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
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Abstract |
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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
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Introduction |
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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.
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Materials and methods |
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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 MantelHaenszel 2 or Fisher's exact test were used to compare proportions; a P value of <0.05 was considered significant.
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Results |
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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: 02). 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 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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Discussion |
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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 00; range: 05). 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.
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Acknowledgements |
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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).
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Footnotes |
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The complete list of study participants is given in the Acknowledgements.
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References |
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