Antibiotic usage in intensive care units: a pharmaco-epidemiological multicentre study

Paolo Malacarne1, Carlotta Rossi2 and Guido Bertolini2,* for the GiViTI group{dagger}

1 UO Anestesia e Rianimazione, Azienda Ospedaliera Pisana, Pisa; 2 GiViTI Coordinating Centre, Istituto di Ricerche Farmacologiche ‘Mario Negri’: Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, 24020 Ranica (Bergamo), Italy

Received 31 October 2003; returned 12 January 2004; revised 22 April 2004; accepted 27 April 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Footnotes
 Acknowledgements
 References
 
Objectives: To prospectively assess the use of antibiotics in ICUs.

Patients and methods: A total of 979 critically ill patients over 14 years of age were recruited in 43 Italian ICUs. For each patient, admission and discharge characteristics, information on the drugs administered, use of antibiotic susceptibility tests (ASTs), presence and severity of sepsis were collected daily until discharge or for a maximum of 21 days.

Results: Most patients with sepsis (99%) received antibiotics, and in almost all (93%) the treatment was started empirically, with broad-spectrum antibiotics. ASTs followed the onset of empirical treatment in 93% of cases. De-escalation was carried out in 16 patients, while in 37.6% of cases an antibiotic had to be changed or added. Antibiotic prophylaxis in surgical patients involved widespread use of drug combinations (31% of cases) and lasted 3 days on average. In non-surgical patients antibiotic prophylaxis lasted 4.6 days and in 42% a third-generation cephalosporin was used.

Conclusions: We found an appropriate approach to the therapeutic use of antibiotics: early empirical onset with broad-spectrum antimicrobial, followed by ASTs in order to target the therapy. However, in more than one-third of the cases the first-line choice was inappropriate. As regards prophylaxis, both surgical and non-surgical patients tended to have excessive duration of treatment, with widespread use of antibiotic combinations, too often involving a third-generation cephalosporin or carbapenem. This indicates a wide gap between clinical guidelines and clinical practice that calls for close assessment.

Keywords: antibiotic use , critical care , prophylaxis , prospective study


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Footnotes
 Acknowledgements
 References
 
Infections are an everyday problem in the intensive care unit (ICU) and antibiotics are therefore commonly used in this setting.1 Besides treatment of infections, antibiotics are administered as prophylaxis to prevent or limit major infections in critically ill patients.2 Thus, appropriate use of antibiotics in ICUs is important in ensuring an optimal clinical outcome, but also in controlling the emergence of resistance among pathogenic microorganisms and in containing costs.3 However, very few studies have assessed daily practice through prospective data collection.4,5

In 1999 Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva (GiViTI) carried out a multicentre bottom-up ICU costing project. We analysed this database with the aim of assessing the use of antibiotics in ICUs from a pharmaco-epidemiological perspective.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Footnotes
 Acknowledgements
 References
 
Each ICU had to enrol 30 consecutive patients over 14 years of age. Data on admission and discharge characteristics, and many other pieces of daily information, were recorded electronically. Daily information included the use of drugs, the use of antibiotic susceptibility tests (ASTs), the presence of systemic inflammatory response syndrome (SIRS), and the presence and severity of sepsis, according to the ACCP/SCCM classification.6 Sepsis was defined as a SIRS accompanying a clinically or microbiologically confirmed infection. Information was collected every day until discharge or for a maximum of 21 days. The electronic form concurrently made several data validity checks. Remaining doubts were resolved with each ICU.

We distinguished antibiotic treatment from prophylaxis according to the presence of sepsis. Antibiotic treatment was further classified as empirical when it started before or on the same day as the AST, and targeted when it started within 4 days of the AST. In the context of empirical antibiotic treatment we also distinguished de-escalation, i.e. the withdrawal of one or more antibiotics after the performance of the AST, from escalation, i.e. the change or addition of one or more antibiotics after the AST.

