Empirical therapy for serious Gram-positive infections: making the right choice

REVIEW 10.1111/j.1469-0691.09.03061.x Empirical therapy for serious Gram-positive infections: making the right choice J. Segreti Department of Internal Medicine, Section of Infectious Diseases, Rush University Medical Center, Chicago, IL, USA Abstract It is well established that delaying the administration of effective antimicrobials for the treatment of serious infections has a significant impact on patient outcomes. In this atmosphere of urgency, decision-making regarding therapy is further complicated by the current high rates of drug resistance among important pathogens, such as Staphylococcus aureus. To improve treatment outcomes, decrease the risk of mortality and reduce hospital costs, physicians should always administer the most appropriate antimicrobial for the given scenario. When a staphylococcal infection is suspected but the resistance phenotype is not known, agents that are effective against methicillin-susceptible S. aureus and methicillin-resistant S. aureus provide optimal empirical coverage. However, the number of such empirical monotherapeutic options is limited. Daptomycin has proven clinical efficacy as compared with comparator agents in Gram-positive infections, and could be considered an appropriate therapy for the treatment of infections caused by either methicillin-susceptible S. aureus or methicillin-resistant S. aureus. Keywords: Complicated skin and soft tissue infection, daptomycin, Gram-positive infections, infective endocarditis, Staphylococcus aureus Clin Microbiol Infect 09; 15 (Suppl. 6): 5 10 Corresponding author and reprint requests: J. Segreti, Department of Internal Medicine, Section of Infectious Diseases, Rush University Medical Center, Chicago, IL 60612, USA E-mail: john_segreti@rush.edu This article forms part of a supplement based on the proceedings of a Novartis-sponsored symposium at the 18th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), April 08, entitled Positive outcomes in Gram-positive infections. The supplement is supported by an educational grant for production and distribution from Novartis, with editorial and writing support provided by Chameleon Communications International with Novartis Pharma AG sponsorship. Introduction Serious Gram-positive infections are a significant problem faced by physicians and can be difficult to diagnose and treat. The increasing incidence of Gram-positive bacteria with decreased susceptibility to many frequently used antimicrobials makes treating these infections even more problematic [1,2]. Optimal outcomes are achieved in patients for whom antimicrobial therapy is appropriate and adequate [3,4]. Adequate therapy can be defined as therapy to which the causative pathogen is susceptible, as determined in vitro on the basis of clinical breakpoints [5,6]. Appropriate therapy is an adequate therapy that is additionally deemed to be relatively favourable with respect to other considerations, including head-to-head clinical trial comparisons with alternative therapies, antimicrobial penetration into tissues, safety and tolerability, and cost-effectiveness [5,6]. Furthermore, an appropriate therapy is given at the correct dose and interval. The impact of inadequate antimicrobial therapy on patient outcomes is significant, increasing the risk of hospital mortality by up to two-fold in serious infections as compared with adequate therapy [5,7 10]. Of further consequence is the finding that the use of an inappropriate or suboptimal empirical therapy for serious infections, including those caused by Staphylococcus aureus, is also associated with increased mortality and duration of hospitalization [3,4,11]. To enable the administration of adequate antimicrobial regimens to patients, clinicians ideally require the results of bacteriological culture and susceptibility tests. Unfortunately, in current practice, obtaining such results may take 2 3 days. To avoid delays in therapy, which can have significant consequences for treatment outcomes in serious infections [12], clinicians regularly make decisions on empirical therapy immediately on presentation, without the benefit of laboratory results, thereby making educated guesses as to the causative pathogens and their resistance phenotypes. This review will discuss two case studies exploring the choice of appropriate Journal Compilation ª09 European Society of Clinical Microbiology and Infectious Diseases

