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Strategies for managing today's infections
REVIEW Strategies for managing today’s infections Y. Carmeli Division of Infectious Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
ABSTRACT Bacterial infections are becoming more difficult to treat. At the present time c. 70% of nosocomial infections are resistant to at least one antimicrobial drug that previously was effective for the causative pathogen. Pathogens that are notorious for their virulence and ability to develop resistance include Staphylococcus aureus, Enterococcus spp., members of the Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species. Notable resistance patterns that have emerged include methicillin resistance in S. aureus, which started in the healthcare setting but has now moved into the community. Vancomycin resistance in enterococci is frequently seen, and vancomycin resistance in methicillin-resistant S. aureus is a public health threat. Resistance patterns seen in pseudomonal and Acinetobacter infections are rapidly shifting. The situation has become sufficiently serious for clinical opinion leaders to call upon governments for assistance in addressing the problem. In this worsening environment, in which patients are at progressively greater risk of untreatable infections, clear recommendations for prescribers are urgently needed. Severity of infection and underlying conditions are key issues, as patients with the most serious diseases are those in most urgent need, and improvements in our ability to predict likely infecting pathogens when empirical therapy is necessary are needed. Risk-factors and local resistance patterns must be accounted for, and initial empirical therapy should be adequately broad spectrum and adequately dosed. Agents must be highly active, able to penetrate adequately to the site of infection, safe, and well-tolerated. infection, community-acquired, empirical therapy, methicillin-resistant Staphylococcus aureus, nosocomial, Panton–Valentine leukocidin, Pseudomonas aeruginosa, resistance, review, virulence Keywords Bacterial
Clin Microbiol Infect 2008; 14 (Suppl. 3): 22–31 INTRODUCTION Although the phenomenon of drug resistance in bacterial pathogens is not new, the high prevalence of drug-resistant highly pathogenic bacteria has been unprecedented in recent years. Data on methicillin-resistant Staphylococcus aureus (MRSA), a key contributor to concern about resistant pathogens, illustrate the scope of this problem. The European Antimicrobial Resistance Surveillance System (EARSS) reported in 2005 [1] on 30 countries that submitted results for MRSA. All of the southern European countries reported high levels of MRSA (eight with rates of over 40%). Four countries (Czech Republic, Slovakia, Hungary and Corresponding author and reprint requests: Y. Carmeli, Division of Infectious Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel E-mail: [email protected] Y. Carmeli declares no conflict of interests.
Germany) with rates of MRSA below 10% in 2001 reported dramatic increases in 2005. Only seven (mainly northern countries) reported MRSA rates below 3%, although significant increases were reported for three of these: The Netherlands (from 0.34% – 0.93%), Denmark (0.28% – 1.7%), and Finland (0.95% – 2.91%). The only exceptions to this trend were France and Slovenia, both of which succeeded in consistently reducing proportions of methicillin-resistant isolates from 2001 to 2005. In the USA, the continuing increase in levels of staphylococcal resistance in hospitals remains a cause for concern. The proportion of isolates of S. aureus that were resistant to methicillin, oxacillin or nafcillin was reported as continuing to rise, and in 2004 it had reached nearly 60%. Furthermore, the hospital is not the only source of resistant pathogens, as genetically distinct MRSA strains have emerged in the community [2]. The challenge of antimicrobial resistance is not limited to MRSA. Currently, the annual incidence
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of nosocomial infections due to any resistant bacterial species in the USA is c. 1.4 million [3]. Severe infections caused by antimicrobial resistance pose obvious treatment challenges. The aim of this article is to review trends in MRSA and other resistant pathogens associated with serious infections, to discuss the characteristics of an optimal antibiotic, and to consider strategies for managing patients infected with resistant organisms. PATIENTS WITH SEVERE INFECTIONS Patients with severe infections have urgent treatment needs; thus, severe infections must be identified quickly. Severity of infection is determined by three factors: (i) host (patient) characteristics, (ii) the disease or syndrome itself, and (iii) the pathogen causing the illness (species, virulence, and susceptibility to antimicrobial agents). Populations in developed countries are ageing, and as a result, patients are increasingly elderly, more debilitated, more likely to have underlying medical conditions, and more likely to be immunosuppressed because of ageing, disease, and ⁄ or medical therapy. Increasing proportions of patients have resistant infections from institutions such as nursing homes and rehabilitation centres. Readmissions related to short hospital stays may introduce into the hospital environment large numbers of patients who have been recently treated with antibiotics [4–7]. Infectious disease syndromes that may immediately be classified as severe infection include those involving the central nervous system, bacteraemia ⁄ sepsis, hospital-acquired pneumonia, and severe soft-tissue infections. Nosocomial bloodstream infections are a major cause of death and morbidity in the USA, with an estimated quarter of a million cases annually [8]. Moreover, the numbers of such infections caused by antibiotic-resistant organisms are increasing in the USA. The nationwide Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE) survey, carried out from 1995 to 2002 in 49 US hospitals recorded 24 179 nosocomial bloodstream infections, 87% of which were monomicrobial [9]. The proportion of S. aureus species with methicillin resistance increased from 22% in 1995 to 57% in 2001. Over the course of
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the survey, vancomycin resistance was seen in 2% of Enterococcus faecalis and 60% of Enterococcus faecium isolates. PATHOGENS ASSOCIATED WITH SERIOUS INFECTIONS MRSA Along with the high prevalence of hospitalacquired MRSA in the USA and its increasing prevalence in other countries, the emergence of community-acquired MRSA infection is of public health concern, particularly because of the risk of transmission [10]. Community-acquired MRSA infections are now being reported in young and healthy individuals with no obvious risk-factors [11–13]. Most cases involve skin and soft-tissue infection, but life-threatening invasive infections such as necrotising pneumonia [14], necrotising fasciitis [15] and sepsis [16] are also being reported. In some areas, community-acquired MRSA infections have become more prevalent than community-acquired infections with methicillin-susceptible strains [10]. Characterisation of 117 community-acquired MRSA isolates from the USA, France, Switzerland, Australia, New Zealand and Western Samoa has identified genes that are unique to communityacquired organisms and are shared by isolates from all three continents (North America, Europe, and Oceania) [17]. These are a type IV SCCmec cassette (a methicillin resistance locus) and the locus for Panton–Valentine leukocidin (PVL). The PVL locus is carried on a bacteriophage and appears to represent a stable marker of community-acquired MRSA in different countries [17]. There appears to be an association between MRSA and the presence of PVL in skin and respiratory tract infections (Strauss et al., 47th ICAAC, abstract K-1092; Strauss et al., 17th European Congress of Clinical Microbiology and Infectious Diseases, abstract O120). In a series of 415 skin and soft-tissue infections (abscesses, wounds, or cellulitis) analysed for PVL expression, PVL-positive strains of MRSA (and methicillin-sensitive S. aureus) were found to be widely prevalent in deep-seated complicated skin and skin structure infections (Strauss et al., 17th European Congress of Clinical Microbiology and Infectious Diseases, abstract O120). PVL expression was significantly more likely to be
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associated with abscess formation than with nonabscess-forming deep infections (Fig. 1). PVL positivity was found to be associated with rapidly progressive, haemorrhagic, necrotising pneumonia, a disorder that mainly affects otherwise healthy children and young adults and that involves high rates of mortality [18]. Of a series of eight patients in France, six died after infection with community-acquired pneumonia caused by S. aureus carrying the PVL gene. Further analysis of eight prospective and eight retrospective cases of pneumonia caused by PVL-positive S. aureus and 36 cases associated with PVL-negative strains showed survival rates 48 h after hospital admission of 63% and 94%, respectively (p 0.007) [18]. Enterococci Enterococci are normal inhabitants of the gastrointestinal tract but may also be associated with infection [19]. In the SCOPE survey, 9% of the causative pathogens in nosocomial bloodstream infections were enterococci [9]. Most clinical laboratories report that 80%–90% of enterococci are E. faecalis, and E. faecium accounts for 5%–10% of isolates [20]. E. faecium strains expressing high levels of resistance to ampicillin emerged in the USA in the late 1980s [21]; vancomycin-resistant Enterococcus (VRE) subsequently appeared in 1989 [20]. Since that time, the incidence of VRE has continued to increase, and VRE now accounts for more than 25% of enterococcal isolates in some intensive care
Fig. 1. Association between Panton–Valentine leukocidin (PVL) gene expression in methicillin-resistant Staphylococcus aureus (MRSA) isolates and type of skin and skin structure infection in 415 S. aureus isolates analysed for PVL (Strauss et al., 17th European Congress of Clinical Microbiology and Infectious Diseases, abstract O120).
