Could we treat Bacteraemia In The Critically Ill with a Short-Course Monotherapy Strategy: Results of a 6 Month Prospective Audit
A Corona, A Wilson, M Grassi, M Singer
antibiotic therapy, bacteraemia, intensive care unit
A Corona, A Wilson, M Grassi, M Singer. Could we treat Bacteraemia In The Critically Ill with a Short-Course Monotherapy Strategy: Results of a 6 Month Prospective Audit. The Internet Journal of Infectious Diseases. 2003 Volume 3 Number 2.
Bacteraemia, both community-acquired and nosocomial, can present within a clinical spectrum ranging from asymptomatic through to septic shock (1). The reported incidence of nosocomial bacteraemia in ICU patients ranges from 2.5-26% (2,3,4,5,6,7,8,9) and is usually related to prolonged ICU and hospital stay. Despite advances in antibiotic therapy and general management of the critically ill patient, bacteraemia carries a high mortality (21-56%), ICU patients are at very high risk of developing bacteraemia as their host defence mechanisms are altered through their underlying illnesses, the extensive use of invasive procedures (catheters, tubes, drains etc), and coexisting endogenous/exogenous immunosuppression (10,11).
Timely selection of appropriate therapy influences patient outcome and is the mainstay of treatment of infection, in conjunction with the removal of foreign bodies, any obvious source of infection, drainage of abscesses and amelioration/cure of the underlying disease (12). The traditional approach to suspected infection in most critically ill patients is commencement of empirical broad-spectrum therapy before the results of cultures are obtained, with subsequent modification, depending on the results and/or the patient's condition (8). However, this approach does carry inherent dangers such as selection for antimicrobial resistance and the risks of drug toxicity.
As no data exist for the optimal therapy of ICU bacteraemia, ICUs apply different philosophies using permutations of short (4-7 days) or long (10-14 days or longer) courses of single or multiple antibiotics. Short courses of monotherapy may potentially not eradicate the organism, resulting in relapse, while prolonged ones may be related to drug toxicity as well as fungal overgrowth. Ironically, both policies are considered to be major influences on selection for anti-microbial resistance (14,15). Methicillin-resistant
Ideally, prospective randomised trials should be conducted to determine optimal antibiotic strategies for bacteraemia-related illnesses. As no data currently exist for the critically ill patient, we decided to conduct a six month prospective observational investigation to inform the design of any future study. We assessed:
The incidence, underlying factors, clinical presentation and severity of illness of community- (C-BACT), hospital- (H-BACT) & ICU-acquired bacteraemia (ICU-BACT), together with the incidence of fungaemia and antibiotic-resistant microorganisms
How patients treated with short course monotherapy respond in terms of clinical improvement/deterioration, ICU survival, long-term infectious complications and the incidence of relapsing episodes due to the same microorganism
Materials and Methods
The University College London Hospitals ICU is a 22-bedded, mixed medical-surgical tertiary referral centre that receives daily input from a consultant microbiologist. Routine antibiotic practice is to use short course monotherapy, unless specifically indicated (e.g. endocarditis, osteomyelitis) and, at 12 monthly intervals, to permutate first-line therapy for presumed Gram-negative community (amoxicillin-clavulanate or cefuroxime) and nosocomial (piperacillin-tazobactam or ceftazidime) pathogens. Second- and third-line therapy consists of ciprofloxacin or a carbapenem. Flucloxacillin and teicoplanin are routinely used for community- and hospital-acquired staphylococcal infections, respectively.
Cumulative Kaplan-Meier plots were constructed from the day of ICU admission and from the onset of ICU-BACT to estimate the probability of developing ICU-BACT
Binary Logistic Regression was used to estimate the effect of each risk factor on a death (yes/no) outcome for ICU-BACT patients. P values less than 0.05 were considered significant.
In the ICU-BACT group, all 11
Table 4 shows that a five-day median course of monotherapy was used in the majority of C-BACT (8 cases, 57%), H-BACT (22 cases, 79%) and ICU-BACT (48 episodes, 80%) patients, despite a lot of them complicated by septic shock (50% for C-BACT, 68% for H-BACT and 31% for ICU-BACT) and/or deep seated infections (50% for C-BACT, 41% for H-BACT and 69% for ICU-BACT. Despite opting for monotherapy, in most cases before culture results were known, antibiotic therapy was not subsequently altered in 73 (93.5%) out of 78 episodes. Two patients with C-BACT, 3 with H-BACT and 5 with ICU-BACT received additional antibiotics due to lack of clinical response, even though therapy was appropriate in terms of laboratory sensitivity testing.
Eleven patients died during therapy, five more within three days of stopping therapy. Excluding those 16 patients not completing their course of antibiotics, the median duration of treatment was not significantly prolonged for either C-BACT [median 6 days (IQR 5-6)], H-BACT [median 5 days (IQR 5-8)], or ICU-BACT [median 5 days (IQR 5-7)]. Only 6 patients received ≥10 days' therapy and two ≥14 days' therapy.
The decision to stop antibiotics was based upon clinical response, i.e. resolution of bacteraemia-related clinical findings ± improvement in related organ dysfunction (e.g. dose of norepinephrine). Using these criteria, a clinical response was recorded in most patients for each episode treated with short course monotherapy (Table 4). Six patients responded to antibiotic therapy with resolution of the related systemic inflammatory response but subsequently died due to persisting organ failure. Fourteen deaths were directly attributable to bacteraemia, where organ function continued to deteriorate despite sensitive antibiotic therapy.
