Correspondence
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Aggressive versus conservative initiation of antibiotics
Sepsis identifi cation in critically ill patients is still a diffi cult task, and the right time to administer antibiotics after clinical signs have been detected remains an unsolved issue.
Nevertheless, in cases of severe sepsis, early use of appropriate antibiotics seems logical, and many retrospective studies have shown a relation between delay in administration of antibiotic therapy and increased risk of death.1–3 Tjasa Hranjec and colleagues4 reported the results of a quasi- experimental study that compared outcomes of treatment with either an aggressive empirical antibiotic strategy or a more conservative strategy for patients admitted to a surgical intensive-care unit (ICU) with sepsis. The investigators reported that the conservative strategy was not associated with higher mortality, and was possibly associated with improved clinical outcomes. The study message is really impressive, but we believe the data and interpretation need some further clarifi cation to put the fi ndings in context.
In the methods, the investigators stated that in the conservative protocol period “antimicrobial drugs were withheld until there was microbiological evidence of infec- tion”.4 Microbiological evidence of infection takes around 48–72 h with typical culture methods, and takes less time only in rare favourable cases or with the use of molecular diagnostic procedures. Therefore, we expected that during the conservative period the median time from clinical signs or blood cultures to antibiotic initiation would be longer than 24 h, but median time from clinical signs to antibiotic initiation was only 24 h (IQR 9–44) and from blood culture samples it was only 22 h (7–58). Therefore, the trigger for initiation of antibiotic therapy in the
conservative period is unclear and should be explained by the authors.
The higher mortality reported in the aggressive treatment period was attributed by the authors to in- adequate empirical therapy and to a longer duration of antibiotic therapy.
This hypothesis might be reasonable, but also seriously challenges the authors’ conclusions. Indeed, a monodimensional empirical therapy restricted to piperacillin/tazobactam plus vancomycin, irrespective of site of infection and patient risk factors for acquisition of multidrug- resistant microorganisms and organ dysfunction, is overly simplistic and not in accordance with contemporary treatment guidelines and good practice for the use of antibiotic therapy. This risk is particularly true in ICUs with a high rate of multidrug-resistant bacterial infections, as in the study ICU where a more tailored approach should be mandatory.
The duration of antibiotic therapy was longer in the aggressive group than in the conservative group (by 5 days on average), but the diff erence in time to antibiotic administration from initial blood culture averaged only 14 h. Therefore, earlier admini- stration of antibiotics in the aggressively managed cohort seems unlikely to be the sole explanation for prolonged treatment courses. If the authors believe that a longer duration of antibiotic therapy was a key factor in mortality diff erence between groups, this reasoning should have to be discussed in their conclusion.
The investigators also reported that 80 patients had candidaemia or invasive candida episodes, and, of those, 38 were not appropriately managed by empirical therapy.
First, the rate of candida infections seems to be very high—80 (7·8%) of 484 patients. In a recent study in 1265 ICUs in 76 countries, the prevalence of candidaemia and invasive candidiasis was 6·9 per 1000 admissions.5 Second, early antifungal therapy is strongly
recommended as an empirical therapy in critically ill patients at high risk of candida infection. Again, we believe that the antibiotics used for empirical therapy in the aggressive protocol might have been suboptimal at best, which truly challenges Hranjec and colleagues’ conclusions.
We declare that we have no confl icts of interest.
*Massimo Girardis, Matteo Bassetti, Russel E Lewis, Pierluigi Viale
Surgical Intensive Care Unit, University Hospital of Modena, 41100 Modena, Italy (MG); Infectious Disease Unit, University Hospital of Udine, Udine, Italy (MB); and Infectious Disease Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy (REL, PV)
1 Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of eff ective antimicrobial therapy is the critical determinant of survival in human septic shock.
Crit Care Med 2006; 34: 1589–96.
2 Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002; 122: 262–68.
3 Kollef M, Micek S, Hampton N, Doherty JA, Kumar A. Septic shock attributed to candida infection: importance of empiric therapy and source control. Clin Infect Dis 2012; 54: 1739–46.
4 Hranjec T, Rosenberger LH, Swenson B, et al.
Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit- acquired infection: a quasi-experimental, before and after observational cohort study.
Lancet Infect Dis 2012; 12: 774–80.
5 Kett DH, Azoulay E, Echeverria PM, Vincent JL, for the Extended Prevalence of Infection in ICU Study (EPIC II) Group of Investigators. Candida bloodstream infections in intensive care units:
analysis of the extended prevalence of infection in intensive care unit study.
Crit Care Med 2011; 39: 665–70.
We read with great interest the Article by Tjasa Hranjec and colleagues,1 who did a quasi-experimental, before and after cohort study to compare aggressive therapy with conservative antimicrobial therapy in patients admitted to a surgical intentive- care unit (ICU). Since the study’s results might substantially aff ect treatment of patients with severe infections in real-life situations, we believe that the limitations of the study design should be thoroughly investigated. We have the following methodological concerns.
