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Antimicrobial treatment for Intensive Care Unit (ICU) infections including the role of the infectious disease specialist
International Journal of Antimicrobial Agents 29 (2007) 494–500
Review
Antimicrobial treatment for Intensive Care Unit (ICU) infections including the role of the infectious disease specialist Silvano Esposito ∗ , Sebastiano Leone Department of Infectious Diseases, Second University of Naples, Naples, Italy Received 24 October 2006; accepted 24 October 2006
Abstract Between 5 and 10% of patients admitted to acute care hospitals acquire one or more infections, and the risks have steadily increased during recent decades. Three types of infection account for more than 60% of all nosocomial infections: pneumonia, urinary tract infection and primary bloodstream infection, all of them associated with the use of medical devices. Nearly 70% of infections are due to micro-organisms resistant to one or more antibiotics (multidrug resistant or MDR). A higher incidence of inappropriate antibiotic therapy is expected when infections are caused by antibiotic-resistant micro-organisms and initial inappropriate empirical therapies, and the further need to modify them substantially increases the mortality risk. Despite new antibacterial agents such as linezolid, and also tigecycline and daptomycin, now being available for the treatment of infections due to MDR micro-organisms, the best strategy for improving the cure rate and minimising the development of resistance, probably remains the infectious disease specialist consultation. © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: ICU infections; Antibiotic therapy; Appropriate and inappropriate therapy; Infectious disease specialist
1. Introduction Nosocomial infections (NIs) are today by far the commonest complications affecting hospitalised patients. Currently, 5–10% of patients admitted to acute care hospitals acquire one or more infections, and the risks have steadily increased during recent decades [1,2]. Although representing only 5–15% of hospital beds, Intensive Care Units (ICUs) account for 10–25% of healthcare costs, corresponding to 1–2% of the gross national product of the United States. NIs affect more than two million persons annually in the United States and involve 5–35% of patients who are admitted to ICUs [3]. Three types of infection account for more than 60% of all nosocomial infections: pneumonia (usually ventilatorassociated), urinary tract infection (UTI) (usually catheterassociated) and primary bloodstream infection (BSI) (usually associated with the use of an intravascular device) [4]. Richards et al. observed that in patients with pneumo∗
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nia, Staphylococcus aureus (17%) was the most frequently reported isolate, and of reported isolates, 59% were Gramnegative bacilli; in patients with UTIs, Escherichia coli (19%) was the most frequently reported organism; in patients with primary BSIs, coagulase-negative staphylococci (39%) were the commonest pathogens reported; S. aureus (12%) was as frequently cultured as enterococci (11%) [4]. Up to 70% of infections are due to micro-organisms resistant to one or more antibiotics [3]. A large study, conducted by the National Nosocomial Infections Surveillance (NNIS) comparing the resistance rates of micro-organisms collected in the period January–December 2003 with those collected in 1998–2002, has established a continuous increasing incidence of antibiotic resistance [5]. The study reported a 20, 15 and 9% increase in Pseudomonas aeruginosa strains resistant to third-generation cephalosporins, imipenem and quinolones, respectively. The proportion of S. aureus isolates resistant to methicillin (MRSA), oxacillin or nafcillin continuously increased, and was nearly 60%. E. coli and Klebsiella pneumoniae resistant to third-generation cephalosporins and
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aztreonam were 5.8 and 20.6%, respectively. However, the rate of increase of antibiotic resistance has diminished for several pathogens, including vancomycin-resistant enterococci, which was reported as 31% in 2000 compared with 12% in 2003. This review will briefly discuss the clinical relevance of antimicrobial resistance and therapeutic options for treatment of NIs in ICUs.
2. Methicillin-resistant staphylococci Methicillin-resistant S. aureus was first described in 1961 and has become a worldwide problem [6]. MRSA is currently the most commonly identified antibiotic-resistant pathogen in US hospitals, and contributes significantly to patient morbidity and mortality [7]. Cosgrove et al. performed a meta-analysis to summarise the impact of methicillin resistance on mortality in S. aureus bacteraemia. The authors described 31 studies on a total of 3963 patients with S. aureus bacteraemia. Analysis showed a significant increase in mortality associated with MRSA bacteraemia (OR, 1.93; 95% CI, 1.54–2.42; P < 0.001) [8]. In another meta-analysis, Whitby et al. observed that bacteraemia caused by MRSA was associated with significantly higher mortality rates than bacteraemia caused by methicillin-sensitive S. aureus (MSSA) (29% versus 12%; P < 0.001) [9]. Melzer et al. observed that the proportion of patients whose death was attributable to MRSA was significantly higher than that for MSSA (11.8% versus 5.1%; OR, 2.49; 95% CI, 1.46–4.24; P < 0.001) [10]. Recently, Zahar et al. observed similar results in ventilatorassociated pneumonia (VAP) due to MRSA. The authors showed that the crude hospital mortality rate was higher for MRSA-infected patients than for MSSA-infected patients (59.4% versus 40%; P = 0.024) [11]. The current drugs of choice for MRSA infections remain glycopeptides, as only very few reports have shown resistance to these antimicrobial agents among staphylococci [12,13]. Despite the high in vitro activity of glycopeptides against staphylococci, Nathwani has observed, in an editorial concerning the role of vancomycin in the therapy of lower respiratory tract infections (LRTIs) due to S. aureus, that glycopeptides may be less effective. The author suggested that pharmacokinetic/pharmacodynamic parameters can be the basis of poor efficacy of vancomycin in the treatment of nosocomial LRTIs. In particular, in nosocomial MRSA pneumonia, MIC values of MRSA make it unlikely that the AUC/MIC value is greater than 125, although the MBC of this organism may be considerably higher than the MIC [14]. New agents with activity against MRSA have been developed recently. Linezolid is the first member of a structurally unique class of antibiotics, the oxazolidinones. This drug has demonstrated activity against Gram-positive organisms resistant to other antimicrobial agents, including MRSA [15]. The clinical efficacy of linezolid as part of a broader empiric regi-
