Highlights
- •Clinical management of drug-resistant BSIs in hospitals is not well-defined.
- •Therapy for drug-resistant BSI caused by E. coli and K. pneumoniae was uniform.
- •Optimal therapy for BSIs caused by drug-resistant P. aeruginosa and VRE is unclear.
- •Such data are needed to determine the treatment costs of drug-resistant infections.
Abstract
Background
To gain a better understanding of clinical practice for the treatment of common drug-resistant infections.
Methods
A web-based anonymous survey was developed to gain a better understanding of clinical practice of patients infected with drug-resistant bloodstream infections (BSI). The survey instrument was a questionnaire requesting doctors to provide their opinion on the most likely choice of an antibiotic, dose and route of administration for patients infected with a drug-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Enterococcus faecium.
Results
All of the survey participants (n = 28) were hospital-based doctors. Choice of therapy for drug-resistant E. coli and K. pneumoniae was uniform across survey participants. However, optimal treatment of ceftazidime-resistant P. aeruginosa and VRE was less clear.
Conclusion
The survey adds to the limited body of evidence in this clinical area and can be a useful tool for health economists in determining the additional cost of treating patients with drug-resistant infections.
Keywords
Introduction
The impact of drug-resistant infections is broad and places a significant burden on the patient, the healthcare system and society more broadly. Despite several high-profile international reports [
1
, 2
, 3
] we currently don't know the health or the economic burden in Australia [[4]
]. Quantifying the impact of drug-resistant infections is necessary for clinical practice improvements as well as to develop measurable indicators to report against the first National Antimicrobial Resistance Strategy [[5]
].Generating an estimate of the cost of drug-resistant infections is a challenge. From the patient or societal perspective, measures of early death, loss of effective labour supply or more broadly a loss of economic viability in a world without antibiotics [
[6]
] are required. Quantifying costs from a healthcare perspective is more attainable and includes estimating the number of hospital bed days [[7]
] and other costs such as staffing and clinical management. Many studies aim to determine the additional length of hospital stay and staff needed to treat patients but very few have focused on determining antibiotic choice, dose and duration of treatment. In light of the growing need for more complicated therapy and increased use of ‘last-line’ reserve agents to treat multi-resistant infections [[8]
], now more than ever such studies are needed. Knowledge gained from clinical management studies would serve to benefit infection control practitioners as well health economists who need this information to generate more accurate estimates of the economic burden of drug-resistance.The current Australian Therapeutic guidelines (eTG) offer the most comprehensive directive of the clinical management of patients with a variety of syndromes including treatment of methicillin-resistant Staphylococcus aureus (MRSA) [
[9]
]. They do not include therapy options for other common hospital-associated drug-resistant infections such as those that comprise the “ESKAPE” pathogens including Enterococcus faecium (E. faecium), Klebsiella pneumoniae (K. pneumoniae) and Pseudomonas aeruginosa (P. aeruginosa). These organisms, both susceptible and resistant, cause as much as two-thirds of all healthcare-associated infections [[10]
] and are increasingly impervious to therapy [[11]
]. The study aimed to gain doctors' views of the most likely antibiotic management of patients with a bloodstream infection (BSI) caused by drug-resistant E. faecium, Escherichia coli, K. pneumoniae and P. aeruginosa.Methods
Development of the survey questions
The questions for the survey were developed and reviewed by an expert panel consisting of two independent infectious diseases experts and two non-clinical researchers. The survey participants were asked to answer questions relating to the treatment of confirmed drug-resistant BSI caused by four pathogenic bacteria. There were 3 main questions pertaining to treatment of third-generation cephalosporin resistant E. coli; third-generation cephalosporin resistant K. pneumoniae; vancomycin-resistant E. faecium and ceftazidime-resistant P. aeruginosa. The following three questions were asked for each of the survey organisms.
Survey questions
- Question 1. Recognising that therapy is determined by laboratory results, what is the most commonly used management for an ‘average’ stable patient with confirmed drug-resistant bloodstream infection
- (i)drug name,
- (ii)route of administration,
- (iii)dose and
- (iv)dosing interval
1For the purpose of this survey an ‘average’ patient is considered to be a stable male (average weight 86 kg) or a stable female (average weight 72 kg). - (i)
- Question 2. Would you use combination therapy to treat confirmed drug-resistant bloodstream infections?
- Question 3. Once the patient is stable, would you consider outpatient parenteral antibiotic therapy for the management of (Y/N).
