Nowadays all the lights are red. Antibiotic resistant strains are more and more prevalent [1] and the availability of new antibiotic agents is becoming exceptional.
More than two-thirds of cases of ICU-acquired bacteremia are caused by multidrug-resistant or extensively drug-resistant bacteria [2]. Although the prevalence of methicillin-resistant Staphylococcus aureus is decreasing, the increasing rates of glycopeptide-resistant enterococci, extended-spectrum β-lactamase-producing Enterobacteriaceae, and Gram-negative bacteria resistant to carbapenems are worrisome.
The spread of bacterial resistance is mediated by three important factors. First, the bacteria itself may acquire resistance by mutation and, more frequently, by plasmid-mediated gene exchange between species in particular within the digestive microbiota. Second, the antibiotic selection pressure promotes the growth of resistant bugs by killing the susceptible ones. Third, cross-transmission of resistant bacteria may facilitate spread from one patient to another.
ICUs are the epicenters of antibiotic resistance because (1) more than 80 % of the patients may receive antibiotic treatment on a given day [3]; (2) the illness severity of the patients and the use of invasive procedures increase the likelihood of successful acquisition and persistent colonization with new strains; (3) the unstable hemodynamic conditions predispose to establishing suboptimal concentrations of antibiotics at the infection site; (4) the high healthcare workload favors the risk of cross-transmission of resistant strains.
To interrupt cross-transmission appropriate hand hygiene, skin cleansing, and contact precautions are key preventive measures. The immediate effect of appropriate antibiotic therapy on emergence and dissemination of antibiotic resistance is more complex and difficult to measure [4, 5]. Indeed, associations between antibiotic exposure and resistance at an individual, unit, hospital, regional, or national level have been frequently demonstrated [6]. However, the total effect of antibiotic pressure is due to a direct effect on the individual who receives the antibiotic agent, but also to the indirect impact on the transmissibility of resistant and susceptible strains within an entity such as an ICU [5].
Many studies demonstrated the link between antibiotic use and antibiotic resistance, both at a unit [5, 7–10] and at an individual level on the infecting flora [5, 11, 12] and on the gut microbiota [13]. However, the intensity of the effect is very difficult to evaluate because of the numerous uncontrolled factors and methodological issues, such as absence of regular screening of the patient’s gut flora [4, 5].
First, on an individual basis, antibiotic therapy clearly increases the risk of antibiotic resistant bacteria selection at the infection site [5, 11, 12]. In healthy subjects and in patients with community-acquired infections, antibiotic agents have a marked effect on intestinal microbiota diversity. The cessation of antimicrobial administration is associated with an incomplete and slow return to the pretreatment state [14]. In ICUs, the impact of antibiotic use on the gut microbiota has been demonstrated. As an example, treatment with imipenem is associated with a more than twofold increase in the imipenem-resistant Gram-negative bacteria. The effect is significant even after a 1-day course of imipenem [13].
The effect on the individual (mainly gut) microbiota varies according to the patients’ characteristics and clinical situations, between molecules, drug concentrations, and duration of antibiotic administration [15]. For instance, prolonged perioperative antibiotic prophylaxis was associated with an increased risk of selection of glycopeptide-resistant enterococci and cephalosporin-resistant enterobacteria [16]. Overall, the impact of a decrease in antimicrobial use is certain, but the effect varies according to patients’ characteristics, clinical conditions, molecules, route of administration, and dosage.
Antibiotics need to be given early to infected people, properly using aggressive initial dosing and stopping early when possible. The main rules for antibiotic treatment are listed in Table 1. One of the possible ways to decrease antibiotic use, and subsequently to constrain antibiotic resistance, is to apply streamlined (or de-escalated) therapy whenever possible.
In a recent article in Intensive Care Medicine, Leone et al. [17] reported a randomized controlled trial (RCT) evaluating the impact of antibiotic treatment de-escalation. It had no significant impact of length of ICU stay and even increased the number of antimicrobial days as well as the risk of superinfection. The impact of de-escalation on individual gut microbiota was not evaluated.
The study is important because it is the first eagerly awaited RCT conducted on this specific topic. Only one previously published controlled clinical trial has been performed, demonstrating that narrow-spectrum antibiotic therapy in neonates decreased the likelihood of resistance [18].
However, the study results should be cautiously analyzed and mitigated. First, patients enrolled were not consecutive as reflected by the relatively low number of patients enrolled per year and per ICU. The appropriateness of the initial antimicrobial dosing was not reported and not followed. Second, there was a large variability in the main judgment criteria that seriously impacts the power of the study. Indeed, the standard deviation of the duration of ICU stay from inclusion to discharge was more than 12 days in both groups. With a 2-day non-inferiority margin, more than 500 patients per arm would have been necessary to allow a definite conclusion to be drawn. Third, the population enrolled was seriously unbalanced, especially for age, SAPS II, the delay between admission and inclusion, the delay between sepsis and inclusion, and the lungs as the source of infection. Note that the authors acknowledged that lung as the source of infection was significantly associated with the length of ICU stay. Fourth, the duration of combination therapy was longer in the continuation group as compared to the de-escalation group; this difference occurs after enrollment and may have been influenced by the open-label nature of the study. Finally, in the subgroup analysis that includes only lung infections, the durations of ICU stay were similar in the de-escalation group (14 vs. 15 in median, P = 0.53). However the number of superinfections was still higher in the de-escalation group (39 vs. 22 %, P = 0.2).