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men for hospital acquired pneumonia (HAP) was analysed in a multinational, randomised, double-blind trial that compared it with vancomycin. The clinical response rate was 53.4% in the linezolid group and 52.1% in the vancomycin group. Microbiological success rates were also similar (67.9% in the linezolid group versus 71.8% in the vancomycin group) [16]. Similar results were observed by Stevens et al. in a randomised, open-label trial comparing linezolid and vancomycin for the treatment of hospitalised adults with known or suspected MRSA infections. This author reported similar clinical and microbiological success rate in the two groups [17]. Quinupristin/dalfopristin (Q/D) exhibits good in vitro activity against MRSA. For the treatment of Gram-positive nosocomial pneumonia, Q/D was found to be equivalent to vancomycin. Clinical success rates among the microbiologically evaluable patients infected with MRSA did not differ between the two treatment groups [18]. New antibacterial agents include tigecycline and daptomycin, but there are no available clinical data for the treatment of ICU infections with these agents. Tigecycline is bacteriostatic against most pathogens but has a broad spectrum of antimicrobial activity and has enhanced penetration into many tissues. Fritsche et al. assessed the antimicrobial activity of tigecycline against organisms causing HAP. S. aureus (49.4% MRSA) was readily inhibited by tigecycline (MIC50 and MIC90 , 0.25 and 0.5 g/mL, respectively) with all strains being inhibited by <1 g/mL [19]. Daptomycin is a lipopeptide antimicrobial that is rapidly bactericidal against S. aureus. It is effective in the therapy of S. aureus bloodstream infections but is inactivated by pulmonary surfactant, making it ineffective in the therapy of pneumonia. Several microbiological studies suggest that the breakpoint of daptomycin should be less than 1 g/mL for S. aureus (both MRSA and MSSA) [20,21].
3. Vancomycin-resistant enterococci Vancomycin-resistant enterococci (VRE) have emerged as important nosocomial pathogens. VRE were first described in 1987 in Europe, and within 10 years VRE were among the most feared pathogens in US hospitals. Studies dealing with the emergence of VRE in the United States revealed that most patients with VRE were in ICUs [22]. The clinical impact of vancomycin resistance among patients with VRE infections is a controversial issue. In a study comparing the prognosis of patients with VRE versus VSE bacteraemia, clinical failure was higher for patients with VRE bacteraemia (60% versus 40%, P < 0.001) [23] but some studies have failed to demonstrate a statistically significant association between vancomycin resistance and mortality [24]. DiazGranados et al. performed a systematic literature review with a meta-analysis to analyse the impact of vancomycin resistance on mortality in VRE bacteraemias. The authors described nine studies including a total of 1612
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enterococcal BSIs episodes. Analysis of the data showed that VRE patients were more likely to die than were those with VSE bacteraemia (OR, 2.52; 95% CI, 1.9–3.4) [25]. Enterococci are intrinsically resistant to multiple antimicrobial agents. The therapeutic options for VRE infections are therefore very limited (fosfomycin, nitrofurantoin, fluoroquinolones, doxycycline and chloramphenicol). Teicoplanin is active in vitro against VanB and VanC enterococci [26]. Two classes of antibiotic have been specifically approved for the treatment of VRE infections: the streptogramins and the oxazolidinones. Quinupristin/dalfopristin (Q/D) has proved effective for treatment of VRE infections due to Enterococcus faecium, whereas Enterococcus faecalis is intrinsically resistant. Clinical response rates with Q/D were 60–70% in patients with bacteraemia [27]. Linezolid has almost uniform activity against enterococci, with MICs of 1–4 g/mL in one study of 180 isolates of various enterococcal species, regardless of vancomycin susceptibility [28]. Initial clinical trials have shown that the drug has efficacy that is probably at least as good as that of Q/D, with fewer adverse reactions [29]. New agents for the treatment of VRE infections are daptomycin and tigecycline. In a worldwide surveillance study, daptomycin was shown to be active against all strains of vancomycin-resistant enterococci [30]. Tigecycline is active against all species of enterococci. Against Enterococcus faecalis and Enterococcus faecium, MIC90 values were 0.12 mg/L for both vancomycin-susceptible and -resistant strains [31]. 4. Extended-spectrum -lactamase (ESBL) Gram-negative pathogens The first reports of ESBLs in Gram-negative bacilli came from Europe and were followed quickly by reports in the United States. This type of antimicrobial resistance is now recognised worldwide. The influence of ESBL production on clinical outcome is a controversial issue. Several studies found no significant association between ESBL production and treatment failure or crude mortality [32]. In contrast, Lautenbach et al., in a case-control study, observed that ESBL-producing E. coli or K. pneumoniae infections were associated with a significantly longer duration of hospital stay and greater hospital costs (P = 0.01 and P < 0.001, respectively). Mortality attributable to infection was greater in case patients than in control patients (15.2% versus 9.1%; OR, 1.91; 95% CI, 0.49–7.42; P = 0.35) [33]. Ariffin et al. found that the overall sepsis-related mortality was significantly higher among patients infected with ceftazidime-resistant K. pneumoniae than among patients infected with ceftazidimesusceptible K. pneumoniae (50.0% versus 13.3%) [34]. A study on bloodstream infections caused by ESBL-producing organisms showed that mortality was considerably higher among patients infected with ESBL-producing strains than among patients infected with non-ESBL-producing strains (24% versus 2%, respectively), and, at the end of therapy, the