Since ACCP/SCCM criteria define sepsis as the presence of both SIRS and proven or suspected infection, we can assume that a patient with only SIRS did not have infection. However, we cannot argue that a patient without SIRS did not have infection.1 We therefore classified the reason for antibiotic administration in patients without sepsis as prophylaxis or unknown. The former was defined as the use of antibiotics in patients with SIRS, or in patients without SIRS if the treatment did not last more than 4 days or no AST was requested. All the other cases were defined as unknown reason.

The Mantel–Haenszel {chi}2 or Fisher's exact test were used to compare proportions; a P value of <0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Footnotes
 Acknowledgements
 References
 
Forty-three adult ICUs participated and recruited 1066 patients. Among patients with sepsis and a length of stay longer than 48 h, we found that in only one case (0.6%) was no antibiotic therapy started. The average treatment duration was 14.1 days (S.D. 6.3), but 15 patients died during their course of treatment and 45 had antibiotics on the day of discharge.

Empirical antibiotic treatment was started in 143 of 153 patients with sepsis. In 98% of these cases two or more antibiotics were used. Table 1 lists the most commonly used antibiotics. In 133 of these patients (93%) one or more AST was carried out. The median time between the start of empirical antibiotic therapy and the first AST was 1 day (IQR: 0–2). The AST findings led to a change in the antibiotic therapy in 66 cases (49.6%). De-escalation accounted for 24% of the changes (16 patients); antibiotic therapy was escalated in the remaining 37.6% of septic patients. Either an antibiotic was changed (11 patients) or one was added (39 patients). Escalation of therapy was not significantly associated with a different mortality (31.0% versus 35.5%; P=0.61).


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Table 1. Antibiotic prescriptions

 
Of the 783 patients who never developed sepsis, 582 (74.7%) received at least one antibiotic. Notably, systemic cefotaxime together with local decontamination was never used. Applying our criteria, we were unable to classify the reason for antibiotic usage in 164 patients (20.9%), while prophylaxis was adopted in 418 (53.4%). The use of antibiotic prophylaxis is significantly more common in surgical patients (36% in non-surgical patients compared with 66% in surgical patients; {chi}2=68.7, P<0.0001). Antibiotic combinations were applied in 31% of surgical patients.

Table 2 presents the duration of treatment and the number of antibiotics used. On average, prophylaxis lasting more than 24 h and more than 72 h was 87% and 40%, respectively, in non-surgical patients, compared with 78% and 19% in surgical patients.


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Table 2. Patients without sepsis: duration of treatment and number of antibiotics according to the reason for usage

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Footnotes
 Acknowledgements
 References
 
The ICU is one of the most important sources of nosocomial infections.1 The high prevalence of infections involves heavy consumption of antimicrobial agents, ~10 times that in general wards.4 Despite this, few studies, mainly single-centre or questionnaire-based surveys,4,5 describe antibiotic use in ICU daily practice.

This prospective multicentre study assesses antibiotic usage in one of the largest number of ICUs. A further strength is that the data collection was not directly intended to assess prescription practice. Hence, the Hawthorne effect, i.e. an increase in the quality of work due to the stimulus of being singled out and observed, can be ruled out.

With regard to the use of antibiotics in patients with sepsis, the usual approach was the recommended approach: early empirical onset with broad-spectrum antimicrobial agents, followed by an AST in order to target therapy.3

In terms of first-choice antibiotics, we observed widespread use of vancomycin and teicoplanin. This practice seems justified by the high rates of methicillin-resistant Staphylococcus aureus (MRSA) in Italian ICUs.7 Our results confirm findings from an earlier study that first-line empirical therapy in critically ill patients is often inadequate and needs to be changed once the AST results are known.8 A number of factors may contribute to inappropriate empirical antibiotic choice on ICUs. First, few ICUs in Italy have a well-organized infection surveillance system, and it would be difficult to base antibiotic choice on the local epidemiology of microbial resistance. Secondly, a scheduled cycling of antibiotics has been proposed9 within ICUs. However, it is not clear which antibiotics should be rotated. Guidelines for coping with specific situations, like ventilator-associated pnemonia (VAP), are available, but many important infections, like bacteraemia, peritonitis and urinary tract infection, remain uncovered. Interestingly, results from another survey on the same ICUs10 showed that decisions to start and stop antibiotic therapy were usually taken by intensive care clinicians alone in over 95% of cases. The overall level of direct input from microbiologists or infectious diseases specialists was low (median 0 visit per week; IQR 0–0; range: 0–5). Indeed, while this kind of pharmaco-epidemiological study is important in identifying inappropriateness, the reasons for that should be investigated with a different approach in a separate study.