Survey administration
The questionnaire was delivered using an online Survey Monkey software (http://www.surveymonkey.com). All responses were anonymous. The link to the survey was sent along with information to participants' pack that clearly detailed the study aims and a letter of encouragement to participate in the survey. The letter was endorsed by a clinical physician. Survey participants were asked to answer questions on the basis of their personal opinion and practice. The survey was distributed through a wide variety of clinical networks across Australia via the internet including the following:
- •Australasian Society of Infectious Diseases (ASID) OzBug forum
- •Australian Centre for Health Services Innovation (AusHSI) clinical networks
- •Distribution through various infectious disease meetings and online groups by the projects advisory group networks
Survey participants
The participants were any practising doctor who worked in a hospital or a health service. No particular specialty was targeted for the survey, hence any clinician was eligible as long as they were registered to practice. In 2015, there were 102,805 registered medical practitioners and approximately 6000 of these were practising physicians, with 5% registered as infectious diseases (approximately n = 300) [
[12]
]. The most likely participants responding following distribution to the aforementioned clinical networks would be in the field of infectious disease or microbiology. More specifically, respondents are likely to be either a doctor in-training or fully qualified specialist within their field.Survey analysis
Simple analysis of counts and proportions were calculated for the survey responses. These were based on the number of responses for each question.
Results
There were a total of 28 doctors that completed the online survey. Of these, all were based in a hospital or tertiary healthcare centre. Given the anonymous nature of the survey, we were not able to further identify the participants including their specialty, position or geographical locality.
Survey questions and responses
Antibiotic choice
Recognising that therapy is determined by laboratory results, what is the most commonly used management for an ‘average’ stable patient with confirmed resistant BSIs (drug name, route of administration, dose and dosing interval) for each of the four organisms.
Treatment of third-generation cephalosporin-resistant E. coli
Background
In 2015, resistance to third-generation cephalosporin's (ceftriaxone) was found in 9.8% of E. coli blood isolates [
[13]
] increase from 9% in 2014 [[14]
] and 7.5% in 2013 [[15]
]. Australia also contributes to the Regional Resistance Surveillance Program for the Asia–Pacific Nations (6 Australian sites with 1136 isolates), where resistance due to ESBL of sampled E. coli isolates was 12% [[16]
]. Multidrug resistance, defined as acquired resistance to more than three antimicrobial classes, rose from 11.7% in 2013 [15
, 17
] to 13.4% [[18]
] in 2014. Resistance rates were higher in strains causing hospital-onset infections than in strains causing community-onset infections [[19]
].Responses
All 28 of the survey participants answered the question relating to this organism. The majority of respondents (68%, n = 19) reported that they would prescribe three doses of meropenem (1–2 g) per day intravenously to treat resistant E. coli (Table 1). The other choice of antibiotics was piperacillin/tazobactam (14.3%, i.v, three doses per day), ciprofloxacin (7.2%; 500 mg, oral, two doses per day), ceftriaxone (3.5%, i.v, one dose per day), ertapenem (3.5%, i.v, one dose per day) or gentamicin (3.5%, i.v, one dose per day).
Table 1Survey results of antibiotic choice and dosing of confirmed drug resistant infections, Australia 2017.
| Antibiotic | Route of administration | Dose | Number of doses | Participants (%) |
|---|---|---|---|---|
| Third-generation cephalosporin-resistant E. coli | ||||
| Meropenem | Intravenous | 1–2 g | Q8h (3) | 19 (68) |
| Piperacillin/tazobactam | Intravenous | 4.5 g | Q8h (3) | 4 (14.3) |
| Ceftriaxone | Intravenous | 1 g | Daily (1) | 1 (3.5) |
| Ertapenem | Intravenous | 1 g | Daily (1) | 1 (3.5) |
| Gentamicin | Intravenous | 400 mg (5 mg/kg) | Daily (1) | 1 (3.5) |
| Ciprofloxacin | Oral | 500 mg | BD (2) | 2 (7.2) |
| Third-generation cephalosporin-resistant K. pneumoniae | ||||