favourable response rate was 53% among patients infected with ESBL-producing strains who received cephalosporin therapy, and 94% among patients infected with non-ESBLproducing strains [35]. Similar results were reported by other authors. For example, an international study conducted by Paterson showed that failure rates exceed 50% when cephalosporins (apparently susceptible in vitro) were used to treat patients with severe infections caused by ESBLproducing Klebsiella spp. [36]. The presence of ESBL-producing Enterobacteriaceae complicates therapy, particularly as these organisms are often multidrug resistant. Current FDA-approved treatment options for ESBLproducing organisms include carbapenems, cefepime, aminoglycosides and fluoroquinolones. Despite their in vitro activity, -lactam/-lactamase inhibitor combinations do not have FDA approval for treating infections caused by ESBLproducing pathogens. Carbapenems are generally considered the most reliable agents. Paterson et al. showed that a carbapenem (primarily imipenem) was associated with a significantly lower 14-day mortality rate than that with other antibiotics with in vitro activity against ESBL-producing bacteria (4.8% versus 27.6%; P = 0.012) [37]. Kang et al. showed that among 133 episodes of bacteraemia due to ESBL-producing E. coli and K. pneumoniae, the 30-day mortality rate was 25.6% (34 of 133). The carbapenemand ciprofloxacin-treated groups had lower mortality rates although statistical significance was not reached (P = 0.128 and 0.164, respectively) [38]. 5. Metallo -lactamases-producing Gram-negative pathogens Since the first report of metallo -lactamase (MBL)producing P. aeruginosa from Japan in 1991, MBLproducing organisms have been reported worldwide [39,40]. For these organisms, there is significantly less to offer in the way of treatment, depending on the susceptibility pattern of the organism to fluoroquinolones, tetracyclines, aminoglycosides, aztreonam and colistin. At present, colistin is the preferred agent for the empirical treatment of MBL-producing pathogens. Recently, there have been many reports on the efficacy of colistin in patients with infections caused by MDR organisms. Karabinis et al. described a case of septic shock due to K. pneumoniae that was resistant to all available antibiotics (MIC of imipenem, 32 g/mL), including carbapenems, and that was successfully treated with colistin [41]. Garnacho-Montero et al. observed that colistin seemed to be a safe and effective (cure rate: 57%) alternative to imipenem for the management of VAP due to carbapenem-resistant strains of Acinetobacter baumannii [42]. An in vitro study observed that tigecycline is active against Gram-negative MDR pathogens. Pach´on-Ib´anez et al. determined the in vitro activities of tigecycline and imipenem against 49 isolates of A. baumannii, including those resistant to imipenem. The
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MIC50 and MIC90 for tigecycline and imipenem were 2 and 2 mg/L, and 32 and 128 mg/L, respectively, with 92 and 20%, respectively, of the strains being susceptible [43].
6. Appropriate and inappropriate antimicrobial therapy Initial inappropriate empirical therapies, and the subsequent need to modify them, substantially increase the mortality risk. Alvarez-Lerma showed that among 490 episodes of pneumonia acquired in the ICU setting, 214 episodes (43.7%) required modification of the initial antibacterial regimen as a result of either isolation of a resistant micro-organism (62.1%), or lack of clinical response to therapy (36.0%). Mortality from VAP was significantly lower among patients receiving initial, appropriate antibacterial therapy than among patients receiving initial inappropriate therapy requiring a treatment change (16.2% versus 24.7%; P = 0.034) [44]. Leibovici et al. showed that mortality associated to sepsis is significantly higher in inappropriately treated patients compared to patients to whom an appropriate antibiotic therapy was administered (20% versus 34%) [45]. Luna et al. showed a significant difference, in terms of mortality, between patients affected by nosocomial pneumonia treated with appropriate or inappropriate therapy (37.5% versus 91.2%) [46]. However, Kollef highlighted that the mortality risk remains high even if the initial empiric therapy is followed by change of therapy focused on the basis of microbiological results [47]. Rello et al., utilising multivariate analysis, have demonstrated that in patients with VAP, previous administration of antibiotics increases the mortality risk due to a higher incidence of antibiotic resistance [48]. In a recent trial, MacArthur et al. reported, in a population of 2634 patients treated for suspected sepsis, a significant difference in mortality between patients receiving adequate therapy compared to inadequate therapy (P < 0.001) [49]; similar results were observed by Behrendt et al. concerning
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mortality due to sepsis (16% versus 28%, P < 0.001) [50]. Another paper underlines the extent to which MRSA can influence the mortality rate as a result of inappropriate therapy (mortality associated with MRSA equal to 21% versus 8% associated to MSSA strains) [51]. The possible risk factors for inappropriate therapy in sepsis were recently investigated by Ibrahim et al. [52]. This included infections caused by Candida spp., previous administration of antibiotics during the hospital stay, presence of a central venous catheter and a low serum albumin concentration on ICU admission. The author reported a higher incidence of inappropriate antibiotic therapy when infections were caused by antibiotic-resistant micro-organisms. In such a scenario, several strategies have been suggested to improve the cure rate and to minimise the development of resistance such as the infectious disease specialist (IDS) consultation.
