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Review
Optimum treatment strategies for carbapenemresistant Acinetobacter baumannii bacteremia Expert Rev. Anti Infect. Ther. Early online, 1–9 (2015)
Jose Garnacho-Montero*1–3, Rosario Amaya-Villar1–3, Carmen Ferra´ndiz-Millon1, Ana Dı´az-Martı´n1,2, Jose Marı´a Lopez-Sa´nchez1 and Antonio Gutierrez-Pizarraya2,3
Carbapenem-resistant Acinetobacter baumannii (CRAB) constitutes an increasing problem worldwide. CRAB bacteremia is associated with a high fatality rate and its optimal treatment has not been established. Early institution of appropriate therapy is shown to improve survival of patients with CRAB bloodstream infection. Regrettably, treatment options are limited. Little information exists about the efficacy of sulbactam for the treatment of CRAB bacteremia. Colistin and tigecycline possess good in vitro activity and represent in many cases the only therapeutic options although clinical data are scarce. The need for a loading dose of colistin has been recently demonstrated to rapidly achieve therapeutic levels. The use of combination therapy is also a matter of debate but current evidence do not support its routine use. KEYWORDS: Acinetobacter baumannii . bacteremia . carbapenem-resistant . colistin . polymyxin . tigecycline .
treatment
1
Unidad Clı´nica de Cuidados Crı´ticos, Hospital Universitario Virgen del Rocı´o, Sevilla, Spain 2 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocı´o/CSIC/Universidad de Sevilla, Sevilla, Spain 3 Red Espan˜ola de Investigacion en Patologı´a Infecciosa (REIPI), Hospital Universitario Virgen del Rocı´o, Sevilla, Spain *Author for correspondence: [email protected]
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Acinetobacter baumannii has gained increasing attention in recent decades because of its potential to cause severe infections and by its ability to develop resistance to practically all the available antimicrobials. Bacteremia is probably with pneumonia, the most significant infection caused by this Gram-negative bacterium. Clinical manifestation of A. baumannii bloodstream infections range from transient bacteremia to severe diseases manifested as septic shock with high mortality. Regarding the origin of bacteremia, the lower respiratory tract is the most frequent source of infection, followed by intravascular catheters. Of note, inappropriate empirical antimicrobial therapy is associated with mortality even after adjustment with confounders [1,2]. Traditionally, carbapenems have been considered the drug of choice for empirical treatment of A. baumannii infections and they are still the first-line agents for the empirical therapy in areas with high rates of susceptibility. However, carbapenem-resistant A. baumannii (CRAB) has emerged as a serious threat for healthcare systems worldwide. Optimal management of infections caused by CRAB represents a real challenge given the paucity of 10.1586/14787210.2015.1032254
alternatives and the uncertainties about their efficacy and safety. This problem is especially pressing in severe infections such as bacteremia. In fact, carbapenem resistance has been identified as an independent variable associated with mortality in patients with A. baumannii bacteremia [3,4]. The inadequate antimicrobial empirical therapy rate is higher in bacteremias caused by carbapenem resistant A. baumannii than in carbapenem susceptible A. baumannii bacteremia cases. Moreover, the use of inactive empirical therapy was an independent predictor for death [5,6]. Very recently, in a cohort of patients with CRAB bacteremia, active antibiotic treatment was identified as a protective factor for 14-day mortality after adjusting with a multivariate Cox analysis that included the propensity score as covariate [7]. Consequently, carbapenems cannot be considered the treatment of choice in those areas with high rate of infections by CRAB. Nowadays, polymyxins are the antimicrobials with the greatest level of in vitro activity against A. baumannii [8–10]. However, polymyxins have been used with caution because they constitute frequently the last resort and their use is
2015 Informa UK Ltd
ISSN 1478-7210
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´ ndiz-Millon, Dı´az-Martı´n, Lopez-Sa ´ nchez & Gutierrez-Pizarraya Garnacho-Montero, Amaya-Villar, Ferra
Box 1. Risk factors for development of CRAB bacteremia. . . . .
.
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. . . .