| Meropenem | Intravenous | 1–2 g | Q8h (3) | 21 (75) |
| Piperacillin/tazobactam | Intravenous | 4.5 g | Q8h (3) | 3 (10.8) |
| Ertapenem | Intravenous | 1 g | Daily (1) | 2 (7.2) |
| Gentamicin | Intravenous | 400 mg (5 mg/kg) | Daily (1) | 1 (3.5) |
| Ciprofloxacin | Oral | 500 mg | BD (2) | 1 (3.5) |
| Ceftazidime-resistant P. aeruginosa | ||||
| Meropenem | Intravenous | 1 g | Q8h (3) | 13 (48.2) |
| Piperacillin/tazobactam | Intravenous | 4.5 g | Q8h (3) | 11 (40.7) |
| Cefepime | Intravenous | 2 g | Q8h (3) | 1 (3.7) |
| Ciprofloxacin | Oral | 750 mg | BD (2) | 2 (7.4) |
| Vancomycin-resistant E. faecium | ||||
| Linezolid | Intravenous | 600 mg | BD (2) | 11 (40.7) |
| Oral | 600 mg | BD (2) | 2 (7.5) | |
| Daptomycin | Intravenous | 600 mg | Daily (1) | 10 (37) |
| Teicoplanin | Intravenous | 10 mg/kg | Daily (1) | 4 (14.8) |
Treatment of third-generation cephalosporin-resistant K. pneumoniae
Background
In 2015, 5.1% K. pneumoniae blood isolates sampled were resistant to third-generation cephalosporins (ceftriaxone) [
[13]
], an increase from 6.6% in 2014 [[14]
] and 6.3% seen in the 2013 [[15]
]. Resistance due to ESBL of all sampled K. pneumoniae infections was 15% in the Regional Resistance Surveillance Programme for which 6 Australian sites participate [[16]
]. Multidrug resistance in K. pneumoniae rose from 7% in 2013 [[15]
] to 9.7% in 2014 [[20]
].Responses
All 28 of the survey participants answered the question relating to this organism. Three quarters (75%, n = 21) of doctors reported that they would prescribe three doses of meropenem (1–2 g) per day intravenously to treat resistant K. pneumoniae (Table 1). The other choices of antibiotics that doctors prescribed were intravenous piperacillin/tazobactam (11%; 4.5 g; three doses per day), ertapenem (7%; 1 g; iv; one dose per day), gentamicin (3.5%; 5 mg/kg; iv; one dose per day) or an oral dose of ciprofloxacin (3.5%; 500 mg; two doses per day).
Treatment of ceftazidime-resistant P. aeruginosa
Background
In 2015, 4.5% of P. aeruginosa clinical isolates from BSI were resistant to ceftazidime, which did not change from the previous year [
[18]
]. Outbreaks of P. aeruginosa have been reported in specific clinical settings including cystic fibrosis patients [[21]
], burns [[22]
] and intensive care and neurosurgical units [[23]
]. Both hospital and community-acquired bloodstream isolates were reported as having a low rate of ciprofloxacin and imipenem resistance [24
, 25
]. The rate of occurrence of multi-drug resistant P. aeruginosa in the Asia–Pacific region was 1.6% [[26]
].Responses
There were 27 (96%) responses relating to the treatment of drug resistant P. aeruginosa. The majority of doctors (48%) reported that they would prescribe three doses of meropenem intravenously followed by 41% (n = 11) of doctors chose would choose to prescribe piperacillin/tazobactam intravenously (4.5 g three times per day).
Treatment of vancomycin-resistant E. faecium (VRE)
Background
In 2015, 48.7% of E. faecium blood isolates were resistant to vancomycin [
[13]
], an increase from 41% in 2014 [[27]
]. VRE has been identified in all states in Australia and reports of colonisation [28
, 29
, 30
, 31
] and infections have been described [24
, 25
, 32
, 33
, 34
, 35
, 36
]. The only state where VRE is notifiable is Tasmania and South Australia reports VRE cases but it is not a notifiable condition.- Worth L.J.
- Slavin M.A.
- Vankerckhoven V.
- Goossens H.
- Grabsch E.A.
- Thursky K.A.
Virulence determinants in vancomycin-resistant Enterococcus faecium vanB: clonal distribution, prevalence and significance of esp and hyl in Australian patients with haematological disorders.
J Hosp Infect. 2008; 68: 137-144
Responses
There were 27 (96%) responses relating to the treatment of VRE, the one missing participant did not respond due to reporting a low number of VRE positive cases within their facility. The majority of doctors reported that they would prescribe linezolid (41%) (i.v, 600 mg two times per day) or daptomycin (37%) (i.v, 600 mg one dose per day) for treatment of VRE BSIs (Table 1). Two doctors reported prescribing an oral dose of linezolid, whilst the remainder 15% chose a daily dose of teicoplanin administered intravenously, one dose per day (10 mg/kg) (Table 1).
Combination therapy
Would you use combination therapy to treat confirmed drug resistant BSIs for each of the four organisms?