7. Role of the infectious disease specialist Several studies have shown the profound impact that IDS consultation can have on the management of severe bacterial infections. In a recent study conducted by ourselves in Italy by interviews with 200 doctors practising in Haematology, Surgery, ICU, Internal Medicine and Infectious Diseases wards (40 interviews in each ward), and addressed to ascertain the management of patients affected by severe bacterial infections, the interviewed specialists stated, in 29.2% of cases, that an IDS consultation was an effective strategy for reducing inappropriate antibiotic therapy (Fig. 1). The influence of the IDS was clearly shown by Byl in a clinical study of 428 episodes of bacteraemia. Empirical treatment was appropriate in 63% of the episodes, but dividing them into episodes treated, or not treated, by the IDS resulted in a significant increase (P < 0.001) for those treated by IDS (78% versus 54%). After the availability of blood culture results, the proportion of appropriate treatments increased to 94%, with 97% for IDS-managed patients and 89% for
Fig. 1. Efficacious strategies to reduce inappropriate antibiotic therapy.
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other patients (P = 0.008). IDSs more frequently changed treatment to oral antibiotics and used fewer broad-spectrum drugs. In this study the appropriateness of empirical treatment was associated with a decrease in infection-related mortality for patients without initial shock (P = 0.017) [53]. Similar results were observed by Fowler et al. who evaluated the impact of the infectious disease specialist on the management of 122 cases of sepsis caused by S. aureus. In this study, patients for whom IDS recommendations were followed were more likely to be cured of their S. aureus infection and less likely to relapse (P < 0.01), despite having significantly more metastatic infections (P < 0.01) at the outset of therapy, than were those for whom recommendations were not followed [54]. Borer et al. observed the impact of regular attendance by an IDS on the management of hospitalised adult patients with community-acquired febrile syndromes. The study was conducted on 402 consecutive febrile adults randomly admitted to one of two internal medicine wards (in ward 1, patients were attended by an IDS, whereas those in ward 2 were attended by physicians from other specialties). Overall, 160 patients were treated in ward 1 and 242 in ward 2. In this study the authors showed that ward 1 patients were significantly more likely to receive appropriate antibiotic therapy compared to ward 2 patients (55.5% versus 43%; P = 0.012). The investigator was of the opinion that an alternative agent should have been given for clinical or economic reasons in 36 and 45% of ward 1 and ward 2 patients, respectively (P = 0.06), and for pharmacological reasons in 6.2 and 8.3% of patients, respectively (P = 0.28). In this study, regular attendance by an IDS resulted in significantly higher rates of accurate diagnosis (24% versus 36%; P = 0.005) [55]. Fluckiger et al. examined the influence of IDS consultation on the antibiotic treatment of 103 patients with bloodstream infections at a Swiss hospital. Optimal antibiotic management was assessed at the time that blood culture results were reported to be positive. ID specialists more frequently switched from a broad-spectrum to a narrowspectrum antimicrobial agent when results of cultures became available (P < 0.001), the empirical therapy they had prescribed was assessed as appropriate more often than was that prescribed by non-ID specialists (P < 0.003). Finally, non-ID physicians misinterpreted the positive culture results for three patients who needed several additional days of hospitalisation [56]. Lemmen et al. evaluated the role of an infectious disease consulting service in a large tertiary university hospital in the management of antibiotic therapy. During a 6-month prospective intervention period, 513 patients out of 3528 (14.5%) underwent an antibiotic course which was evaluated as adequate in 394 cases (76.8%). Inappropriateness was attributable to an inadequate antimicrobial choice in 72 out of 119 cases (60.5%) and to no indication for treatment in 38 out of 119 cases (32%). Pathogen-specific antibiotic therapies were inappropriate significantly more often than the empirical ones (P < 0.001). No increase in infection-
related mortality or length of stay was observed [57]. By assessing the influence of the IDS’s consultation on antibiotic prescription in a neurological intensive care unit, the same authors revealed that such a service allows a significant decrease in isolation of Stenotrophomonas maltophilia (P < 0.05), Enterobacter cloacae (P < 0.05), multiresistant P. aeruginosa (P < 0.05) and Candida spp. (P < 0.05), without any change in the infection control guidelines [58].
8. Conclusions In our opinion future strategies for antimicrobial use in the ICU should be based on: 1. More potent (and not necessarily broader-spectrum) antimicrobial agents given at the outset of therapy. 2. Appropriate doses, dosing intervals and duration of antibiotic treatment. 3. Closer collaboration between the medical staff in the ICU wards and the infectious disease specialist, who can bridge the gap between available guidelines and the individual needs of the patient, thereby improving the ‘decisionmaking process’.
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[53] Byl B, Clevenbergh P, Jacobs F, et al. Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia. Clin Infect Dis 1999;29:60–6. [54] Fowler VG, Sanders LL, Sexton DJ, et al. Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious disease specialist: experience with 244 patients. Clin Infect Dis 1998;27:478–86. [55] Borer A, Gilad J, Meydan N. Impact of regular attendance by infectious disease specialists on the management of hospitalised adults with community-acquired febrile syndromes. Clin Microbiol Infect 2004;10:911–6.