With regard to antibiotic prophylaxis, a clear distinction should be made between surgical and non-surgical patients. Many guidelines are available for surgical patients and there is agreement in recommending cefazolin, cefoxitin and cefuroxime as first choice, or ceftriaxone, ceftizoxime and glycopeptides as second choice, for no more than 24 h.2 Our data are far from these recommendations, mainly for an excessive duration of treatment (3 days). There is also widespread use of drug combinations. Antibiotic combinations are widely accepted if used appropriately in certain surgical procedures or patients. These are: cephalosporin with metronidazole in intra-abdominal surgery; cefazolin or clindamycin with gentamicin in cardiac or head-and-neck surgery; ampicillin with gentamicin when endocarditis risk is apparent; and glycopeptide with gentamicin if the patient is a known MRSA carrier or there is a high local prevalence of MRSA.2 However, these combinations were infrequent in our study (19 patients overall). Interestingly, adherence to internationally accepted guidelines was low in other studies too.11

Concerning prophylaxis in non-surgical patients, after excluding a few specific conditions like neutropenia, the only two approaches for which there is evidence (albeit disputed) are selective digestive decontamination (SDD) and VAP prophylaxis, but limited to certain situations. While SDD was never used in this series, we observed lengthy treatment (4.6 days), mainly with inappropriate antibiotics (third-generation cephalosporin in 42% of cases), in too many patients (36% of non-surgical patients without sepsis). Prophylaxis in non-surgical patients is not supported by any randomized clinical trial and is not recommended by any scientific society. It is probably nourished by the idea that low bacterial growth could protect against infections. This policy increases antibiotic resistance and induces false confidence among physicians who consequently pay less attention to the possibility of occult infections.

Finally, we were not able to classify the reason for antibiotic use for 164 patients. This group included a number of patients with infection without SIRS. In a recent paper,1 20% of ICU infections were of this kind. This is a considerable proportion, which is compatible with our results and calls for further attention.

In summary, the literature offers many suggestions on the best antibiotic policy in critically ill patients, but they are not always based on high-level evidence. This makes it difficult to judge daily practice and, consequently, to organize a helpful benchmarking programme. Consequently, antibiotic prescribing remains far from the guidelines, probably because intensive care physicians are receptive to different advice.10 These circumstances urgently call for high-quality evidence in this field and further stress the importance of establishing local and national surveillance systems, as well as the development of multi-disciplinary approaches to antibiotic management and guideline production.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Footnotes
 Acknowledgements
 References
 
GiViTI is the recipient of an educational grant from AstraZeneca Italy and Sevit.