facilities [22]. A 10-year survey of enterococcal isolates at a major medical centre in Chicago that was carried out from 1993 to 2002 [23] showed a significant increase in the proportion of enterococci identified as E. faecium from 12.7% – 22.2% (p <0.001). The proportion of E. faecium isolates that were resistant to vancomycin increased from 28.9% to 72.4% (p <0.001). Pseudomonas aeruginosa P. aeruginosa is a leading nosocomial pathogen that is often associated with pneumonia, particularly in the intensive care setting [24]. In addition to pneumonia, P. aeruginosa may be associated with bacteraemia, endocarditis, exacerbation of cystic fibrosis, keratitis and traumatic endophthalmitis [25]. Neutropenic and mechanically ventilated patients are at particular risk of pseudomonal infection, and mortality rates in infected individuals exceed 30% [24]. The importance and virulence of P. aeruginosa have been stressed, with this organism remaining identifiable in respiratory samples for as long as 48 h after effective antimicrobial therapy has been initiated. In addition, type III secretory proteins are recognised as important virulence factors. The type III secretion phenotype in P. aeruginosa has been associated with worse outcomes in patients with ventilator-associated pneumonia [24]. P. aeruginosa has high inherent resistance to many drug classes, in part because of its semipermeable outer-membrane and possession of efflux systems that reduce intracellular concentrations of antimicrobial agents. Alarmingly, P. aeruginosa also frequently mutates during courses of therapy. Current treatment options are therefore limited and empirical treatments are commonly inadequate [26,27]. P. aeruginosa isolates are occasionally resistant to all antibiotics, a problem that appears to be growing with the emergence of integrins that carry gene cassettes encoding both carbapenemases and amikacin acetyltransferases [26]. Falling rates of susceptibility of P. aeruginosa to available antibacterial agents have been documented (Fig. 2). Data from the Tracking Resistance in the United States Today study, which collected 2394 isolates from 2001 to 2003, showed piperacillin–tazobactam, cefepime and ceftazidime to be the most active agents against P. aeruginosa, although susceptibility to any single agent tested
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Fig. 2. Multidrug resistance (‡3 drugs) among Pseudomonas aeruginosa isolates tested with a panel of six antibiotics in the USA, 1997–2000 [26]. Isolates were from over 250 hospitals participating in the Surveillance Network Database USA.
was below 90% [28]. Susceptibility to ciprofloxacin or levofloxacin was c. 67%, and c. 9% of isolates were multidrug-resistant. The prevalence of multidrug-resistant isolates increased from 7.2% in 2001 to 9.9% in 2003. Acinetobacter baumannii A. baumannii is also emerging as a worldwide cause of nosocomial infections. Acinetobacter spp. were generally considered to be low-virulence organisms that had been reported to increase in virulence in critically ill or immunocompromised patients [29]. Over the last decade, reports from various parts of the world have suggested that epidemic and more virulent strains of A. baumannii are spreading in hospitals [30]. Disorders with which this microorganism is associated include pneumonia, bacteraemia, meningitis and urinary tract and skin and soft-tissue infections. Isolates resistant to nearly all commercially available antimicrobial agents have been identified, and treatment options for severe A. baumannii infections are becoming limited [31,32]. CURRENT TREATMENT OPTIONS FOR MRSA The agents most commonly used to treat MRSA infections are glycopeptides. Vancomycin has been the standard treatment and, until recently, the only option for the management of patients with MRSA [33]. Unfortunately, the efficacy of this group appears to be inferior to the b-lactams and continues to diminish, with shifting MICs and increasing emergence of vancomycin-inter-
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mediate S. aureus and vancomycin-resistant S. aureus [34–36]. The emergence of these strains in addition to the spread of MRSA from the hospital to community settings has become a major cause of concern to clinicians and microbiologists. Teicoplanin is available as an alternative antiMRSA glycopeptide and has been suggested in cases where patients cannot tolerate vancomycin [37], but this agent has unpredictable pharmacokinetics, and low dosages have been associated with treatment failure [38]. Therapeutic drug monitoring for teicoplanin has been advocated but is not widely practised [38]. The novel cephalosporin ceftobiprole has shown good activity against MRSA. Patients with suspected MRSA-associated complicated skin and skin structure infections were enrolled in a double-blind, randomised study comparing ceftobiprole 500 mg twice-daily with vancomycin 1 g twice-daily in 15 countries (Strauss et al., 44th Annual Meeting of IDSA, abstract 138). Pathogens were isolated from 613 of 784 patients enrolled. S. aureus was found in 494 baseline samples, among which 190 ceftobiprole-treated and 173 vancomycin-treated cases were evaluable. MRSA was isolated in 122 (21.8%) of clinically evaluable patients, with clinical cure rates (after 7–14 days) as shown in Table 1. MRSA infections were especially prevalent in the USA; cure rates with ceftobiprole exceeded 90% and tended to be higher than US cure rates with vancomycin. Ceftobiprole has also been shown to have good activity against PVL-positive MRSA and methicillin-susceptible S. aureus (Strauss et al., 47th ICAAC, abstract K-1092). Along with glycopeptides such as vancomycin [33], current treatment options for MRSA include oxazolidinones (linezolid) [39], daptomycin [40], and the expanded-spectrum glycylcycline, tigecycline [41]. Other potential treatments are trimethoprim–sulfamethoxazole [42] and clindamycin [43]. With the exception of tigecycline, these agents have a relatively narrow spectrum of activity, which frequently leads to the need for combination therapy in the empirical setting. Some currently available agents do not always achieve the required penetration into target tissues. Vancomycin has shown poor penetration into the lungs in pharmacokinetic studies [44,45]. In addition, the drug has shown low cerebrospinal fluid penetration in infants undergoing shunt
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Population
All Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Ceftobiprole
Ceftobiprole
Vancomycin
Vancomycin
USA 92.9% (52 ⁄ 56) 85.5% (53 ⁄ 62) 92.7% (38 ⁄ 41) 85.0% (34 ⁄ 40) All countries 94.7% (180 ⁄ 190) 94.2% (163 ⁄ 173) 91.9% (57 ⁄ 62) 90.0% (54 ⁄ 60)
insertion [46], and suboptimal responses in patients with bacteraemia and endocarditis have been reported [47–49]. Daptomycin has shown poor lung tissue penetration in animal studies, in addition to inactivation by lung surfactant [50,51]. Systemic glycopeptides have also been recommended for acute cancellous bone infections, but vancomycin concentrations in cortical bone are less satisfactory [38]. The toxicity profile of current agents should also be considered when selecting treatments for patients with documented or suspected MRSA infection. The nephrotoxicity and ototoxicity of vancomycin is well-appreciated and can be a particular problem at the aggressive doses used to treat MRSA [52,53]. Using vancomycin in combination therapies to broaden the empirical spectrum has the potential to expose more patients to the risk of these toxicities. Linezolid has been investigated as an alternative to vancomycin and other older agents in patients with multidrugresistant Gram-positive infections. While this drug is generally well-tolerated, nearly 10% of 796 patients in a compassionate-use programme experienced gastrointestinal disturbances, and thrombocytopenia was seen in 7.4% of cases [39]. STRATEGIES FOR TREATING TODAY’S SERIOUS INFECTIONS The characteristics of an appropriate empirical antimicrobial therapy are described in the article by Chastre in this issue [54]. An ideal initial antibiotic should be effective against a broad range of pathogens, including resistant organisms, highly active at the site of infection (with mechanistic, pharmacokinetic and pharmacodynamic characteristics consistent with this requirement), safe and non-toxic with few adverse effects, and convenient to use. The issue of range of coverage is often used as a rationale for the initial empirical use of combination therapy in serious infections, with the com-