[56] Fluckiger U, Zimmmerli W, Sax H, et al. Clinical impact of an infectious disease service on the management of bloodstream infection. Eur J Clin Microbiol Infect Dis 2000;19:493–500. [57] Lemmen SW, Becker G, Frank U, Daschner FD. Influence of an infectious disease consulting service on quality and costs of antibiotic prescriptions in a university hospital. Scand J Infect Dis 2001;33:219–21. [58] Lemmen SW, Hafner H, Kotterik S, Lutticken R, Topper R. Influence of an infectious disease service on antibiotic prescription behaviour and selection of multiresistant pathogens. Infection 2000;28: 384–7.
Review
Antimicrobial treatment for Intensive Care Unit (ICU) infections including the role of the infectious disease specialist Silvano Esposito ∗ , Sebastiano Leone Department of Infectious Diseases, Second University of Naples, Naples, Italy Received 24 October 2006; accepted 24 October 2006
Abstract Between 5 and 10% of patients admitted to acute care hospitals acquire one or more infections, and the risks have steadily increased during recent decades. Three types of infection account for more than 60% of all nosocomial infections: pneumonia, urinary tract infection and primary bloodstream infection, all of them associated with the use of medical devices. Nearly 70% of infections are due to micro-organisms resistant to one or more antibiotics (multidrug resistant or MDR). A higher incidence of inappropriate antibiotic therapy is expected when infections are caused by antibiotic-resistant micro-organisms and initial inappropriate empirical therapies, and the further need to modify them substantially increases the mortality risk. Despite new antibacterial agents such as linezolid, and also tigecycline and daptomycin, now being available for the treatment of infections due to MDR micro-organisms, the best strategy for improving the cure rate and minimising the development of resistance, probably remains the infectious disease specialist consultation. © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: ICU infections; Antibiotic therapy; Appropriate and inappropriate therapy; Infectious disease specialist
1. Introduction Nosocomial infections (NIs) are today by far the commonest complications affecting hospitalised patients. Currently, 5–10% of patients admitted to acute care hospitals acquire one or more infections, and the risks have steadily increased during recent decades [1,2]. Although representing only 5–15% of hospital beds, Intensive Care Units (ICUs) account for 10–25% of healthcare costs, corresponding to 1–2% of the gross national product of the United States. NIs affect more than two million persons annually in the United States and involve 5–35% of patients who are admitted to ICUs [3]. Three types of infection account for more than 60% of all nosocomial infections: pneumonia (usually ventilatorassociated), urinary tract infection (UTI) (usually catheterassociated) and primary bloodstream infection (BSI) (usually associated with the use of an intravascular device) [4]. Richards et al. observed that in patients with pneumo∗
Corresponding author. Tel.: +39 081 566 62 18; fax: +39 081 566 62 03. E-mail address: [email protected] (S. Esposito).
nia, Staphylococcus aureus (17%) was the most frequently reported isolate, and of reported isolates, 59% were Gramnegative bacilli; in patients with UTIs, Escherichia coli (19%) was the most frequently reported organism; in patients with primary BSIs, coagulase-negative staphylococci (39%) were the commonest pathogens reported; S. aureus (12%) was as frequently cultured as enterococci (11%) [4]. Up to 70% of infections are due to micro-organisms resistant to one or more antibiotics [3]. A large study, conducted by the National Nosocomial Infections Surveillance (NNIS) comparing the resistance rates of micro-organisms collected in the period January–December 2003 with those collected in 1998–2002, has established a continuous increasing incidence of antibiotic resistance [5]. The study reported a 20, 15 and 9% increase in Pseudomonas aeruginosa strains resistant to third-generation cephalosporins, imipenem and quinolones, respectively. The proportion of S. aureus isolates resistant to methicillin (MRSA), oxacillin or nafcillin continuously increased, and was nearly 60%. E. coli and Klebsiella pneumoniae resistant to third-generation cephalosporins and
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aztreonam were 5.8 and 20.6%, respectively. However, the rate of increase of antibiotic resistance has diminished for several pathogens, including vancomycin-resistant enterococci, which was reported as 31% in 2000 compared with 12% in 2003. This review will briefly discuss the clinical relevance of antimicrobial resistance and therapeutic options for treatment of NIs in ICUs.