6 Clinical Microbiology and Infection, Volume 15, Supplement 6, December 09 CMI empirical therapy for serious infections caused by Gram-positive organisms with unknown methicillin susceptibility. The Empirical Dilemma What is the impact of choosing inappropriate therapy? In the USA [13] and a number of European countries (including the UK, Italy and Greece) [1], infections caused by methicillin-resistant S. aureus (MRSA) can account for up to 50% of all nosocomial S. aureus infections. At a time when MRSA rates are high or increasing in many countries [1], the traditional options for treating suspected S. aureus infections create an empirical dilemma: should the clinician select an agent that is most appropriate against methicillinsusceptible S. aureus (MSSA) but not MRSA, or one that is most appropriate against MRSA but not MSSA? Choosing vancomycin as the empirical therapy in all cases of suspected S. aureus infections may not be the most appropriate option, despite its adequacy according to in vitro susceptibility data [14]. For example, several recent studies have indicated that vancomycin may be inferior to b-lactams for the empirical treatment of MSSA infections. For MSSA bacteraemia, vancomycin was associated with significantly higher rates of treatment failure [15 17] and infection-related mortality than treatment with b-lactams [16,17]. Similarly, for MSSA infective endocarditis (IE), empirical therapy with vancomycin was associated with significantly greater infection-related mortality than treatment with b-lactams [18], and complication rates during therapy and durations of intensive-care unit stay were significantly higher with vancomycin [19]. In addition, there is mounting evidence that the value of the MIC of vancomycin within the susceptible range ( 2.0 mg/l) influences clinical outcome, potentially rendering adequate therapy relatively inappropriate. For example, Sakoulas et al. [] found that a vancomycin MIC of 1.0 2.0 mg/l was associated with significantly lower vancomycin treatment success rates in MRSA bacteraemia than a vancomycin MIC of 0.5 mg/ml (55.6% vs. 9.5%; p ¼0.01). Similarly, Lodise et al. [21] determined that vancomycin MICs of 1.5 mg/l were associated with a 2.4-fold increase in treatment failure as compared with vancomycin MICs of 1.0 mg/l (36.4% vs. 15.4%; p ¼0.049). Other data suggest that increased doses of vancomycin may not compensate for elevated MICs [22], and high vancomycin doses (4 g) are associated with an increased risk of nephrotoxicity [23]. Choosing the most appropriate empirical therapy for a patient is critical in reducing the risk of morbidity and mortality [3,12]. The likelihood of patients receiving inadequate empirical therapy increases with the increasing prevalence of infections caused by antimicrobial-resistant bacteria. Local epidemiology and resistance rates should therefore be taken into consideration [6]. Several studies have demonstrated that the administration of inadequate empirical antimicrobial therapy (Fig. 1) [5,7 10] and, furthermore, inappropriate empirical therapy (Fig. 2) [4,11] significantly increase the rate of mortality in infections such as bloodstream infections, MRSA sterile site infections, nosocomial pneumonia, and ventilator-associated pneumonia. In addition, delaying therapy for S. aureus bacteraemia has been shown to increase the risk of mortality and the overall length of hospitalization [12]; early administration of appropriate therapy in S. aureus infections is key to reducing these risks. Identification of bacteria from patient isolates can take up to 3 days from presentation of the patient to the healthcare facility, with the potential for contamination of samples by S. aureus colonizing p <0.001 Adequate Inadequate 100 91 80 p <0.001 Mortality (%) 60 40 28.4 61.9 p <0.05 15.6 37 38 p =0.039 16.2 24.7 p =0.015 16.6 26.1 0 n = 345 n = 147 n = 86 n = 27 Ibrahim et al. Rello et al. 00 5 1997 7 n = 16 n = 34 Luna et al. 1997 8 n = 284 n = 146 Alvarez-Lerma et al. 1996 10 n = 169 n = 380 Schramm et al. 06 9 Bloodstream infections Ventilator-associated pneumonia Nosocomial pneumonia Mixed MRSA infections FIG. 1. The impact of inadequate therapy on mortality rates in bloodstream infections, ventilator-associated pneumonia, nosocomial pneumonia and methicillin-resistant Staphylococcus aureus (MRSA) sterile site infections [5,7 10].

CMI Segreti Empirical therapy: making the right choice 7 Mortality (%) 70 60 50 40 30 p =0.0001 34 Appropriate therapy Inappropriate therapy 18.2 p =0.046 35.3 10 n = 2158 n = 1255 n = 55 n = 51 0 Leibovici et al. Cheong et al. 1998 4 08 11 FIG. 2. The impact of inappropriate therapy on mortality rates in bloodstream infections [4,11]. As defined by relevant investigators: therapy was appropriate if it was started within 2 days of the first positive blood culture, if the infecting microorganism was subsequently found to be susceptible in vitro to the drug administered, and if the antimicrobial was given intravenously [4]; therapy was appropriate if the initial antimicrobials, which were administered within 24 h after the acquisition of a blood culture sample, included at least one antimicrobial that was active in vitro and when the dosage and route of administration were consistent with current medical standards [11]. the skin [24]. Delaying therapy for this length of time is often not an option, so an empirical therapy is required to treat the suspected infection. Case Study I Infective Endocarditis (IE) IE is a common complication among intravenous drug users (IVDUs), with an incidence of 1 5% per year, and is responsible for 5 10% of the overall death rate in these patients [25]. The tricuspid valve (right-sided) is most frequently affected in IVDUs [26,27]; however, both left-sided and right-sided valves are involved in approximately 5 10% of cases [28]. This predisposition to right-sided IE in IVDUs is thought to be attributable to the injection of bacterial loads, either as