Table 1. Staphylococcal infections and cure rates in patients with complicated skin and skin structure infections treated with ceftobiprole 500 mg twice-daily or vancomycin 1 g twice-daily (Strauss et al., 44th Annual Meeting of IDSA, abstract 138)
bination being switched to monotherapy once culture data become available (de-escalation or step-down therapy). The rationale for the empirical use of combination antibiotics for proven or suspected bacterial infections is to ensure initial broad-spectrum coverage. Subsequently, once culture data are available, the treatment regimen could be de-escalated to focused monotherapy in which the switch agent is microbiologically appropriate for the infecting pathogen. The debate about combination therapy is ongoing, but the issue has been analysed in detail by Safdar et al. [55], who carried out a meta-analysis of 17 studies (of which five were prospective cohort studies and two were prospective, randomised trials) in patients with Gram-negative bacteraemia. Most studies used b-lactams or aminoglycosides alone and in combination. The pooled odds ratio of 0.96 indicated no benefit in terms of mortality rate for combination therapy, although the study did not assess other outcomes, such as microbiological cure and emergence of resistance. The general applicability of the finding is uncertain, as 11 of the 17 studies focused on a particular organism (five studies were on P. aeruginosa and four on Klebsiella spp.). In addition, there was considerable heterogeneity among studies, reflecting the widely varying study designs, different organisms analysed and antibiotics studied. The fact that many of the studies were observational also means that confounding factors (e.g., severity of illness; underlying disease) cannot be ruled out. Further study will be required to clarify the benefit of combination therapy. The evidence shows that failure to initially treat high-risk microbiologically documented infections appropriately is associated with increased rates of mortality and morbidity [56]. Risk stratification should therefore be employed to identify patients at high risk of infection with resistant strains of bacteria (e.g., patients with prior antibiotic treatment during hospitalisation, prolonged stay in hospital and invasive devices); indeed, this
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approach may be considered to be pre-emptive. Expert opinion in the USA suggests that such high-risk patients should be treated with combination therapy designed to cover most pathogens likely to be implicated in any infection in the setting in question, with de-escalation being thought of as a strategy to balance the need for appropriate initial therapy with the avoidance of unnecessary antibiotic utilisation [56]. When prescribing antimicrobial therapy for patients with infections, the clinician must take commonly encountered resistant organisms into account. Risk-factors for MRSA that prescribers must be alert to include those common to all S. aureus infections such as skin pathology (e.g., wounds or dermatitis) and needle use (as in patients with diabetes, those needing dialysis, and those with intravenous catheters). Those specific to MRSA include prolonged hospitalisation, contact with healthcare institutions, proximity to an MRSA carrier, and prior treatment with certain antibiotics [57–60]. A case-control study carried out in 121 patients with MRSA and 123 patients with methicillin-susceptible S. aureus showed factors independently associated with MRSA infection to be previous hospitalisation, longer length of stay before infection, previous surgery, enteral feeding, macrolide use and levofloxacin use [61]. The epidemiology of MRSA and especially community-acquired MRSA is evolving rapidly. Previously, risk-factors for MRSA in the community were well-defined and included a history of prolonged hospitalisation, prior admission to a nursing home or other long-term care facility, and injectable drug use [57–59]. But communityacquired MRSA infections are now being reported in specific populations of young and healthy individuals associated with no obvious risk factors, such as professional football players and children [11–13]. Other specific populations that have been identified as being at risk for community-acquired MRSA from other studies include injection drug users, those with prior endocarditis, those with hospitalisation within the previous year, sports participants, incarcerated persons, military recruits, and a number of distinct ethnic populations, including Alaskan natives, Native Americans, and Pacific Islanders [57,59]. Findings from the Minnesota Department of Health provide an important perspective on the
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risk of community-acquired MRSA infection. A prospective study analysed all MRSA infections identified in 2000 at 12 laboratories in a sentinel surveillance network [60]. Of 1100 infections, 131 (12%) were community-acquired MRSA infections. Skin and soft-tissue infections were more common in community-associated infections than in those associated with healthcare settings, and most cases of community-acquired MRSA were initially treated with antibiotics to which they were not susceptible. Notably, the Minnesota laboratories also found that community-acquired MRSA isolates had distinct exotoxin genes (e.g., PVL) and antimicrobial susceptibility profiles (Table 2). These findings suggest strongly that any person presenting to a hospital emergency room with a skin or skin structure infection in the USA should be suspected of having communityacquired MRSA. Community-acquired MRSA may be a common cause of bacteraemia. A study by Huang et al. of antimicrobial resistance in hospitals in San Francisco County from 1996 through 1999 showed high rates of MRSA bacteraemia detected at admission and during the first day of hospitalisation; these rates were as high or higher than those detected upon or 2 weeks after admission (Fig. 3), which would presumably be nosocomial infections [62]. Table 2. Antimicrobial susceptibility of community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus isolates in Minnesota for the year 2000. Adapted with permission [60]. Drugs showing statistically significant differences (p £0.001) between community- and healthcare-associated isolates are highlighted in bold Percentage of isolates susceptible
Antibiotic Methicillin Ciprofloxacin Clindamycin Erythromycin Gentamicin Rifampicin Tetracycline Trimethoprim– sulfamethoxazole Vancomycin
Communityassociated (n = 106)
Healthcareassociated (n = 211)
0 79 83 44 94 96 92 95
0 16 21 9 80 94 92 90
100
100
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Fig. 3. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) isolates obtained from blood samples by hospital day of admission from a study of San Francisco County hospitals from 1996 to 1999. Reproduced with permission [62].