2. Methicillin-resistant staphylococci Methicillin-resistant S. aureus was first described in 1961 and has become a worldwide problem [6]. MRSA is currently the most commonly identified antibiotic-resistant pathogen in US hospitals, and contributes significantly to patient morbidity and mortality [7]. Cosgrove et al. performed a meta-analysis to summarise the impact of methicillin resistance on mortality in S. aureus bacteraemia. The authors described 31 studies on a total of 3963 patients with S. aureus bacteraemia. Analysis showed a significant increase in mortality associated with MRSA bacteraemia (OR, 1.93; 95% CI, 1.54–2.42; P < 0.001) [8]. In another meta-analysis, Whitby et al. observed that bacteraemia caused by MRSA was associated with significantly higher mortality rates than bacteraemia caused by methicillin-sensitive S. aureus (MSSA) (29% versus 12%; P < 0.001) [9]. Melzer et al. observed that the proportion of patients whose death was attributable to MRSA was significantly higher than that for MSSA (11.8% versus 5.1%; OR, 2.49; 95% CI, 1.46–4.24; P < 0.001) [10]. Recently, Zahar et al. observed similar results in ventilatorassociated pneumonia (VAP) due to MRSA. The authors showed that the crude hospital mortality rate was higher for MRSA-infected patients than for MSSA-infected patients (59.4% versus 40%; P = 0.024) [11]. The current drugs of choice for MRSA infections remain glycopeptides, as only very few reports have shown resistance to these antimicrobial agents among staphylococci [12,13]. Despite the high in vitro activity of glycopeptides against staphylococci, Nathwani has observed, in an editorial concerning the role of vancomycin in the therapy of lower respiratory tract infections (LRTIs) due to S. aureus, that glycopeptides may be less effective. The author suggested that pharmacokinetic/pharmacodynamic parameters can be the basis of poor efficacy of vancomycin in the treatment of nosocomial LRTIs. In particular, in nosocomial MRSA pneumonia, MIC values of MRSA make it unlikely that the AUC/MIC value is greater than 125, although the MBC of this organism may be considerably higher than the MIC [14]. New agents with activity against MRSA have been developed recently. Linezolid is the first member of a structurally unique class of antibiotics, the oxazolidinones. This drug has demonstrated activity against Gram-positive organisms resistant to other antimicrobial agents, including MRSA [15]. The clinical efficacy of linezolid as part of a broader empiric regi-
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men for hospital acquired pneumonia (HAP) was analysed in a multinational, randomised, double-blind trial that compared it with vancomycin. The clinical response rate was 53.4% in the linezolid group and 52.1% in the vancomycin group. Microbiological success rates were also similar (67.9% in the linezolid group versus 71.8% in the vancomycin group) [16]. Similar results were observed by Stevens et al. in a randomised, open-label trial comparing linezolid and vancomycin for the treatment of hospitalised adults with known or suspected MRSA infections. This author reported similar clinical and microbiological success rate in the two groups [17]. Quinupristin/dalfopristin (Q/D) exhibits good in vitro activity against MRSA. For the treatment of Gram-positive nosocomial pneumonia, Q/D was found to be equivalent to vancomycin. Clinical success rates among the microbiologically evaluable patients infected with MRSA did not differ between the two treatment groups [18]. New antibacterial agents include tigecycline and daptomycin, but there are no available clinical data for the treatment of ICU infections with these agents. Tigecycline is bacteriostatic against most pathogens but has a broad spectrum of antimicrobial activity and has enhanced penetration into many tissues. Fritsche et al. assessed the antimicrobial activity of tigecycline against organisms causing HAP. S. aureus (49.4% MRSA) was readily inhibited by tigecycline (MIC50 and MIC90 , 0.25 and 0.5 g/mL, respectively) with all strains being inhibited by <1 g/mL [19]. Daptomycin is a lipopeptide antimicrobial that is rapidly bactericidal against S. aureus. It is effective in the therapy of S. aureus bloodstream infections but is inactivated by pulmonary surfactant, making it ineffective in the therapy of pneumonia. Several microbiological studies suggest that the breakpoint of daptomycin should be less than 1 g/mL for S. aureus (both MRSA and MSSA) [20,21].
3. Vancomycin-resistant enterococci Vancomycin-resistant enterococci (VRE) have emerged as important nosocomial pathogens. VRE were first described in 1987 in Europe, and within 10 years VRE were among the most feared pathogens in US hospitals. Studies dealing with the emergence of VRE in the United States revealed that most patients with VRE were in ICUs [22]. The clinical impact of vancomycin resistance among patients with VRE infections is a controversial issue. In a study comparing the prognosis of patients with VRE versus VSE bacteraemia, clinical failure was higher for patients with VRE bacteraemia (60% versus 40%, P < 0.001) [23] but some studies have failed to demonstrate a statistically significant association between vancomycin resistance and mortality [24]. DiazGranados et al. performed a systematic literature review with a meta-analysis to analyse the impact of vancomycin resistance on mortality in VRE bacteraemias. The authors described nine studies including a total of 1612
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enterococcal BSIs episodes. Analysis of the data showed that VRE patients were more likely to die than were those with VSE bacteraemia (OR, 2.52; 95% CI, 1.9–3.4) [25]. Enterococci are intrinsically resistant to multiple antimicrobial agents. The therapeutic options for VRE infections are therefore very limited (fosfomycin, nitrofurantoin, fluoroquinolones, doxycycline and chloramphenicol). Teicoplanin is active in vitro against VanB and VanC enterococci [26]. Two classes of antibiotic have been specifically approved for the treatment of VRE infections: the streptogramins and the oxazolidinones. Quinupristin/dalfopristin (Q/D) has proved effective for treatment of VRE infections due to Enterococcus faecium, whereas Enterococcus faecalis is intrinsically resistant. Clinical response rates with Q/D were 60–70% in patients with bacteraemia [27]. Linezolid has almost uniform activity against enterococci, with MICs of 1–4 g/mL in one study of 180 isolates of various enterococcal species, regardless of vancomycin susceptibility [28]. Initial clinical trials have shown that the drug has efficacy that is probably at least as good as that of Q/D, with fewer adverse reactions [29]. New agents for the treatment of VRE infections are daptomycin and tigecycline. In a worldwide surveillance study, daptomycin was shown to be active against all strains of vancomycin-resistant enterococci [30]. Tigecycline is active against all species of enterococci. Against Enterococcus faecalis and Enterococcus faecium, MIC90 values were 0.12 mg/L for both vancomycin-susceptible and -resistant strains [31]. 