Three H-BACT and two ICU-BACT patients who died while still receiving antibiotics developed breakthrough bacteraemia, three being due to
Six of the seven patients with more than one bacteraemia (i.e. H-BACT + ICU-BACT, or C-BACT + H-BACT) died, with five being directly related. Six of the ten patients developing more than one ICU-BACT episode died, four being directly related. Of the six patients relapsing with the same microorganism, four died though only one was directly related to the bacteraemia. Three of the 46 (55%) (38 treated with mono-therapy) bacteraemic patients who survived were transferred to other hospitals and the remaining 43 discharged to hospital wards. During a 3-week (IQR 7-75) median follow-up, none developed either relapses or further bacteraemic episodes. No long-term complications such as osteomyelitis or endocarditis have since come to our attention. Six (2 C-BACT, 2 H-BACT, 2 ICU-BACT) patients subsequently died in hospital.
Numerous studies have focused on the incidence of nosocomial bacteraemia in the ICU, stressing the high related mortality (2,3,4,5,6,7,8,9). Though appropriate and adequate antibiotic therapy is likely to influence patient outcome, remarkably, no clinical trials have been conducted to define optimal therapy for bacteraemia in the critically ill. As no data exist to inform practice, ICUs have evolved their own strategies. From informal discussions, many UK ICUs use short duration therapy (5-7 days), while North American and mainland European ICUs generally use longer courses (7-14 days). Definitive assessment of the efficacy of short course monotherapy requires large, randomised, prospective multicentre studies. However, we are encouraged by the generally satisfactory clinical response, the low rate of breakthrough bacteraemia, the low numbers requiring addition of antibiotics due to clinical deterioration, and the low relapse rate, even in those suffering from septic shock or severe sepsis. These data are consistent with those reported in the literature (10,12). As further corroboration, no bacteraemic patient discharged to the wards developed either relapse or a new episode of bacteraemia, nor any late related infections such as endocarditis or osteomyelitis.
In our practice, antibiotic therapy is usually stopped promptly on resolution of bacteraemia-related clinical findings ± improvement in related organ dysfunction. However, due to the severity of underlying disease and concurrent multiple organ failure, it is often difficult to establish when clinical response actually occurs, or whether death can be directly or indirectly attributed to the bacteraemia. Clinical response could be corroborated by microbiological response, i.e. negative blood cultures taken after cessation of appropriate therapy. However, our standard practice dictates that blood cultures are not taken unless the patient clinically deteriorates and infection is suspected. Furthermore, concurrent renal and/or hepatic dysfunction may result in an antibiotic presence persisting for days (or even weeks). Thus, for the purpose of this observational study, a positive microbiological response included either non-appearance of the infecting micro-organism or the lack of clinical need for subsequent blood cultures, extended into the duration of hospital stay post-ICU discharge to exclude late re-occurrence.
In keeping with accepted practice, longer duration combination therapy was prescribed for deep-seated infections such as endocarditis, necrotizing fascitiis, osteomyelitis, and faecal peritonitis. Relapses were more frequent in these patients, with failure to eradicate microorganisms being more likely with intra-vascular device colonisation and persistence of intra-abdominal abscesses. The worse clinical response and higher mortality in these patients reflects their underlying illness severity. Similarly, the worse outcome in H-BACT patients reflects their higher APACHE II score, their underlying disease severity and the high proportion (46%) of immunosuppression. The higher mortality in ward patients has been attributed to delays in antibiotic treatment and inadequate resuscitation (24).
Patients that developed ICU-BACT were sicker on ICU admission compared to other long stay (≥3 days) patients not developing ICU-BACT. This increased susceptibility is related to their underlying disease processes and the greater requirement for invasive procedures (e.g. vascular access, mechanical ventilation) (3,4,5,6,7,8,9). If admission illness severity was taken into account, logistic regression showed that ICU-BACT was not an independent variable predictive of death, notwithstanding its effect on prolonging stay (10).
The low incidence of ICU-acquired multi-drug resistant microorganisms and the zero incidence of ESBL-producing Gram-negative pathogens is uncommon when compared to recent North American and European studies that routinely express concern about the high frequency of such infections (25,26,27). All ICU-acquired
Our incidence of 1.4 ICU acquired fungaemias per 500 patients (0.5% of long stay patients) is similar to two multicentre studies from Germany and Spain, but much lower than reported by the EPIC or SENTRY surveillance studies (4,26,27,32,33). Any link between short course monotherapy and a low incidence of fungaemia and multi-drug resistant Gram-negative bacteraemia must remain as supposition at present, but offers an important hypothesis that warrants further investigation. In support of this theory, multi-drug resistant Gram-negative bacteraemia and fungaemia occurred more often in those H-BACT patients suffering from malignancy, with prolonged hospital stay and/or receiving prolonged courses of antibiotic therapy. Moreover, as reported by others (32,33), we recorded a higher prevalence of non-albicans
The limitations of this study are its observational nature and the relatively small numbers of patients considered. However, this study is the first, to our knowledge, that suggests short course monotherapy does result in a satisfactory clinical response and a low relapse rate. The concurrent low rate of ICU-acquired fungaemia and multi-drug resistant and ESBL- producing Gram-negative pathogens suggests the intriguing possibility that these findings are related. Presentation of this work has stimulated the development of a large, prospective, international audit that is underway. Verification of the above findings will hopefully lead to randomised controlled studies and important guidance as to optimal antibiotic treatment strategies in the critically ill.
Dr Alberto Corona, Bloomsbury Institute of Intensive Care Medicine, University College London, Jules Thorn Building, Middlesex Hospital, Mortimer Street, London W1N 3AA, UK E-mail: email@example.com Tel: +39-0383-805701 Fax +39-0383-805701
Appendix 1: Definitions (taken from References 1, 10-12, 23, 34-37)
Coagulase-negative staphylococcus and all common skin contaminants (
Death was considered