MRSA infection may be predictable at the individual patient level on the basis of endemic status. Two studies in patients with skin and softtissue infections carried out in 2003 in the USA and Canada encouraged inclusion of persons with MRSA. The respective proportions of patients with MRSA were 65% and 79%, with physicians’ predictions of this type of infection having a positive predictive value of 68%. The most common reasons for suspecting MRSA were high prevalence in the community (67%) and prior MRSA infection (23%). In a further study in which suspected MRSA constituted grounds for exclusion, the proportion of MRSA infections was reported to be 46%, with a physicians’ negative predictive value of 64% by (Carmeli et al., 45th ICAAC, abstract L-1574). The dynamic epidemiological picture of S. aureus and MRSA requires healthcare providers to be constantly aware of current epidemiological trends, which include local and regional patterns and global migration of specific strains [63]. Consequences of treatment delay Inappropriate or delayed treatment in patients with severe infections has serious implications for patient outcomes. The classic 1985 study by Bodey et al. was a retrospective review of 410 cases of Pseudomonas bacteraemia in patients with cancer that illustrates this point [64]. Pseudomonas bacteraemia was most common among patients with acute leukaemia; most patients had acquired their infections in hospital, and 51% had received
antibiotics for other infections during the preceding week. Shock was documented in 33% of patients, and 32% had concomitant pneumonia. The overall cure rate was 62%. The importance of appropriate therapy was apparent: a cure rate of 67% was noted in patients who received appropriate antibiotics, but this dropped to only 14% in those who did not receive appropriate antimicrobial therapy. Moreover, a 1- to 2-day delay in the administration of appropriate antibiotic therapy reduced the cure rate from 74% – 46%. Patients who received an anti-pseudomonal b-lactam, with or without an aminoglycoside, had significantly higher cure rates than those who received an aminoglycoside only (72% and 71% vs. 29%). More recent studies of the detrimental effects of delay of appropriate antimicrobial treatment are reviewed in the articles by Davey and Chastre in this issue [54,65]. These studies show that treatment delay leads to treatment failure and to increases in rates of morbidity and mortality and thus must be avoided. ADDITIONAL STRATEGIC ISSUES A need to improve physician awareness of the effect of prompt and effective diagnosis on the likelihood of successful therapy when using antibiotics in an environment in which drugresistant microorganisms are becoming more prevalent is apparent. As highlighted earlier in the present review, appropriate and adequate therapy at the earliest opportunity avoids treatment delay and dramatically increases the probability of successful eradication of infection. Appropriate sample cultures are needed as soon as possible in order to inform treatment decisions after initial empirical therapy. Indeed, times to diagnosis must be shortened; in particular, faster delivery of samples to laboratories, more rapid processing times and quicker reporting are all simple means by which delivery of effective treatment can be hastened. Some individualisation of treatment decisions is also required. Formulaic treatment plans (where an infection type is directed towards a fixed treatment type) may be over-simplistic and may not provide solutions in this complex setting. Severity of infection must be considered, together with likely infecting pathogens (based on identifiable risk-factors as discussed earlier) and what is known about local resistance
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patterns. Adoption of de-escalation therapy allows clinicians to initiate therapy with a broad-spectrum antibiotic and follow with focused treatment once culture data become available. If implemented successfully, these measures would be expected to improve patient outcomes by decreasing rates of mortality, preventing organ dysfunction, decreasing length of stay, decreasing costs, and possibly reducing overall antibiotic pressure. Use of escalation therapy, whereby treatments are ‘stepped up’, is likely to delay the use of appropriate and adequate treatment, the principles of which involve the use of highly active agents, achievement of appropriate levels of antibacterial agent at the infection site, and use of agents known to act effectively at the target site without risk of inactivation or premature elimination. CONCLUSION Resistant, virulent pathogens have emerged over the last decades in healthcare settings and in the community, in many parts of the world; some resistant species, such as MRSA, have reached endemic levels. The prevalence of these pathogens, changes in healthcare settings, new findings on the mechanisms of development of resistance and the availability of new antimicrobial agents call for adaptation of treatment strategies to improve patients’ outcomes. Antibiotic selection pressure should be minimised without compromising patients’ outcomes. Thus, choice of empirical therapy should be individualised and take into consideration the clinical syndrome, the affected patient’s medical history, the suspected organisms, and the severity of the infection. The patient’s risk of infection with a resistant organism should be considered on the basis of past exposures, co-morbid conditions, and the local epidemiology. Decisions regarding antimicrobial therapy should also take into account safety and tolerability. REFERENCES 1. EARSS. EARSS annual report 2005. Bilthoven, The Netherlands, December 2006. http://www.rivm.nl/earss/Images/EARSS%202005_tcm61-34899.pdf 2. Moran GJ, Krishnadasan A, Gorwitz RJ et al. Methicillinresistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355: 666– 674.
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R, eds. Principles and practice of infectious diseases, 5th edn. New York: Churchill Livingstone, 2000: 2147–2152. Rice LB. Emergence of vancomycin-resistant enterococci. Emerg Infect Dis 2001; 7: 183–187. NNIS. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2003, issued August 2003. Am J Infect Control 2003; 31: 481–498. Treitman AN, Yarnold PR, Warren J, Noskin GA. Emerging incidence of Enterococcus faecium among hospital isolates (1993 to 2002). J Clin Microbiol 2005; 43: 462–463. Garau J, Gomez L. Pseudomonas aeruginosa pneumonia. Curr Opin Infect Dis 2003; 16: 135–143. Giamarellou H. Therapeutic guidelines for Pseudomonas aeruginosa infections. Int J Antimicrob Agents 2000; 16: 103– 106. Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 2002; 34: 634–640. Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS. Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culturepositive pneumonia. Chest 2005; 128: 3854–3862. Karlowsky JA, Jones ME, Thornsberry C, Evangelista AT, Yee YC, Sahm DF. Stable antimicrobial susceptibility rates for clinical isolates of Pseudomonas aeruginosa from the 2001–2003 tracking resistance in the United States today surveillance studies. Clin Infect Dis 2005; 40 (suppl 2): S89– S98. Bergogne-Berezin E, Towner KJ. Acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev 1996; 9: 148–165. Abbo A, Carmeli Y, Navon-Venezia S, Siegman-Igra Y, Schwaber MJ. Impact of multi-drug-resistant Acinetobacter baumannii on clinical outcomes. Eur J Clin Microbiol Infect Dis 2007; 26: 793–800. Scheetz MH, Qi C, Warren JR et al. In vitro activities of various antimicrobials alone and in combination with tigecycline against carbapenem-intermediate or -resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2007; 51: 1621–1626. Jain R, Danziger LH. Multidrug-resistant Acinetobacter infections: an emerging challenge to clinicians. Ann Pharmacother 2004; 38: 1449–1459. Wunderink RG, Rello J, Cammarata SK, Croos-Dabrera RV, Kollef MH. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003; 124: 1789–1797. Appelbaum PC. The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. Clin Microbiol Infect 2006; 12 (suppl 1): 16–23. Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol 2006; 44: 3883–3886. Awad SS, Elhabash SI, Lee L, Farrow B, Berger DH. Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy. Am J Surg 2007; 194: 606–610. Rayner C, Munckhof WJ. Antibiotics currently used in the treatment of infections caused by Staphylococcus aureus. Intern Med J 2005; 35 (suppl 2): S3–S16.
38. Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006; 57: 589–608. 39. Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis 2003; 36: 159–168. 40. Fowler VG Jr, Boucher HW, Corey GR et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355: 653–665. 41. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 doubleblind phase 3 comparison studies with vancomycin–aztreonam. Clin Infect Dis 2005; 41 (suppl 5): S341–S353. 42. Grim SA, Rapp RP, Martin CA, Evans ME. Trimethoprim– sulfamethoxazole as a viable treatment option for infections caused by methicillin-resistant Staphylococcus aureus. Pharmacotherapy 2005; 25: 253–264. 43. Martinez-Aguilar G, Hammerman WA, Mason EO Jr, Kaplan SL. Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus in children. Pediatr Infect Dis J 2003; 22: 593–598. 44. Cruciani M, Gatti G, Lazzarini L et al. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother 1996; 38: 865–869. 45. Scheetz MH, Wunderink RG, Postelnick MJ, Noskin GA. Potential impact of vancomycin pulmonary distribution on treatment outcomes in patients with methicillin-resistant Staphylococcus aureus pneumonia. Pharmacotherapy 2006; 26: 539–550. 46. Fan-Havard P, Nahata MC, Bartkowski MH, Barson WJ, Kosnik EJ. Pharmacokinetics and cerebrospinal fluid (CSF) concentrations of vancomycin in pediatric patients undergoing CSF shunt placement. Chemotherapy 1990; 36: 103–108. 47. Deresinski S. Counterpoint: vancomycin and Staphylococcus aureus—an antibiotic enters obsolescence. Clin Infect Dis 2007; 44: 1543–1548. 48. Drees M, Boucher H. New agents for Staphylococcus aureus endocarditis. Curr Opin Infect Dis 2006; 19: 544–550. 49. Stevens DL. The role of vancomycin in the treatment paradigm. Clin Infect Dis 2006; 42 (suppl 1): S51–S57. 50. Paterson DL. Clinical experience with recently approved antibiotics. Curr Opin Pharmacol 2006; 6: 486–490. 51. Schmidt-Ioanas M, de Roux A, Lode H. New antibiotics for the treatment of severe staphylococcal infection in the critically ill patient. Curr Opin Crit Care 2005; 11: 481–486. 52. Jeffres MN, Isakow W, Doherty JA, Micek ST, Kollef MH. A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia. Clin Ther 2007; 29: 1107–1115. 53. Begg EJ, Barclay ML, Kirkpatrick CM. The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol 2001; 52 (suppl 1): 35S–43S. 54. Chastre J. Evolving problems with resistant pathogens. Clin Microbiol Infect 2008; 14 (suppl. 3): 3–14.
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55. Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis 2004; 4: 519–527. 56. Kollef MH. Optimizing antibiotic therapy in the intensive care unit setting. Crit Care 2001; 5: 189–195. 57. Charlebois ED, Bangsberg DR, Moss NJ et al. Populationbased community prevalence of methicillin-resistant Staphylococcus aureus in the urban poor of San Francisco. Clin Infect Dis 2002; 34: 425–433. 58. Mulligan ME, Murray-Leisure KA, Ribner BS et al. Methicillin-resistant Staphylococcus aureus: a consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med 1993; 94: 313–328. 59. Weber JT. Community-associated methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2005; 41 (suppl. 4): S269–S272. 60. Naimi TS, LeDell KH, Como-Sabetti K et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290: 2976– 2984.
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61. Graffunder EM, Venezia RA. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials. J Antimicrob Chemother 2002; 49: 999–1005. 62. Huang SS, Labus BJ, Samuel MC, Wan DT, Reingold AL. Antibiotic resistance patterns of bacterial isolates from blood in San Francisco County, California, 1996–1999. Emerg Infect Dis 2002; 8: 195–201. 63. Tristan A, Bes M, Meugnier H et al. Global distribution of Panton–Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus, 2006. Emerg Infect Dis 2007; 4: 594–600. 64. Bodey GP, Jadeja L, Elting L. Pseudomonas bacteremia. Retrospective analysis of 410 episodes. Arch Intern Med 1985; 145: 1621–1629. 65. Davey PG, Marwick C. Appropriate vs. inappropriate antimicrobial therapy. Clin Microbiol Infect 2008; 14 (suppl. 3): 15–21. 66. Bolon MK, Morlote M, Weber SG, Koplan B, Carmeli Y, Wright SB. Glycopeptides are no more effective than betalactam agents for prevention of surgical site infection after cardiac surgery: a meta-analysis. Clin Infect Dis 2004; 38: 1357–1363.
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ABSTRACT Bacterial infections are becoming more difficult to treat. At the present time c. 70% of nosocomial infections are resistant to at least one antimicrobial drug that previously was effective for the causative pathogen. Pathogens that are notorious for their virulence and ability to develop resistance include Staphylococcus aureus, Enterococcus spp., members of the Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species. Notable resistance patterns that have emerged include methicillin resistance in S. aureus, which started in the healthcare setting but has now moved into the community. Vancomycin resistance in enterococci is frequently seen, and vancomycin resistance in methicillin-resistant S. aureus is a public health threat. Resistance patterns seen in pseudomonal and Acinetobacter infections are rapidly shifting. The situation has become sufficiently serious for clinical opinion leaders to call upon governments for assistance in addressing the problem. In this worsening environment, in which patients are at progressively greater risk of untreatable infections, clear recommendations for prescribers are urgently needed. Severity of infection and underlying conditions are key issues, as patients with the most serious diseases are those in most urgent need, and improvements in our ability to predict likely infecting pathogens when empirical therapy is necessary are needed. Risk-factors and local resistance patterns must be accounted for, and initial empirical therapy should be adequately broad spectrum and adequately dosed. Agents must be highly active, able to penetrate adequately to the site of infection, safe, and well-tolerated. infection, community-acquired, empirical therapy, methicillin-resistant Staphylococcus aureus, nosocomial, Panton–Valentine leukocidin, Pseudomonas aeruginosa, resistance, review, virulence Keywords Bacterial
Clin Microbiol Infect 2008; 14 (Suppl. 3): 22–31 INTRODUCTION Although the phenomenon of drug resistance in bacterial pathogens is not new, the high prevalence of drug-resistant highly pathogenic bacteria has been unprecedented in recent years. Data on methicillin-resistant Staphylococcus aureus (MRSA), a key contributor to concern about resistant pathogens, illustrate the scope of this problem. The European Antimicrobial Resistance Surveillance System (EARSS) reported in 2005 [1] on 30 countries that submitted results for MRSA. All of the southern European countries reported high levels of MRSA (eight with rates of over 40%). Four countries (Czech Republic, Slovakia, Hungary and Corresponding author and reprint requests: Y. Carmeli, Division of Infectious Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel E-mail: [email protected] Y. Carmeli declares no conflict of interests.