Length of stay Prior colonization with CRAB Admission to the ICU Previous use of antibiotics: carbapenems and third-generation cephalosporins Medical underlying conditions Immunosuppression Unscheduled admission Respiratory failure at admission Older age
Adapted from references [5,7,11].
not absent of side effects. Thus, selection of patients who should receive empirical treatment covering CRAB is essential. The most frequently reported risk factors for CRAB bacteremia are listed in BOX 1 [5,7,11]. Several studies have reported a direct relation between colonization pressure and the acquisition of this pathogen [12,13]. Therefore, infections occurring during an outbreak or in a patient previously colonized by CRAB are the most powerful reasons for CRAB empirical coverage [14]. Therapeutic options for CRAB bacteremia
Most data regarding therapy for CRAB invasive infections including bacteremia come from case series and retrospective studies, though some clinical trials have been finished. These trials enrolled patients with different infections caused by difficult-to-treat Gram-negative bacteria and not exclusively CRAB. Pneumonia is the most frequent source of infection in these clinical trials. We summarize the most current knowledge regarding pharmacokinetic and pharmacodynamic properties, optimum dosing, clinical efficacy and safety of the available antimicrobial options for CRAB bacteremia. Sulbactam
Sulbactam is a potent b-lactamases inhibitor but possesses bactericidal activity against A. baumannii. In the majority of the studies, sulbactam has been used with ampicillin, although this association is not necessary given that ampicillin/sulbactam activity against A. baumannii is exclusively due to sulbactam. Regrettably, a steady increase in the resistance to sulbactam in A. baumannii clinical isolates has been reported in the last decade [15]. Sulbactam is a drug with undetermined breakpoints for Acinetobacter strains, but isolates with a MIC £4 mg/l are considered as susceptible [15]. Ampicillin/sulbactam was more effective than polymyxins in a retrospective study that included CRAB infections of diverse origins (although up to 30% of the patients in both groups were also treated with a carbapenem). Bloodstream infections were the most common infection site (62%) and urinary tract infections were not excluded from this analysis [16]. The lack of a loading dose of colistin and of the use of the current dosages to optimize the antimicrobial properties of polymyxins could explain these results. doi: 10.1586/14787210.2015.1032254
Valuable information about efficacy of sulbactam and the optimal dosing for severe infections have been obtained in two studies carried out in patients with ventilator-associated pneumonia (VAP). A randomized study evaluated the efficacy and safety of sulbactam (administered as ampicillin–sulbactam 2:1) in high doses (18/9 g vs 24/12 g every 24 h) in patients with VAP caused by multidrug-resistant strains of A. baumannii. The clinical and bacteriological cure was similar with both regimens and with excellent tolerance [17]. This same group compared in 28 patients with multidrug-resistant A. baumannii VAP, ampicillin–sulbactam (9 g every 8 h) with colistin (3 MIU every 8 h). Clinical and microbiological response was similar in both groups. The rate of renal impairment was higher with the use of colisitin (33 vs 15.3%), although this difference did not achieve statistical significance due to the low number of patients enrolled [18]. A recent study performed in healthy volunteers concluded that a 4-h infusion of 3 g of sulbactam every 8 h constitutes the best treatment option for lesssusceptible strains (MIC 8 mg/l) (TABLE 1) [19]. Polymyxins
Polymyxins are a group of polypeptide cationic antibiotics. Only polymyxin B and polymyxin E (colistin) are available for clinical use. It is noteworthy that the precise determination of in vitro activity for polymyxins is challenging because their physical–chemical properties can be influenced by the medium composition. Dilution methods are clearly preferred over disc susceptibility testing methods [20]. The addition of a surfactant (polysorbate 80) to the broth microdilution panels improves their accuracy for MIC determination [21]. Major errors have also been described with the E-test that cannot be considered as an accurate alternative [22]. Over the last decade, our knowledge on the clinical pharmacokinetic of colistin has increased considerably. Colistin is administered as an inactive form, colistimethate sodium (CMS) that undergoes rapid hydrolysis to colistin. Several studies have pointed out that intravenous administration of CMS may lead to inappropriately low plasma concentrations and is associated with higher mortality. Thus, low daily dosage of colistin was identified as an independent predictor of mortality (OR: 0.81; 95% CI: 0.68–0.96) in patients with VAP [23]. Plachouras et al. [24] has recently determined the need of a colistin loading dose for rapid achievement of the target serum concentrations. In 18 critically ill patients receiving 3 million IU of CMS 8-hourly, plasma drug levels were insufficient for the first 2–3 days. The authors recommended a loading dose of 9 million IU and 4.5 million IU 12-hourly because colistin exhibited a half-life that was relatively long in relation to the dosing interval. The target of colistin should be based on MIC, site of infection and severity of infection. However, it can be complicated to obtain therapeutic levels for A. baumannii with MIC >1 mg/l [25]. The clinical efficacy and the lack of toxicity of this regimen have been confirmed in a series of critically ill patients with bacteremia or VAP caused by multidrug-resistant Expert Rev. Anti Infect. Ther.