List of participating clinicians with their city in brackets: Barberis Bruno (Rivoli, TO); Biancofiore Gianni (Pisa); Carnevale Livio (Pavia); Cesaro Paolo (Giugliano in Campania, NA); Ciceri Gabriella Desio, MI); Ciceri Rita (Lecco); Cirillo Francesco Maria (Legnago, VR); Del Sarto Paolo (Massa); Digito Antonio (Vicenza); Doldo Giuseppe (Reggio Calabria); Franco Gabriele (Castellana Grotte, BA); Fulgenzi Giuliano (Pesaro); Garelli Alberto (Ravenna); Giannoni Stefano (Empoli, FI); Gorietti Adonella (Perugia); Guadagnucci Alberto (Massa); Lagomarsini Ginetta (Pisa); Lavacchi Luca (Pistoia); Maitan Stefano (Faenza, RA); Malacarne Paolo (Pisa); Mancinelli Annetta (Chieti); Mantovani Giorgio (Ferrara); Marafon Silvio (Vicenza); Marcora Barbara (Monza, MI); Melis Piergiorgio (Lucca); Muttini Stefano (Vimercate, MI); Negri Giovanni (Pavia); Neri Massimo (Bologna); Paternesi Nazareno (Macerata); Pecunia Laura (Genova); Pennacchioni Silvio (Ancona); Pergolo Augusto (Genova); Pessina Carla (Rho, MI); Postiglione Maurizio (Napoli); Quattrocchi Pasqualino (Catania); Radrizzani Danilo (Legnago, MI); Rossi Giancarlo (Livorno); Rotelli Stefano (Milano); Salvi Giovanni (Imperia); Segala Vincenzo (Torino); Siviero Silvano (Rovigo); Solinas Giommaria (Lanusei, NU); Spadini Elisabetta (Parma); Tavola Mario (Lecco); Terragni Pierpaolo (Torino); Todesco Livio (Cittadella, PD); Trivella Patrizia (Bergamo); Visconti Maria Grazia (Cernusco sul Naviglio, MI); Zanforlin Giancarlo (Milano); Zappa Sergio (Brescia).


    Footnotes
 
* Corresponding author. Tel: +39-035-4535313; Fax: +39-035-4535371; Email: giviti{at}marionegri.it

{dagger} The complete list of study participants is given in the Acknowledgements. Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Footnotes
 Acknowledgements
 References
 
1 . Alberti, C., Brun-Buisson, C., Burchardi, H. et al. (2002). Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Medicine 28, 108–21.[CrossRef][ISI][Medline]

2 . Mangram, A. J., Horan, T. C., Pearson, M. L. et al. (1999). Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infection Control and Hospital Epidemiology 20, 250–78.[ISI][Medline]

3 . Hoffken, G. & Niederman, M. S. (2002). Nosocomial pneumonia: the importance of a de-escalating strategy for antibiotic treatment of pneumonia in the ICU. Chest 122, 2183–96.[Abstract/Free Full Text]

4 . Roder, B. L., Nielsen, S. L., Magnussen, P. et al. (1993). Antibiotic usage in an intensive care unit in a Danish university hospital. Journal of Antimicrobial Chemotherapy 32, 633–42.[Abstract]

5 . Bergmans, D. C., Bonten, M. J., Gaillard, C. A. et al. (1997). Indications for antibiotic use in ICU patients: a one-year prospective surveillance. Journal of Antimicrobial Chemotherapy 39, 527–35.[Abstract]

6 . American College of Chest Physicians/Society of Critical Care Medicine (1992). Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Critical Care Medicine 20, 864–74.[ISI][Medline]

7 . Vincent, J. L., Bihari, D. J., Suter, P. M. et al. (1995). The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. Journal of the American Medical Association 274, 639–44.[Abstract]

8 . Alvarez-Lerma, F. (1996). Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive Care Medicine 22, 387–94.[ISI][Medline]

9 . Raymond, D. P., Pelletier, S. J., Crabtree, T. D. et al. (2001). Impact of a rotating empiric antibiotic schedule on infectious mortality in an intensive care unit. Critical Care Medicine 29, 1101–8.[ISI][Medline]

10 . Corona, A., Bertolini, G., Ricotta, A. M. et al. (2003). Variability of treatment duration for bacteraemia in the critically ill: a multinational survey. Journal of Antimicrobial Chemotherapy 52, 849–52.[Abstract/Free Full Text]

11 . Van Kasteren, M. E., Kullberg, B. J., De Boer, A. S. et al. (2003). Adherence to local hospital guidelines for surgical antimicrobial prophylaxis: a multicentre audit in Dutch hospitals. Journal of Antimicrobial Chemotherapy 51, 1389–96.[Abstract/Free Full Text]





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