Germany) with rates of MRSA below 10% in 2001 reported dramatic increases in 2005. Only seven (mainly northern countries) reported MRSA rates below 3%, although significant increases were reported for three of these: The Netherlands (from 0.34% – 0.93%), Denmark (0.28% – 1.7%), and Finland (0.95% – 2.91%). The only exceptions to this trend were France and Slovenia, both of which succeeded in consistently reducing proportions of methicillin-resistant isolates from 2001 to 2005. In the USA, the continuing increase in levels of staphylococcal resistance in hospitals remains a cause for concern. The proportion of isolates of S. aureus that were resistant to methicillin, oxacillin or nafcillin was reported as continuing to rise, and in 2004 it had reached nearly 60%. Furthermore, the hospital is not the only source of resistant pathogens, as genetically distinct MRSA strains have emerged in the community [2]. The challenge of antimicrobial resistance is not limited to MRSA. Currently, the annual incidence
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of nosocomial infections due to any resistant bacterial species in the USA is c. 1.4 million [3]. Severe infections caused by antimicrobial resistance pose obvious treatment challenges. The aim of this article is to review trends in MRSA and other resistant pathogens associated with serious infections, to discuss the characteristics of an optimal antibiotic, and to consider strategies for managing patients infected with resistant organisms. PATIENTS WITH SEVERE INFECTIONS Patients with severe infections have urgent treatment needs; thus, severe infections must be identified quickly. Severity of infection is determined by three factors: (i) host (patient) characteristics, (ii) the disease or syndrome itself, and (iii) the pathogen causing the illness (species, virulence, and susceptibility to antimicrobial agents). Populations in developed countries are ageing, and as a result, patients are increasingly elderly, more debilitated, more likely to have underlying medical conditions, and more likely to be immunosuppressed because of ageing, disease, and ⁄ or medical therapy. Increasing proportions of patients have resistant infections from institutions such as nursing homes and rehabilitation centres. Readmissions related to short hospital stays may introduce into the hospital environment large numbers of patients who have been recently treated with antibiotics [4–7]. Infectious disease syndromes that may immediately be classified as severe infection include those involving the central nervous system, bacteraemia ⁄ sepsis, hospital-acquired pneumonia, and severe soft-tissue infections. Nosocomial bloodstream infections are a major cause of death and morbidity in the USA, with an estimated quarter of a million cases annually [8]. Moreover, the numbers of such infections caused by antibiotic-resistant organisms are increasing in the USA. The nationwide Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE) survey, carried out from 1995 to 2002 in 49 US hospitals recorded 24 179 nosocomial bloodstream infections, 87% of which were monomicrobial [9]. The proportion of S. aureus species with methicillin resistance increased from 22% in 1995 to 57% in 2001. Over the course of
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the survey, vancomycin resistance was seen in 2% of Enterococcus faecalis and 60% of Enterococcus faecium isolates. PATHOGENS ASSOCIATED WITH SERIOUS INFECTIONS MRSA Along with the high prevalence of hospitalacquired MRSA in the USA and its increasing prevalence in other countries, the emergence of community-acquired MRSA infection is of public health concern, particularly because of the risk of transmission [10]. Community-acquired MRSA infections are now being reported in young and healthy individuals with no obvious risk-factors [11–13]. Most cases involve skin and soft-tissue infection, but life-threatening invasive infections such as necrotising pneumonia [14], necrotising fasciitis [15] and sepsis [16] are also being reported. In some areas, community-acquired MRSA infections have become more prevalent than community-acquired infections with methicillin-susceptible strains [10]. Characterisation of 117 community-acquired MRSA isolates from the USA, France, Switzerland, Australia, New Zealand and Western Samoa has identified genes that are unique to communityacquired organisms and are shared by isolates from all three continents (North America, Europe, and Oceania) [17]. These are a type IV SCCmec cassette (a methicillin resistance locus) and the locus for Panton–Valentine leukocidin (PVL). The PVL locus is carried on a bacteriophage and appears to represent a stable marker of community-acquired MRSA in different countries [17]. There appears to be an association between MRSA and the presence of PVL in skin and respiratory tract infections (Strauss et al., 47th ICAAC, abstract K-1092; Strauss et al., 17th European Congress of Clinical Microbiology and Infectious Diseases, abstract O120). In a series of 415 skin and soft-tissue infections (abscesses, wounds, or cellulitis) analysed for PVL expression, PVL-positive strains of MRSA (and methicillin-sensitive S. aureus) were found to be widely prevalent in deep-seated complicated skin and skin structure infections (Strauss et al., 17th European Congress of Clinical Microbiology and Infectious Diseases, abstract O120). PVL expression was significantly more likely to be
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associated with abscess formation than with nonabscess-forming deep infections (Fig. 1). PVL positivity was found to be associated with rapidly progressive, haemorrhagic, necrotising pneumonia, a disorder that mainly affects otherwise healthy children and young adults and that involves high rates of mortality [18]. Of a series of eight patients in France, six died after infection with community-acquired pneumonia caused by S. aureus carrying the PVL gene. Further analysis of eight prospective and eight retrospective cases of pneumonia caused by PVL-positive S. aureus and 36 cases associated with PVL-negative strains showed survival rates 48 h after hospital admission of 63% and 94%, respectively (p 0.007) [18]. Enterococci Enterococci are normal inhabitants of the gastrointestinal tract but may also be associated with infection [19]. In the SCOPE survey, 9% of the causative pathogens in nosocomial bloodstream infections were enterococci [9]. Most clinical laboratories report that 80%–90% of enterococci are E. faecalis, and E. faecium accounts for 5%–10% of isolates [20]. E. faecium strains expressing high levels of resistance to ampicillin emerged in the USA in the late 1980s [21]; vancomycin-resistant Enterococcus (VRE) subsequently appeared in 1989 [20]. Since that time, the incidence of VRE has continued to increase, and VRE now accounts for more than 25% of enterococcal isolates in some intensive care
Fig. 1. Association between Panton–Valentine leukocidin (PVL) gene expression in methicillin-resistant Staphylococcus aureus (MRSA) isolates and type of skin and skin structure infection in 415 S. aureus isolates analysed for PVL (Strauss et al., 17th European Congress of Clinical Microbiology and Infectious Diseases, abstract O120).
facilities [22]. A 10-year survey of enterococcal isolates at a major medical centre in Chicago that was carried out from 1993 to 2002 [23] showed a significant increase in the proportion of enterococci identified as E. faecium from 12.7% – 22.2% (p <0.001). The proportion of E. faecium isolates that were resistant to vancomycin increased from 28.9% to 72.4% (p <0.001). Pseudomonas aeruginosa P. aeruginosa is a leading nosocomial pathogen that is often associated with pneumonia, particularly in the intensive care setting [24]. In addition to pneumonia, P. aeruginosa may be associated with bacteraemia, endocarditis, exacerbation of cystic fibrosis, keratitis and traumatic endophthalmitis [25]. Neutropenic and mechanically ventilated patients are at particular risk of pseudomonal infection, and mortality rates in infected individuals exceed 30% [24]. The importance and virulence of P. aeruginosa have been stressed, with this organism remaining identifiable in respiratory samples for as long as 48 h after effective antimicrobial therapy has been initiated. In addition, type III secretory proteins are recognised as important virulence factors. The type III secretion phenotype in P. aeruginosa has been associated with worse outcomes in patients with ventilator-associated pneumonia [24]. P. aeruginosa has high inherent resistance to many drug classes, in part because of its semipermeable outer-membrane and possession of efflux systems that reduce intracellular concentrations of antimicrobial agents. Alarmingly, P. aeruginosa also frequently mutates during courses of therapy. Current treatment options are therefore limited and empirical treatments are commonly inadequate [26,27]. P. aeruginosa isolates are occasionally resistant to all antibiotics, a problem that appears to be growing with the emergence of integrins that carry gene cassettes encoding both carbapenemases and amikacin acetyltransferases [26]. Falling rates of susceptibility of P. aeruginosa to available antibacterial agents have been documented (Fig. 2). Data from the Tracking Resistance in the United States Today study, which collected 2394 isolates from 2001 to 2003, showed piperacillin–tazobactam, cefepime and ceftazidime to be the most active agents against P. aeruginosa, although susceptibility to any single agent tested
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Fig. 2. Multidrug resistance (‡3 drugs) among Pseudomonas aeruginosa isolates tested with a panel of six antibiotics in the USA, 1997–2000 [26]. Isolates were from over 250 hospitals participating in the Surveillance Network Database USA.