Optimum treatment strategies for CRAB bacteremia
Review
Table 1. Recommended doses of antimicrobials for CRAB A. baumannii bacteremia in patients with normal renal function. Antibiotic
Loading dose
Daily dose
Observations
Meropenem
Not required
2 g/8 h
Extended infusion (3–4 h) is recommended. In this case, first dose should be administered in 30 min. Always in combination therapy for CRAB
Sulbactam†
Not required
9–12 g/day (in three or four doses)
4-h infusion is recommended
Colistin (administered as the pro-drug CMS)†
6–9 UI of CMS
9 UI/day in two or three doses
Loading dose is necessary including patients with renal dysfunction. No dose adjustment in patients on CRRT§
Polymyxin B
Not established
1.5–3 mg/kg/day in two doses
Continuous infusion may be suitable. Same dose in patients on CRRT
Minocycline
200 mg
100 mg/12 h
The manufacturer recommends dosage adjustment in patients with renal dysfunction (clearance of creatinine 12 l/kg), penetrating well into different tissues but with low serum concentration declining rapidly after intravenous administration. This characteristic makes this drug not initially appropriate for the treatment of primary bacteremia. In fact, the steady-state peak concentration of tigecycline in serum after intravenous administration of the standard dosification was 0.72 ± 0.24 mg/l [47]. Therefore, treatment with tigecycline at the standard dosing regimen for bloodstream infections caused by A. baumannii strains with a MIC close to the breakpoint (£2 mg/l) may be insufficient. More recently, peak tigecycline serum concentrations were highly variable and concentrations increased with dose reaching serum levels above 1 mg/l after administration of a loading dose of 200 mg and a maintenance dose of 100 mg every 12 h [48]. Small non-comparative series have reported relatively poor clinical and microbiological outcomes with tigecycline for tigecycline-susceptible CRAB bacteremia [49–51]. The high severity of illness and the notable delays in initiation of effective antimicrobial therapy could also explain these results. Recently, a high-dose regimen (loading dose 200 mg followed by 100 mg every 12 h) has been successfully and safely used in critically ill patients with severe infections due to multidrugresistant bacteria although the number of primary bacteremia was anecdotal [52]. Fosfomycin
Fosfomycin is a broad-spectrum agent that inhibits the first step of peptidoglycan synthesis. Unfortunately, resistance doi: 10.1586/14787210.2015.1032254
frequently occurs when used in monotherapy; therefore, it should be used in combination with another antimicrobial. Although fosfomycin exhibits poor activity against A. baumannii, the combination of colistin plus fosfomycin exhibits synergistic activity against A. baumannii. A recent open trial evaluated monotherapy with colistin compared to the combination of colistin plus fosfomycin in CRAB. Microbiological response was significantly higher in the combination group, and a nonsignificant trend toward higher clinical cure and lower mortality was observed in this group. Bacteremia represents a small proportion of the cases included in this trial [53]. Other alternatives
Minocycline is a tetracycline antibiotic that retains good activity against multidrug-resistant A. baumannii including isolates resistant to carbapenemsref1. Interpretative criteria supported by international societies establish isolates with MIC £4 mg/l as susceptible, 8 mg/l as intermediate and ‡16 mg/l as resistant [54,55]. Clinical experience with minocycline for A. baumannii infections is scarce. However, clinical cure rate was around 80%, although only a small number of these patients had A. baumannii bloodstream infections. Even though monotherapy with minocycline is theoretically possible, it should be avoided to lessen the risk for drug resistance [54,56]. Interestingly, minocycline could be a valid alternative for strains resistant to tigecycline. Trimethoprim-sulfamethoxazole also exhibits in vitro activity against multidrug-resistant A. baummannii. In a recent study, accepting the Clinical and Laboratory Standards Institute breakpoint of sulfamethoxazole for Enterobacteriaceae (256 mg/l), 70% of the A. baumannii isolates were considered susceptible to trimethoprim-sulfamethoxazole [57]. Unfortunately, clinical information about its clinical utility is lacking. Combination therapy
Animal models suggest that infections caused by CRAB could be treated with a carbapenem in combination with another antibiotic (rifampicin or sulbactam) [58–60]. However, clinical experience in patents with CRAB bacteremia has produced disappointing results [61,62]. Synergy of colistin with diverse antibiotics such as imipenem, rifampin, fosfomycin, sulbactam or tigecycline has also been proved in experimental models [63–65]. Although MDR-A strains are supposed to be colistin-sensitive, in vitro heteroresistance has been reported [66]. This fact constitutes an undeniable argument for the use of combination therapy. However, clinical studies have not generally confirmed the theoretical beneficial effects of combination therapy in patients with severe infections. The combination of colistin plus rifampin has been evaluated in observational studies and clinical trials. Retrospective series concluded that this combination could be associated with a higher rate of clinical cure without apparent side effects [67–69]. Nevertheless, a recent randomized clinical trial did not find clinical superiority of the combination of colistin plus rifampicin over monotherapy with colistin in patients with severe infections (20.1% with bacteremia) caused by extensively drug-resistant Expert Rev. Anti Infect. Ther.