part of the particulate matter or as a contaminant, directly into the venous system [28]. The most frequent causes of bacterial IE are Gram-positive organisms, with S. aureus being the bacterial species that is most often isolated [29,30]. Worldwide, the S. aureus isolates causing IE in IVDUs are usually methicillin-susceptible [28]. IE caused by MRSA is associated with a higher rate of persistent bacteraemia than the infection caused by MSSA, and has a non-significant trend towards higher mortality rates [30]. Here, I report on the case of a patient with right-sided IE who was successfully treated with empirical daptomycin. A 32-year-old male with a history of intravenous drug use, who had been suffering with fever and chills for 3 days, was admitted to hospital. He had been admitted previously on multiple occasions for trauma, and had received a gunshot wound to the abdomen 2 months earlier, which was complicated by an MRSA catheter-related bloodstream infection. However, prior antimicrobial therapy was not documented. Clinical examination of the patient revealed tachycardia and a II/VI systolic ejection murmur; the patient s abdomen was benign, and his chest was clear to auscultation. He presented with a temperature of 40 C, respiratory and heart rates of 24 breaths/min and 108 beats/min, respectively, blood pressure of 104/72 mmhg, and right atrial O 2 saturation of 99%. No Osler s nodes, splinter haemorrhages or Janeway s lesions were present. Laboratory results revealed an elevated white blood cell count (15.4 10 9 /L) and anaemia (haemoglobin 10.4 g/dl, haematocrit 32%); blood urea nitrogen and creatinine were within normal ranges. Empirical treatment with daptomycin (6 mg/kg every 24 h) and piperacillin tazobactam was started (4.5 g every 6 h) after admission and initial diagnostic studies. Blood cultures drawn on admission grew Gram-positive cocci in clusters, which were later (48 h after admission) identified as MRSA with a vancomycin MIC of 2 mg/l and a daptomycin MIC of 0.5 mg/l. In addition, the organism was susceptible to tetracyclines, trimethoprim sulphamethoxazole and rifampin, and resistant to quinolones and clindamycin. Transthoracic echocardiography findings were normal, but transoesophageal echocardiography showed an 8-mm vegetation on the tricuspid valve. Daptomycin treatment was continued, but piperacillin tazobactam was discontinued following a 2-day treatment duration. Blood cultures were negative for growth on the third day of antimicrobial therapy. The patient was transferred to a chronic-care facility to complete a 6-week course of daptomycin, but signed out, against medical advice, after a total of 3 weeks of therapy, and was lost to follow-up. His condition on discharge was good. This patient was suffering from S. aureus bacteraemia with concurrent right-sided IE, and the bacteraemia resolved after administration of an appropriate empirical treatment regimen. In IVDUs, when treating endocarditis caused by S. aureus, it has been shown that infection-related mortality is reduced if an appropriate empirical regimen is chosen (Fig. 3) [18]. For this patient, it was unknown initially whether the infecting organism was MSSA or MRSA; therefore, the best possible option was therapy that covered both. In this case, administering an antimicrobial ineffective against MRSA would have delayed the receipt of adequate

8 Clinical Microbiology and Infection, Volume 15, Supplement 6, December 09 CMI Infection-related mortality (%) 100 80 60 40 0 p =0.005 11.4 All 39.3 27.3 p =0.08 66.7 Left-side/bilateral involvement -Lactam (n = 44) Vancomycin (n = 28) p =0.04 Right-side involvement p =0.02 Definite infective endocarditis by Duke criteria FIG. 3. Infection-related mortality according to the type of empirical therapy (b-lactam or vancomycin) in intravenous drug users with methicillin-susceptible Staphylococcus aureus endocarditis [18]. 6.1 26.3 13.9 40.7 treatment, increasing the patient s risk of mortality. In addition, the high vancomycin MIC for the MRSA isolate indicates an elevated likelihood that vancomycin would not have been an effective therapy [ 22,31 34], and may therefore not have been the most appropriate option in this case. Empirical monotherapy options that provide coverage against both MSSA and MRSA are limited. Daptomycin is one such agent, having been shown to be as effective as comparators for treating right-sided IE caused by either MSSA or MRSA in a phase III trial [35]. Another property of daptomycin that makes it appropriate for the treatment of this patient population is its rapid bactericidal activity, which is considered to be important for treatment efficacy in serious infections such as IE [36,37]. Daptomycin demonstrates concentration-dependent killing in in vitro models of IE, with a more rapid rate of bacterial killing than vancomycin [38], as well as against high-dose inocula and organisms in the stationary growth phase [39,40]. The mechanism of action of daptomycin, i.e. rapidly bactericidal but not bacteriolytic [41], is another potential benefit of this agent, as its use should not lead to any major clinical symptoms associated with the rapid lysis of bacteria within the body [42]. Case Study 2 