was below 90% [28]. Susceptibility to ciprofloxacin or levofloxacin was c. 67%, and c. 9% of isolates were multidrug-resistant. The prevalence of multidrug-resistant isolates increased from 7.2% in 2001 to 9.9% in 2003. Acinetobacter baumannii A. baumannii is also emerging as a worldwide cause of nosocomial infections. Acinetobacter spp. were generally considered to be low-virulence organisms that had been reported to increase in virulence in critically ill or immunocompromised patients [29]. Over the last decade, reports from various parts of the world have suggested that epidemic and more virulent strains of A. baumannii are spreading in hospitals [30]. Disorders with which this microorganism is associated include pneumonia, bacteraemia, meningitis and urinary tract and skin and soft-tissue infections. Isolates resistant to nearly all commercially available antimicrobial agents have been identified, and treatment options for severe A. baumannii infections are becoming limited [31,32]. CURRENT TREATMENT OPTIONS FOR MRSA The agents most commonly used to treat MRSA infections are glycopeptides. Vancomycin has been the standard treatment and, until recently, the only option for the management of patients with MRSA [33]. Unfortunately, the efficacy of this group appears to be inferior to the b-lactams and continues to diminish, with shifting MICs and increasing emergence of vancomycin-inter-
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mediate S. aureus and vancomycin-resistant S. aureus [34–36]. The emergence of these strains in addition to the spread of MRSA from the hospital to community settings has become a major cause of concern to clinicians and microbiologists. Teicoplanin is available as an alternative antiMRSA glycopeptide and has been suggested in cases where patients cannot tolerate vancomycin [37], but this agent has unpredictable pharmacokinetics, and low dosages have been associated with treatment failure [38]. Therapeutic drug monitoring for teicoplanin has been advocated but is not widely practised [38]. The novel cephalosporin ceftobiprole has shown good activity against MRSA. Patients with suspected MRSA-associated complicated skin and skin structure infections were enrolled in a double-blind, randomised study comparing ceftobiprole 500 mg twice-daily with vancomycin 1 g twice-daily in 15 countries (Strauss et al., 44th Annual Meeting of IDSA, abstract 138). Pathogens were isolated from 613 of 784 patients enrolled. S. aureus was found in 494 baseline samples, among which 190 ceftobiprole-treated and 173 vancomycin-treated cases were evaluable. MRSA was isolated in 122 (21.8%) of clinically evaluable patients, with clinical cure rates (after 7–14 days) as shown in Table 1. MRSA infections were especially prevalent in the USA; cure rates with ceftobiprole exceeded 90% and tended to be higher than US cure rates with vancomycin. Ceftobiprole has also been shown to have good activity against PVL-positive MRSA and methicillin-susceptible S. aureus (Strauss et al., 47th ICAAC, abstract K-1092). Along with glycopeptides such as vancomycin [33], current treatment options for MRSA include oxazolidinones (linezolid) [39], daptomycin [40], and the expanded-spectrum glycylcycline, tigecycline [41]. Other potential treatments are trimethoprim–sulfamethoxazole [42] and clindamycin [43]. With the exception of tigecycline, these agents have a relatively narrow spectrum of activity, which frequently leads to the need for combination therapy in the empirical setting. Some currently available agents do not always achieve the required penetration into target tissues. Vancomycin has shown poor penetration into the lungs in pharmacokinetic studies [44,45]. In addition, the drug has shown low cerebrospinal fluid penetration in infants undergoing shunt
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Population
All Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Ceftobiprole
Ceftobiprole
Vancomycin
Vancomycin
USA 92.9% (52 ⁄ 56) 85.5% (53 ⁄ 62) 92.7% (38 ⁄ 41) 85.0% (34 ⁄ 40) All countries 94.7% (180 ⁄ 190) 94.2% (163 ⁄ 173) 91.9% (57 ⁄ 62) 90.0% (54 ⁄ 60)
insertion [46], and suboptimal responses in patients with bacteraemia and endocarditis have been reported [47–49]. Daptomycin has shown poor lung tissue penetration in animal studies, in addition to inactivation by lung surfactant [50,51]. Systemic glycopeptides have also been recommended for acute cancellous bone infections, but vancomycin concentrations in cortical bone are less satisfactory [38]. The toxicity profile of current agents should also be considered when selecting treatments for patients with documented or suspected MRSA infection. The nephrotoxicity and ototoxicity of vancomycin is well-appreciated and can be a particular problem at the aggressive doses used to treat MRSA [52,53]. Using vancomycin in combination therapies to broaden the empirical spectrum has the potential to expose more patients to the risk of these toxicities. Linezolid has been investigated as an alternative to vancomycin and other older agents in patients with multidrugresistant Gram-positive infections. While this drug is generally well-tolerated, nearly 10% of 796 patients in a compassionate-use programme experienced gastrointestinal disturbances, and thrombocytopenia was seen in 7.4% of cases [39]. STRATEGIES FOR TREATING TODAY’S SERIOUS INFECTIONS The characteristics of an appropriate empirical antimicrobial therapy are described in the article by Chastre in this issue [54]. An ideal initial antibiotic should be effective against a broad range of pathogens, including resistant organisms, highly active at the site of infection (with mechanistic, pharmacokinetic and pharmacodynamic characteristics consistent with this requirement), safe and non-toxic with few adverse effects, and convenient to use. The issue of range of coverage is often used as a rationale for the initial empirical use of combination therapy in serious infections, with the com-
Table 1. Staphylococcal infections and cure rates in patients with complicated skin and skin structure infections treated with ceftobiprole 500 mg twice-daily or vancomycin 1 g twice-daily (Strauss et al., 44th Annual Meeting of IDSA, abstract 138)
bination being switched to monotherapy once culture data become available (de-escalation or step-down therapy). The rationale for the empirical use of combination antibiotics for proven or suspected bacterial infections is to ensure initial broad-spectrum coverage. Subsequently, once culture data are available, the treatment regimen could be de-escalated to focused monotherapy in which the switch agent is microbiologically appropriate for the infecting pathogen. The debate about combination therapy is ongoing, but the issue has been analysed in detail by Safdar et al. [55], who carried out a meta-analysis of 17 studies (of which five were prospective cohort studies and two were prospective, randomised trials) in patients with Gram-negative bacteraemia. Most studies used b-lactams or aminoglycosides alone and in combination. The pooled odds ratio of 0.96 indicated no benefit in terms of mortality rate for combination therapy, although the study did not assess other outcomes, such as microbiological cure and emergence of resistance. The general applicability of the finding is uncertain, as 11 of the 17 studies focused on a particular organism (five studies were on P. aeruginosa and four on Klebsiella spp.). In addition, there was considerable heterogeneity among studies, reflecting the widely varying study designs, different organisms analysed and antibiotics studied. The fact that many of the studies were observational also means that confounding factors (e.g., severity of illness; underlying disease) cannot be ruled out. Further study will be required to clarify the benefit of combination therapy. The evidence shows that failure to initially treat high-risk microbiologically documented infections appropriately is associated with increased rates of mortality and morbidity [56]. Risk stratification should therefore be employed to identify patients at high risk of infection with resistant strains of bacteria (e.g., patients with prior antibiotic treatment during hospitalisation, prolonged stay in hospital and invasive devices); indeed, this