Background
There is limited published literature regarding the use of combination antibacterial therapy for the treatment of BSI in Australia. Combination therapy, guided by consultation with an infectious disease specialist, is a possible strategy to reduce the risk of inadequate antimicrobial therapy [
37
, 38
] and an Australian trial is underway to determine the benefit of combination antibiotic therapy for MRSA [[39]
]. No other similar data are available to determine the benefit of combination therapy for the resistant organism surveyed.Responses
All 28 participants answered this question. For treatment of third-generation cephalosporin resistant E. coli, K. pneumoniae and for VRE treatment, all survey participants reported that combination therapy was not appropriate (Table 2). However, for treatment of ceftazidime-resistant P. aeruginosa 15% (n = 4) of doctors would consider combination therapy.
Outpatient parenteral antimicrobial therapy (OPAT)
Once the patient is stable, would you consider OPAT for the management of the four drug-resistant BSIs?
Background
Outpatient parenteral antimicrobial therapy (OPAT) has become established as a standard of care in many Australian hospitals to treat a variety of infections [
40
, 41
, 42
]. A recent issues paper, suggests that treating acutely ill patients at home, rather than in hospital, could reduce treatment costs by up to 50%, mortality rates by 20% and decrease hospital readmission by a quarter [[43]
].Responses
All participants answered this question. Treating doctors would consider outpatient parenteral antimicrobial therapy (OPAT) for the treatment of a stable drug-resistant E. coli and K. pneumoniae, 97% and 93% respectively (Table 2). Similarly, for patients that are stable and infected with ceftazidime-resistant P. aeruginosa and VRE, OPAT was an option but the responses were more varied for the latter two organisms.
Table 2Survey responses (n = 28) for use of combination therapy and OPAT, Australia 2017.
| Organism | Combination therapy | OPAT | ||
|---|---|---|---|---|
| Yes (%) | No (%) | Yes (%) | No (%) | |
| Third-generation E. coli | 28 (100.0) | 0 | 27 (96.4) | 1 (3.6) |
| Third-generation resistant K. pneumonia | 28 (100.0) | 0 | 26 (92.8) | 2 (7.2) |
| Ceftazidime-resistant P. aeruginosa | 4 (15.2) | 24 (74.8) | 23 (82.1) | 5 (17.9) |
| Vancomycin-resistant E. faecium | 28 (100.0) | 0 | 23 (82.1) | 5 (17.9) |
For the purpose of supporting health economists in determining the cost of therapy, a framework of the most likely antibiotics used during treatment of drug-resistant and drug-susceptible infections in Australia was developed (Table 3). This framework is based on the results of the survey responses combined with reported standard treatment of drug-susceptible BSIs [
[9]
].Table 3Antibiotic therapy for drug-resistant compared to drug-susceptible BSIs in Australia, 2017.
| Causative organism | Therapy options |
|---|---|
| Drug susceptible E. coli [9] | Ceftriaxone; 2 g; intravenous; daily or Cefotaxime; 2 g; intravenous; 8-hourly or Gentamicin; 7 mg/kg; intravenous; daily |
| 3 GC-resistant E. coli | Meropenem; 1–2 g; intravenous; 8-hourly Once patient is stable consider OPAT |
| Drug susceptible K. pneumoniae [9] | Ceftriaxone; 2 g; intravenous; daily or Cefotaxime; 2 g; intravenous; 8-hourly or Gentamicin; 7 mg/kg; intravenous; daily |
| 3GC-resistant K. pneumoniae | Meropenem; 1–2 g; intravenous; 8-hourly Once patient is stable consider OPAT |
| Drug-susceptible P. aeruginosa [9] | Ceftazidime; 2 g; 8-hourly or Piperacillin/tazobactam; 4.5 g; 6-hourly or Gentamicin; 7 mg/kg; intravenous; daily |
| Ceftazidime-resistant P. aeruginosa | Meropenem; 1 g; intravenous; 8-hourly or Piperacillin/tazobactam; 4.5 g; intravenous; 8-hourly Once patient is stable consider OPAT |
| Drug-susceptible E. faecium [9] | Vancomycin; 15–20 mg/kg; 8–12 hourly |
| Vancomycin-resistant E. faecium | Linezolid; 600 mg; intravenous; 12-hourly or Daptomycin; 600 mg; intravenous; daily Once patient is stable consider OPAT |
3GC: third-generation cephalosporin; OPAT: outpatient parenteral antimicrobial therapy.