Community-Acquired MRSA (CA-MRSA) CA-MRSA is defined as an MRSA infection acquired outside of healthcare-associated settings [43]. Several risk factors have been identified for the development of infections caused by CA-MRSA, including participation in contact sports, residence in correctional facilities, and attendance at day-care and other institutional centres [44]. Military recruits and homosexual men are also at particular risk for CA-MRSA infection [44]. Although risk factors are useful for assessing the risk of infection with antimicrobial-resistant Gram-negative bacteria, they are much less predictive of infection with MRSA in the USA, because of the high prevalence of this strain in community-acquired infections [45]. A recent study has shown that empirical treatment of CA-MRSA complicated skin and soft tissue infections (csstis), guided by an algorithm that promotes the use of antimicrobials that are active in vitro against CA-MRSA, is associated with improved clinical outcomes as compared with administering empirical therapy that is less effective against MRSA [46]. Here, I report the case of a patient with a community-acquired cssti and concurrent bacteraemia who was successfully treated empirically with daptomycin. A 30-year-old man, released from a state correctional facility 14 months earlier, was admitted to hospital with fever, chills and facial cellulitis. The patient presented with swelling and redness of the lips and left side of the face (with no periorbital oedema or drainage), a temperature of 39.4 C, a heart rate of 110 beats/min, a respiratory rate of breaths/min, and a blood pressure of 128/82 mmhg. Blood analyses revealed that the patient was human imunodeficiency virusnegative. Treatment was initially started with ampicillin sulbactam (3.0 g intravenously every 6 h). However, cultures from blood drawn on admission were shown to be positive for Gram-positive cocci, so treatment was switched after 1 day to daptomycin (6 mg/kg every 24 h) to provide coverage against both MSSA and MRSA. Blood cultures were later shown to be positive for MRSA that was susceptible to vancomycin (MIC 0.5 mg/l), erythromycin (MIC 2 mg/l), clindamycin (MIC <2 mg/l), levofloxacin (MIC <1 mg/l), rifampin (MIC 1 mg/l), tetracycline (MIC 2 mg/l), trimethoprim sulphamethoxazole (MIC 2/38 mg/l) and daptomycin (MIC 0.5 mg/l), according to CLSI breakpoints [47]. Transoesophageal echocardiography findings were negative for vegetations, and a computerized tomography scan of the facial bones was negative for abscess, osteomyelitis and sinusitis. The patient received daptomycin treatment for 14 days;

CMI Segreti Empirical therapy: making the right choice 9 repeat blood cultures after this time were negative, and the facial cellulitis resolved. The emergence and spread of CA-MRSA in the USA has reduced the utility of traditional risk factors for identifying patients with MRSA. Therefore, in such a scenario, it may be appropriate to presume that any serious infection potentially caused by staphylococci could be MRSA until culture results are available. In many European countries, MRSA rates [1] are such that coverage against MRSA with empirical therapy should be strongly considered for hospital-acquired staphylococcal infections. However, CA-MRSA has also been documented in several European countries [48], raising the possibility that Europe may follow a trend similar to that in the USA. In the future, even community-acquired staphylococcal infections may need to be treated empirically as MRSA. Daptomycin has been shown to be rapidly bactericidal in vitro against CA-MRSA strains, with 99% of bacteria being killed in less than 2 h at 4 MIC [49], and has also been shown to be as effective as comparator therapies for treating csstis caused by Gram-positive bacteria, including MSSA, MRSA and enterococci [50]. These data indicate that daptomycin is an effective choice for the empirical treatment of suspected Gram-positive csstis. Summary Choosing the most appropriate empirical therapy is critical for obtaining the best patient outcomes. However, determination of the optimal treatment regimen is often complicated by the possibility of reduced antimicrobial sensitivity of the infecting bacterial strains. Treatment of infections caused by S. aureus can be particularly complex because of varying prevalences of MRSA, and the consequences of increased mortality and hospital length of stay associated with the use of inappropriate empirical therapies. The optimal empirical coverage against Gram-positive pathogens should include agents that are effective against antimicrobial-susceptible and antimicrobial-resistant strains. Because of its rapid bactericidal activity and proven clinical efficacy in infections caused by Gram-positive bacteria, including antimicrobial-resistant strains such as MRSA, daptomycin may be an appropriate option for the empirical treatment of serious Gram-positive infections, independent of methicillin susceptibility [35,50]. Acknowledgements Editorial and writing support for the author of this article was provided by L. Huson of Chameleon Communications International with Novartis Pharma AG sponsorship. 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