymczak JE, Feemster KA, Zaoutis TE, Gerber JS. Pediatrician perceptions of an outpatient antimicrobial stewardship intervention. Infect Control Hosp Epidemiol 2014; 35 (suppl 3): S69–78.

target these impediments, resources to implement the strategies, and leadership that understands the urgency and complexity of the task. In view of the lack of progress so far, mandatory implementation of these steps could be necessary to achieve notable change.

Teillant and colleagues describe a future in which patients who need surgery or chemotherapy can no longer be protected from life-threatening infections by antibiotic prophylaxis. All clinicians have a responsibility to prevent this situation from becoming our patients’ reality by supporting efforts to combat antimicrobial resistance worldwide and by supporting antimicrobial stewardship at home.

Joshua WolfDepartment of Infectious Diseases, St Jude Children’s Research Hospital, Mailstop 320, Memphis, TN 38105, USA; and Department of Paediatrics, University of Melbourne, Parkville, VIC, Australiajoshua.wolf@stjude.org

I declare no competing interests.

1 Teillant A, Gandra S, Barter D, Morgan DJ, Laxminarayan R. Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a systematic review and modelling study. Lancet Infect Dis 2015; published online Oct 16. http://dx.doi.org/10.1016/S1473-3099(15)00317-5.

2 Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. Atlanta: Centers for Disease Control and Prevention, 2013.