Discussion
This is the first Australian survey to provide detailed evidence of antibiotic choices made by doctors treating patients with drug-resistant infections. Using these data a framework to inform much needed economic models of the additional cost of treating patients infected with a drug-resistant compared to drug-susceptible organism was developed. Additionally, this survey brings to light several areas of practice for which little clinical evidence exists and demonstrates that whilst eTG are widely used in Australian hospitals, there is broad variation in the management of drug-resistant infections for which no guidelines exists.
Despite concerns of the effectiveness of β-lactam and carbapenem antibiotics in treating BSIs, they remain the drugs of choice for the treatment of resistant E. coli, K. pneumoniae and P. aeruginosa in this survey. No difference in mortality and length of hospitalisation was found between these two classes, however an increased risk of infection with a multi-drug resistant organism was observed for patients treated with carbapenem [
[44]
]. The suitability of piperacillin–tazobactam as a ‘carbapenem sparing’ alternative for the treatment of BSI caused by gram-negative bacteria is currently under investigation in the MERINO trail in Australia [[45]
]. A notable variation in therapy options identified in the survey was treatment of patients infected with VRE as doctors chose to prescribe either linezolid (41%) or daptomycin (37%). Studies have demonstrated that patients treated with linezolid have a lower mortality rate [- Harris P.N.
- Peleg A.Y.
- Iredell J.
- Ingram P.R.
- Miyakis S.
- Stewardson A.J.
- et al.
Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial.
Trials. 2015; 16: 24
[46]
], but a higher treatment failure and increased duration of bacteraemia when compared to patients treated with daptomycin for VRE [[47]
]. The optimum antibiotic choice for patients infected with VRE appears to be less clear from our survey and highlights the importance of a clearer understanding of therapy options, as globally Australia has one of the highest rates of VRE [[13]
].The use of OPAT delivery model, in particular for the treatment of stable patients infected with third-generation cephalosporin-resistant E. coli and K. pneumoniae was unanimous in the survey participants and may present an opportunity for cost saving in the appropriate situation, as well as other notable patient-specific benefits [
48
, 49
, 50
].There are a number of limitations to this study which are necessary to consider when interpreting the results. Firstly, given the limited evidence-base of the clinical management of drug-resistant infections in Australia and the variability in treatment options for urinary or other sites of infection, the study focused only on the impact for patients with a BSI. Secondly, despite all efforts to distribute the online survey as widely as possible, we did not have a high response rate with only 28 participants in total. The responses are likely to be far broader and more varied, if a greater number of doctors participated in the survey. If all participants' were infectious disease specialists, then our survey would have captured an approximate 10% of this population (28 participants out of a total of approximately 300 infectious disease specialists in Australia [
[12]
]). However, this survey provides a limited understanding of the generalisability of the study participants', their level of expertise and geographical locations.This is the first study to report the clinical management of patients infected with drug-resistant infections in Australia. It serves clinicians to better define the optimal treatment regimens and to carefully consider risk factors such as selective pressure which may contribute to increased resistance in the population [
[45]
]. This study also provides health economists with an invaluable tool to assist in generating locally-informed estimates of the cost of treating drug-resistant compared to drug-susceptible infections. Taken together, this survey has been successful in identifying areas where practice can be improved and where further research is needed.- Harris P.N.
- Peleg A.Y.
- Iredell J.
- Ingram P.R.
- Miyakis S.
- Stewardson A.J.
- et al.
Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial.
Trials. 2015; 16: 24
Ethics
This study was assessed as meeting the conditions within section 5.1.22 of the Australian National Statement on Ethical Conduct in Human Research (2007), and approval was granted by the QUT University Human Research Ethics Committee (1600001230). Potential participants were fully informed about the research via a participant information letter and consent was inferred through the completion and return of the survey.
Authorship statement
TW conceptualised the survey, conducted the analysis of the data, drafted and revised the paper.
Conflict of interest
Author declares no conflict of interest.
Funding
This work arose from the Centre of Research Excellence in Reducing Healthcare Associated Infections, which is funded by the National Health and Medical Research Council (NHMRC) grant GNT1030103. This research presented in this article is solely the responsibility of the authors and does not reflect the views of the NHMRC.
Provenance and peer review
Not commissioned; externally peer reviewed.
Acknowledgements
The author would like to thank Dr Kate Halton, Dr Kate Clezy and Dr Emma Goeman for reviewing the questionnaire and for their support in distribution of the survey to their networks, and to Dr Anthony Ryan for his input in providing critical review of the manuscript.
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Article info
Publication history
Published online: January 10, 2018
Accepted:
November 29,
2017
Received:
November 21,
2017
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© 2017 The Author(s). Published by Elsevier B.V. on behalf of Australasian College for Infection Prevention and Control.
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