Correspondence
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First, the study should have included an appropriate control group of patients in the surgical ICU in whom aggressive therapy was continued for the whole study period.
Such a control group is necessary to control for non-intervention factors aff ecting mortality, such as the “improved ability of clinicians to recognise, diagnose, and treat infections” (as the investigators acknowledge).1 This control group is particularly important for the measure ment of the resistant infec- tion rate (the main secondary out- come in this study) and is required for quasi-experimental study designs.2
Second, the investigators claimed that their analyses were by intention to treat, but they concentrated on infected patients with microbiological evidence only. They do not present the results of patients with negative microbiological cultures who were also given treatment. The number of these excluded patients in both groups might have been substantial. According to a cluster randomised trial that ran in three European countries and included 2326 patients receiving antibiotics for suspected bacterial infections, the proportion of patients with infections and negative cultures was about 75%.3 Furthermore, according to the principles of an intention-to-treat analysis, the investigators should have also identifi ed, analysed, and reported the patients in the conservative treatment group who were potential candidates for aggressive therapy.
Then, both groups would have been comparable with respect to baseline characteristics.
Third, when studying mortality, the unit of inference is the patient and not the site of infection (as used by Hranjec and colleagues). We used the reported values to recalculate the actual 95% CI of the estimated unadjusted odds ratio (OR) of 2·44 for the risk of mortality, comparing
of 2731 patients with septic shock revealed that each 1 h delay in antibiotic initiation was associated with a 7·6% reduction in survival.2 28% of patients were ultimately culture negative, and culture- negative patients had an increased risk of death. Other studies have reported similar results.3 Therefore, Hranjec and colleagues’ conservative approach (used unless a surgical site infection was suspected) was brave. An opt-out clause allowed the use of empirical antibiotics for patients needing vasoactive drugs, but this clause was rarely used;
median time to antibiotics in the 46% of the conservative group who were in shock was similar (20 h vs 22 h) to the entire cohort. Although the investigators appropriately limit their interpretation to a dis- cussion of haemodynamically stable patients, their data suggest that the conservative approach might equally apply to patients with septic shock. Contradicting so many previous studies warrants a search for alternative explanations.
Vancomycin-resistant entero- coccus was commonly identified in both study groups (8–10%), as were Candida spp and resistant Pseudo- monas aeruginosa. Empirical anti- biotics in the aggressive protocol were piperacillin/tazobactam and van comycin, inadequate for these organisms. The benefits of waiting for positive cultures before starting antibiotics might therefore be confined to ICUs with a high incidence of resistant infections.
Patients in the aggressive ap- proach group received their first dose of antibiotic very late: a median of 12 h (IQR 3–30) after blood cultures were taken. This timeframe was contrary to the study protocol and the Surviving Sepsis guidelines,4 which recommend antibiotics be started within the first hour. An emergency department can achieve a median time from presentation to antibiotic administration of less When to start antibiotics in critically
ill patients with suspected infection is unclear. The 1483 patient before and after study by Tjasa Hranjec and colleagues1 reported that a conservative approach (ie, antibiotics given only when positive culture results were obtained), compared with an aggressive approach (ie, antibiotics given immediately after cultures were drawn), was associated with lower mortality (13% vs 27%; p=0·015).
At face value, the implications for intensive-care unit (ICU) practice are profound.
In view of previous evidence, this study had a bold design. An audit aggressive with conservative therapy.
The standard error of OR is exp
√(1/27+1/74+1/13+1/87), thus the actual CI is much wider (1·18–5·07) than reported (1·51–3·95).
Studies such as the one reported by Hranjec and colleagues should use all possible mechanisms to minimise risk of bias, since they are often used as the basis for starting further expensive and time-consuming multi- centre studies.4
We declare that we have no confl icts of interest.
*Martin Wolkewitz, Evelina Tacconelli, Martin Schumacher
[email protected] Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg, 79104 Freiburg, Germany (MW, MS); and Infectious Diseases, Department of Internal Medicine I, University of Tübingen, Tübingen, Germany (ET) 1 Hranjec T, Rosenberger LH, Swenson B, et al.
Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit- acquired infection: a quasi-experimental, before and after observational cohort study.
Lancet Infect Dis 2012; 12: 774–80.
2 Shardell M, Harris AD, El-Kamary SS, Furuno JP, Miller RR, Perencevich EN. Statistical analysis and application of quasi experiments to antimicrobial resistance intervention studies.
Clin Infect Dis 2007; 45: 901–07.
3 Paul M, Andreassen S, Tacconelli E, et al.
Improving antibiotic therapy using TREAT, a computerized decision support system: cluster randomised trial. J Antimicr Chemother 2006;
58: 1238–45.
4 Noble DW, Gould IM. Antibiotics for surgical patients: the faster the better? Lancet Infect Dis 2012; 12: 741–42.