4. Extended-spectrum -lactamase (ESBL) Gram-negative pathogens The first reports of ESBLs in Gram-negative bacilli came from Europe and were followed quickly by reports in the United States. This type of antimicrobial resistance is now recognised worldwide. The influence of ESBL production on clinical outcome is a controversial issue. Several studies found no significant association between ESBL production and treatment failure or crude mortality [32]. In contrast, Lautenbach et al., in a case-control study, observed that ESBL-producing E. coli or K. pneumoniae infections were associated with a significantly longer duration of hospital stay and greater hospital costs (P = 0.01 and P < 0.001, respectively). Mortality attributable to infection was greater in case patients than in control patients (15.2% versus 9.1%; OR, 1.91; 95% CI, 0.49–7.42; P = 0.35) [33]. Ariffin et al. found that the overall sepsis-related mortality was significantly higher among patients infected with ceftazidime-resistant K. pneumoniae than among patients infected with ceftazidimesusceptible K. pneumoniae (50.0% versus 13.3%) [34]. A study on bloodstream infections caused by ESBL-producing organisms showed that mortality was considerably higher among patients infected with ESBL-producing strains than among patients infected with non-ESBL-producing strains (24% versus 2%, respectively), and, at the end of therapy, the
favourable response rate was 53% among patients infected with ESBL-producing strains who received cephalosporin therapy, and 94% among patients infected with non-ESBLproducing strains [35]. Similar results were reported by other authors. For example, an international study conducted by Paterson showed that failure rates exceed 50% when cephalosporins (apparently susceptible in vitro) were used to treat patients with severe infections caused by ESBLproducing Klebsiella spp. [36]. The presence of ESBL-producing Enterobacteriaceae complicates therapy, particularly as these organisms are often multidrug resistant. Current FDA-approved treatment options for ESBLproducing organisms include carbapenems, cefepime, aminoglycosides and fluoroquinolones. Despite their in vitro activity, -lactam/-lactamase inhibitor combinations do not have FDA approval for treating infections caused by ESBLproducing pathogens. Carbapenems are generally considered the most reliable agents. Paterson et al. showed that a carbapenem (primarily imipenem) was associated with a significantly lower 14-day mortality rate than that with other antibiotics with in vitro activity against ESBL-producing bacteria (4.8% versus 27.6%; P = 0.012) [37]. Kang et al. showed that among 133 episodes of bacteraemia due to ESBL-producing E. coli and K. pneumoniae, the 30-day mortality rate was 25.6% (34 of 133). The carbapenemand ciprofloxacin-treated groups had lower mortality rates although statistical significance was not reached (P = 0.128 and 0.164, respectively) [38]. 5. Metallo -lactamases-producing Gram-negative pathogens Since the first report of metallo -lactamase (MBL)producing P. aeruginosa from Japan in 1991, MBLproducing organisms have been reported worldwide [39,40]. For these organisms, there is significantly less to offer in the way of treatment, depending on the susceptibility pattern of the organism to fluoroquinolones, tetracyclines, aminoglycosides, aztreonam and colistin. At present, colistin is the preferred agent for the empirical treatment of MBL-producing pathogens. Recently, there have been many reports on the efficacy of colistin in patients with infections caused by MDR organisms. Karabinis et al. described a case of septic shock due to K. pneumoniae that was resistant to all available antibiotics (MIC of imipenem, 32 g/mL), including carbapenems, and that was successfully treated with colistin [41]. Garnacho-Montero et al. observed that colistin seemed to be a safe and effective (cure rate: 57%) alternative to imipenem for the management of VAP due to carbapenem-resistant strains of Acinetobacter baumannii [42]. An in vitro study observed that tigecycline is active against Gram-negative MDR pathogens. Pach´on-Ib´anez et al. determined the in vitro activities of tigecycline and imipenem against 49 isolates of A. baumannii, including those resistant to imipenem. The
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MIC50 and MIC90 for tigecycline and imipenem were 2 and 2 mg/L, and 32 and 128 mg/L, respectively, with 92 and 20%, respectively, of the strains being susceptible [43].
6. Appropriate and inappropriate antimicrobial therapy Initial inappropriate empirical therapies, and the subsequent need to modify them, substantially increase the mortality risk. Alvarez-Lerma showed that among 490 episodes of pneumonia acquired in the ICU setting, 214 episodes (43.7%) required modification of the initial antibacterial regimen as a result of either isolation of a resistant micro-organism (62.1%), or lack of clinical response to therapy (36.0%). Mortality from VAP was significantly lower among patients receiving initial, appropriate antibacterial therapy than among patients receiving initial inappropriate therapy requiring a treatment change (16.2% versus 24.7%; P = 0.034) [44]. Leibovici et al. showed that mortality associated to sepsis is significantly higher in inappropriately treated patients compared to patients to whom an appropriate antibiotic therapy was administered (20% versus 34%) [45]. Luna et al. showed a significant difference, in terms of mortality, between patients affected by nosocomial pneumonia treated with appropriate or inappropriate therapy (37.5% versus 91.2%) [46]. However, Kollef highlighted that the mortality risk remains high even if the initial empiric therapy is followed by change of therapy focused on the basis of microbiological results [47]. Rello et al., utilising multivariate analysis, have demonstrated that in patients with VAP, previous administration of antibiotics increases the mortality risk due to a higher incidence of antibiotic resistance [48]. In a recent trial, MacArthur et al. reported, in a population of 2634 patients treated for suspected sepsis, a significant difference in mortality between patients receiving adequate therapy compared to inadequate therapy (P < 0.001) [49]; similar results were observed by Behrendt et al. concerning
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mortality due to sepsis (16% versus 28%, P < 0.001) [50]. Another paper underlines the extent to which MRSA can influence the mortality rate as a result of inappropriate therapy (mortality associated with MRSA equal to 21% versus 8% associated to MSSA strains) [51]. The possible risk factors for inappropriate therapy in sepsis were recently investigated by Ibrahim et al. [52]. This included infections caused by Candida spp., previous administration of antibiotics during the hospital stay, presence of a central venous catheter and a low serum albumin concentration on ICU admission. The author reported a higher incidence of inappropriate antibiotic therapy when infections were caused by antibiotic-resistant micro-organisms. In such a scenario, several strategies have been suggested to improve the cure rate and to minimise the development of resistance such as the infectious disease specialist (IDS) consultation.