Given the absence of difference in mortality between groups, the repeated results of observational studies showing de-escalation and reduced treatment duration as proper ways to reduce antibiotic use, and the serious flaws of this RCT, de-escalation should remain recommended and be carefully evaluated in further studies.
References
World Health Organization (2014) Antimicrobial resistance: global report on surveillance. Available via http://www.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1. WHO, Geneva
Tabah A, Koulenti D, Laupland K, Misset B, Valles J, Bruzzi de Carvalho F, Paiva JA, Cakar N, Ma X, Eggimann P, Antonelli M, Bonten MJ, Csomos A, Krueger WA, Mikstacki A, Lipman J, Depuydt P, Vesin A, Garrouste-Orgeas M, Zahar JR, Blot S, Carlet J, Brun-Buisson C, Martin C, Rello J, Dimopoulos G, Timsit JF (2012) Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med 38:1930–1945
Zahar JR, Timsit JF, Garrouste-Orgeas M, Francais A, Vesin A, Descorps-Declere A, Dubois Y, Souweine B, Haouache H, Goldgran-Toledano D, Allaouchiche B, Azoulay E, Adrie C (2011) Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Crit Care Med 39:1886–1895
Schechner V, Temkin E, Harbarth S, Carmeli Y, Schwaber MJ (2013) Epidemiological interpretation of studies examining the effect of antibiotic usage on resistance. Clin Microbiol Rev 26:289–307
Harbarth S, Harris AD, Carmeli Y, Samore MH (2001) Parallel analysis of individual and aggregated data on antibiotic exposure and resistance in gram-negative bacilli. Clin Infect Dis 33:1462–1468
Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, Huskins WC, Paterson DL, Fishman NO, Carpenter CF, Brennan PJ, Billeter M, Hooton TM (2007) Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44:159–177
Fournier P, Schwebel C, Maubon D, Vesin A, Lebeau B, Foroni L, Hamidfar-Roy R, Cornet M, Timsit JF, Pelloux H (2011) Antifungal use influences candida species distribution and susceptibility in the intensive care unit. J Antimicrob Chemother 66:2880–2886
Fridkin SK, Edwards JR, Courval JM, Hill H, Tenover FC, Lawton R, Gaynes RP, McGowan JE Jr (2001) The effect of vancomycin and third-generation cephalosporins on prevalence of vancomycin-resistant enterococci in 126 US adult intensive care units. Ann Intern Med 135:175–183
Rahal JJ, Urban C, Horn D, Freeman K, Segal-Maurer S, Maurer J, Mariano N, Marks S, Burns JM, Dominick D, Lim M (1998) Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA 280:1233–1237
Meyer E, Gastmeier P, Deja M, Schwab F (2013) Antibiotic consumption and resistance: data from Europe and Germany. Int J Med Microbiol 303:388–395
Paramythiotou E, Lucet JC, Timsit JF, Vanjak D, Paugam-Burtz C, Trouillet JL, Belloc S, Kassis N, Karabinis A, Andremont A (2004) Acquisition of multidrug-resistant Pseudomonas aeruginosa in patients in intensive care units: role of antibiotics with anti pseudomonal activity. Clin Infect Dis 38:670–677
Planquette B, Timsit JF, Misset BY, Schwebel C, Azoulay E, Adrie C, Vesin A, Jamali S, Zahar JR, Allaouchiche B, Souweine B, Darmon M, Dumenil AS, Goldgran-Toledano D, Mourvillier BH, Bedos JP (2013) Pseudomonas aeruginosa ventilator-associated pneumonia. Predictive factors of treatment failure. Am J Respir Crit Care Med 188:69–76
Armand-Lefevre L, Angebault C, Barbier F, Hamelet E, Defrance G, Ruppe E, Bronchard R, Lepeule R, Lucet JC, El Mniai A, Wolff M, Montravers P, Plesiat P, Andremont A (2013) Emergence of imipenem-resistant gram-negative bacilli in intestinal flora of intensive care patients. Antimicrob Agents Chemother 57:1488–1495
Dethlefsen L, Relman DA (2011) Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 108(Suppl 1):4554–4561
Andersson DI, Hughes D (2014) Microbiological effects of sublethal levels of antibiotics. Nat Rev Microbiol 12:465–478
Harbarth S, Samore MH, Lichtenberg D, Carmeli Y (2000) Prolonged antibiotic prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance. Circulation 101:2916–2921
Leone M, Bechis C, Baumstarck K, Lefrant JY, Albanese J, Jaber S, Lepape A, Constantin JM, Papazian L, Bruder N, Allaouchiche B, Bezulier K, Antonini F, Textoris J, Martin C (2014) De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial. Intensive Care Med. doi:10.1007/s00134-014-3411-8
de Man P, Verhoeven BA, Verbrugh HA, Vos MC, van den Anker JN (2000) An antibiotic policy to prevent emergence of resistant bacilli. Lancet 355:973–978
Acknowledgments
SH received funding from the European Commission (FP7-HEALTH-2009-SINGLE STAGE-SATURN contract no. 241796). Work by JFT and SH related to this narrative review has received support from the Innovative Medicines Initiative Joint Undertaking under the Combatting Bacterial Resistance in Europe [COMBACTE] grant agreement no. 115523, resources of which are composed of financial contribution from the European Union’s 7th Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution.
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Timsit, JF., Harbarth, S. & Carlet, J. De-escalation as a potential way of reducing antibiotic use and antimicrobial resistance in ICU. Intensive Care Med 40, 1580–1582 (2014). https://doi.org/10.1007/s00134-014-3485-3
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DOI: https://doi.org/10.1007/s00134-014-3485-3