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approach may be considered to be pre-emptive. Expert opinion in the USA suggests that such high-risk patients should be treated with combination therapy designed to cover most pathogens likely to be implicated in any infection in the setting in question, with de-escalation being thought of as a strategy to balance the need for appropriate initial therapy with the avoidance of unnecessary antibiotic utilisation [56]. When prescribing antimicrobial therapy for patients with infections, the clinician must take commonly encountered resistant organisms into account. Risk-factors for MRSA that prescribers must be alert to include those common to all S. aureus infections such as skin pathology (e.g., wounds or dermatitis) and needle use (as in patients with diabetes, those needing dialysis, and those with intravenous catheters). Those specific to MRSA include prolonged hospitalisation, contact with healthcare institutions, proximity to an MRSA carrier, and prior treatment with certain antibiotics [57–60]. A case-control study carried out in 121 patients with MRSA and 123 patients with methicillin-susceptible S. aureus showed factors independently associated with MRSA infection to be previous hospitalisation, longer length of stay before infection, previous surgery, enteral feeding, macrolide use and levofloxacin use [61]. The epidemiology of MRSA and especially community-acquired MRSA is evolving rapidly. Previously, risk-factors for MRSA in the community were well-defined and included a history of prolonged hospitalisation, prior admission to a nursing home or other long-term care facility, and injectable drug use [57–59]. But communityacquired MRSA infections are now being reported in specific populations of young and healthy individuals associated with no obvious risk factors, such as professional football players and children [11–13]. Other specific populations that have been identified as being at risk for community-acquired MRSA from other studies include injection drug users, those with prior endocarditis, those with hospitalisation within the previous year, sports participants, incarcerated persons, military recruits, and a number of distinct ethnic populations, including Alaskan natives, Native Americans, and Pacific Islanders [57,59]. Findings from the Minnesota Department of Health provide an important perspective on the
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risk of community-acquired MRSA infection. A prospective study analysed all MRSA infections identified in 2000 at 12 laboratories in a sentinel surveillance network [60]. Of 1100 infections, 131 (12%) were community-acquired MRSA infections. Skin and soft-tissue infections were more common in community-associated infections than in those associated with healthcare settings, and most cases of community-acquired MRSA were initially treated with antibiotics to which they were not susceptible. Notably, the Minnesota laboratories also found that community-acquired MRSA isolates had distinct exotoxin genes (e.g., PVL) and antimicrobial susceptibility profiles (Table 2). These findings suggest strongly that any person presenting to a hospital emergency room with a skin or skin structure infection in the USA should be suspected of having communityacquired MRSA. Community-acquired MRSA may be a common cause of bacteraemia. A study by Huang et al. of antimicrobial resistance in hospitals in San Francisco County from 1996 through 1999 showed high rates of MRSA bacteraemia detected at admission and during the first day of hospitalisation; these rates were as high or higher than those detected upon or 2 weeks after admission (Fig. 3), which would presumably be nosocomial infections [62]. Table 2. Antimicrobial susceptibility of community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus isolates in Minnesota for the year 2000. Adapted with permission [60]. Drugs showing statistically significant differences (p £0.001) between community- and healthcare-associated isolates are highlighted in bold Percentage of isolates susceptible
Antibiotic Methicillin Ciprofloxacin Clindamycin Erythromycin Gentamicin Rifampicin Tetracycline Trimethoprim– sulfamethoxazole Vancomycin
Communityassociated (n = 106)
Healthcareassociated (n = 211)
0 79 83 44 94 96 92 95
0 16 21 9 80 94 92 90
100
100
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Fig. 3. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) isolates obtained from blood samples by hospital day of admission from a study of San Francisco County hospitals from 1996 to 1999. Reproduced with permission [62].
MRSA infection may be predictable at the individual patient level on the basis of endemic status. Two studies in patients with skin and softtissue infections carried out in 2003 in the USA and Canada encouraged inclusion of persons with MRSA. The respective proportions of patients with MRSA were 65% and 79%, with physicians’ predictions of this type of infection having a positive predictive value of 68%. The most common reasons for suspecting MRSA were high prevalence in the community (67%) and prior MRSA infection (23%). In a further study in which suspected MRSA constituted grounds for exclusion, the proportion of MRSA infections was reported to be 46%, with a physicians’ negative predictive value of 64% by (Carmeli et al., 45th ICAAC, abstract L-1574). The dynamic epidemiological picture of S. aureus and MRSA requires healthcare providers to be constantly aware of current epidemiological trends, which include local and regional patterns and global migration of specific strains [63]. Consequences of treatment delay Inappropriate or delayed treatment in patients with severe infections has serious implications for patient outcomes. The classic 1985 study by Bodey et al. was a retrospective review of 410 cases of Pseudomonas bacteraemia in patients with cancer that illustrates this point [64]. Pseudomonas bacteraemia was most common among patients with acute leukaemia; most patients had acquired their infections in hospital, and 51% had received
antibiotics for other infections during the preceding week. Shock was documented in 33% of patients, and 32% had concomitant pneumonia. The overall cure rate was 62%. The importance of appropriate therapy was apparent: a cure rate of 67% was noted in patients who received appropriate antibiotics, but this dropped to only 14% in those who did not receive appropriate antimicrobial therapy. Moreover, a 1- to 2-day delay in the administration of appropriate antibiotic therapy reduced the cure rate from 74% – 46%. Patients who received an anti-pseudomonal b-lactam, with or without an aminoglycoside, had significantly higher cure rates than those who received an aminoglycoside only (72% and 71% vs. 29%). More recent studies of the detrimental effects of delay of appropriate antimicrobial treatment are reviewed in the articles by Davey and Chastre in this issue [54,65]. These studies show that treatment delay leads to treatment failure and to increases in rates of morbidity and mortality and thus must be avoided. ADDITIONAL STRATEGIC ISSUES A need to improve physician awareness of the effect of prompt and effective diagnosis on the likelihood of successful therapy when using antibiotics in an environment in which drugresistant microorganisms are becoming more prevalent is apparent. As highlighted earlier in the present review, appropriate and adequate therapy at the earliest opportunity avoids treatment delay and dramatically increases the probability of successful eradication of infection. Appropriate sample cultures are needed as soon as possible in order to inform treatment decisions after initial empirical therapy. Indeed, times to diagnosis must be shortened; in particular, faster delivery of samples to laboratories, more rapid processing times and quicker reporting are all simple means by which delivery of effective treatment can be hastened. Some individualisation of treatment decisions is also required. Formulaic treatment plans (where an infection type is directed towards a fixed treatment type) may be over-simplistic and may not provide solutions in this complex setting. Severity of infection must be considered, together with likely infecting pathogens (based on identifiable risk-factors as discussed earlier) and what is known about local resistance
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patterns. Adoption of de-escalation therapy allows clinicians to initiate therapy with a broad-spectrum antibiotic and follow with focused treatment once culture data become available. If implemented successfully, these measures would be expected to improve patient outcomes by decreasing rates of mortality, preventing organ dysfunction, decreasing length of stay, decreasing costs, and possibly reducing overall antibiotic pressure. Use of escalation therapy, whereby treatments are ‘stepped up’, is likely to delay the use of appropriate and adequate treatment, the principles of which involve the use of highly active agents, achievement of appropriate levels of antibacterial agent at the infection site, and use of agents known to act effectively at the target site without risk of inactivation or premature elimination. CONCLUSION Resistant, virulent pathogens have emerged over the last decades in healthcare settings and in the community, in many parts of the world; some resistant species, such as MRSA, have reached endemic levels. The prevalence of these pathogens, changes in healthcare settings, new findings on the mechanisms of development of resistance and the availability of new antimicrobial agents call for adaptation of treatment strategies to improve patients’ outcomes. Antibiotic selection pressure should be minimised without compromising patients’ outcomes. Thus, choice of empirical therapy should be individualised and take into consideration the clinical syndrome, the affected patient’s medical history, the suspected organisms, and the severity of the infection. The patient’s risk of infection with a resistant organism should be considered on the basis of past exposures, co-morbid conditions, and the local epidemiology. Decisions regarding antimicrobial therapy should also take into account safety and tolerability. REFERENCES 1. EARSS. EARSS annual report 2005. Bilthoven, The Netherlands, December 2006. http://www.rivm.nl/earss/Images/EARSS%202005_tcm61-34899.pdf 2. Moran GJ, Krishnadasan A, Gorwitz RJ et al. Methicillinresistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355: 666– 674.
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