7. Role of the infectious disease specialist Several studies have shown the profound impact that IDS consultation can have on the management of severe bacterial infections. In a recent study conducted by ourselves in Italy by interviews with 200 doctors practising in Haematology, Surgery, ICU, Internal Medicine and Infectious Diseases wards (40 interviews in each ward), and addressed to ascertain the management of patients affected by severe bacterial infections, the interviewed specialists stated, in 29.2% of cases, that an IDS consultation was an effective strategy for reducing inappropriate antibiotic therapy (Fig. 1). The influence of the IDS was clearly shown by Byl in a clinical study of 428 episodes of bacteraemia. Empirical treatment was appropriate in 63% of the episodes, but dividing them into episodes treated, or not treated, by the IDS resulted in a significant increase (P < 0.001) for those treated by IDS (78% versus 54%). After the availability of blood culture results, the proportion of appropriate treatments increased to 94%, with 97% for IDS-managed patients and 89% for
Fig. 1. Efficacious strategies to reduce inappropriate antibiotic therapy.
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other patients (P = 0.008). IDSs more frequently changed treatment to oral antibiotics and used fewer broad-spectrum drugs. In this study the appropriateness of empirical treatment was associated with a decrease in infection-related mortality for patients without initial shock (P = 0.017) [53]. Similar results were observed by Fowler et al. who evaluated the impact of the infectious disease specialist on the management of 122 cases of sepsis caused by S. aureus. In this study, patients for whom IDS recommendations were followed were more likely to be cured of their S. aureus infection and less likely to relapse (P < 0.01), despite having significantly more metastatic infections (P < 0.01) at the outset of therapy, than were those for whom recommendations were not followed [54]. Borer et al. observed the impact of regular attendance by an IDS on the management of hospitalised adult patients with community-acquired febrile syndromes. The study was conducted on 402 consecutive febrile adults randomly admitted to one of two internal medicine wards (in ward 1, patients were attended by an IDS, whereas those in ward 2 were attended by physicians from other specialties). Overall, 160 patients were treated in ward 1 and 242 in ward 2. In this study the authors showed that ward 1 patients were significantly more likely to receive appropriate antibiotic therapy compared to ward 2 patients (55.5% versus 43%; P = 0.012). The investigator was of the opinion that an alternative agent should have been given for clinical or economic reasons in 36 and 45% of ward 1 and ward 2 patients, respectively (P = 0.06), and for pharmacological reasons in 6.2 and 8.3% of patients, respectively (P = 0.28). In this study, regular attendance by an IDS resulted in significantly higher rates of accurate diagnosis (24% versus 36%; P = 0.005) [55]. Fluckiger et al. examined the influence of IDS consultation on the antibiotic treatment of 103 patients with bloodstream infections at a Swiss hospital. Optimal antibiotic management was assessed at the time that blood culture results were reported to be positive. ID specialists more frequently switched from a broad-spectrum to a narrowspectrum antimicrobial agent when results of cultures became available (P < 0.001), the empirical therapy they had prescribed was assessed as appropriate more often than was that prescribed by non-ID specialists (P < 0.003). Finally, non-ID physicians misinterpreted the positive culture results for three patients who needed several additional days of hospitalisation [56]. Lemmen et al. evaluated the role of an infectious disease consulting service in a large tertiary university hospital in the management of antibiotic therapy. During a 6-month prospective intervention period, 513 patients out of 3528 (14.5%) underwent an antibiotic course which was evaluated as adequate in 394 cases (76.8%). Inappropriateness was attributable to an inadequate antimicrobial choice in 72 out of 119 cases (60.5%) and to no indication for treatment in 38 out of 119 cases (32%). Pathogen-specific antibiotic therapies were inappropriate significantly more often than the empirical ones (P < 0.001). No increase in infection-
related mortality or length of stay was observed [57]. By assessing the influence of the IDS’s consultation on antibiotic prescription in a neurological intensive care unit, the same authors revealed that such a service allows a significant decrease in isolation of Stenotrophomonas maltophilia (P < 0.05), Enterobacter cloacae (P < 0.05), multiresistant P. aeruginosa (P < 0.05) and Candida spp. (P < 0.05), without any change in the infection control guidelines [58].
8. Conclusions In our opinion future strategies for antimicrobial use in the ICU should be based on: 1. More potent (and not necessarily broader-spectrum) antimicrobial agents given at the outset of therapy. 2. Appropriate doses, dosing intervals and duration of antibiotic treatment. 3. Closer collaboration between the medical staff in the ICU wards and the infectious disease specialist, who can bridge the gap between available guidelines and the individual needs of the patient, thereby improving the ‘decisionmaking process’.
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