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Optimum treatment strategies for CRAB bacteremia
A. baumannii, although microbiological eradication was significantly higher in the combination group [70]. Another clinical trial that compared colistin plus rifampicin with colistin in patients with VAP caused by CRAB reported similar cure rates and mortality in both study arms [71]. A recent systematic review has confirmed the lack of clinical efficacy using the combination of colistin plus rifampin in severe A. baumannii infections. Furthermore, rifampicin use was associated with a higher incidence of liver toxicity than monotherapy with colistin [72]. The combination of colistin plus sulbactam has not provided better clinical results that the monotherapy with colistin [73]. It is worth mentioning a retrospective study that compared monotherapy with colistin with patients that received combination therapy (colistin plus carbapenem, sulbactam, tigecycline or other agents) in 250 patients with extensively resistant A. baumannii bacteremia. Rates of 14-day survival and microbiological cure were significantly higher in the combination group but without differences in the hospital survival [74]. An observational study that included 101 patients with A. baumannii infection failed to demonstrate clinical benefit of combination therapy after adjusting for confounding variables. Colistin plus tigecycline (27.3%) and carbapenem plus tigecycline (12.1%) were the most frequently used combinations [75]. Conversely, a recent systematic review concludes that combination is superior to monotherapy in severely ill patients with A. baumannii infections. Nevertheless, the small sample sizes and the retrospective design impede to find robust evidence that would lead to a firm recommendation [76]. Diverse in vitro studies have documented the existence of an unforeseen potent synergism of the combination of colistin with a glycopeptide against CRAB [77,78]. In a retrospective series, clinical benefit of the combination of colistin plus vancomycin was not documented in 57 patients (29 treated with combination therapy and 28 with monotherapy with colistin) with CRAB pneumonia and bacteremia (14% of the patients had primary bacteremia). In addition, the rate of renal failure was significantly higher in patients on combination therapy compared with those on monotherapy with colistin [79]. Conversely, a multicenter study that included 166 infections caused by different GNBs concluded that therapy with colistin plus a glycopeptide for at least 5 days was a protective factor for 30-day mortality [80]. In this series, A. baumannii represented only 60% of the patients, and the advantage of combination therapy in terms of cure rate could not be demonstrated in patients with A. baumannii infections. A strong synergy against A. baumannii has also been reported with another glycopeptide (teicoplanin) and with other anti-Gram-positive antibiotics such as telavancin (a new lipoglycopeptide) or daptomycin. Nevertheless, the utility of these combinations against colistin-resistant strain is limited [81–84]. Of note, the combination of daptomycin plus low doses of colistin is active against A. baumannii but is not useful against pathogenic Gram-negative bacilli [83]. Well-designed clinical studies are urgently needed to determine the clinical utility of these observations. informahealthcare.com
Review
Duration of therapy
There are neither observational studies nor clinical trials that have assessed the duration of antimicrobial therapy for A. baumannii bacteremia. Therefore, no specific recommendations about the length of therapy for CRAB bacteremia can be performed. The optimal duration must balance sufficient time to cure the infection and not promoting resistance emergence. Expert commentary
Adequate empirical therapy of severe infections caused by CRAB bacteremia is crucial in terms of survival. Due to the increasing antimicrobial resistance and the lack of well-designed studies, empirical treatments for A. baumannii infections often represent a challenge. Traditionally, carbapenems have been the drug of choice for the empirical treatment of A. baumannii infections and they are still the first-line agents for the empirical therapy in areas with high rates of susceptibility. Colistin may be administered empirically in institutions with a high rate of infections due to CRAB. It is suggested as part of the empirical treatment in patients with high suspicion of CRAB bacteremia, such as in outbreaks or in patients colonized with this pathogen. We do recommend the use of a loading dose of 6–9 MU in all patients independently of their renal function. Maintenance dose should be individually adjusted according to creatinine clearance. With creatinine clearance above 50 ml/min, maintenance doses of 9 MU every day (divided in two or three doses) should be administered. For patients undergoing continuous renal replacement therapy, a daily dose of 9 MU is suggested. In the directed therapy, colistin should be preserved for treating infections produced by A. baumannii strains showing resistance to all beta-lactams and sulbactam. Due to its pharmacokinetic/pharmacodynamic characteristics, tigecycline is not a suitable option for CRAB primary bacteremia. If no other alternative is available or they are contraindicated due to toxicity, we recommend high doses of tigecycline: loading dose 200 mg followed by 100 mg every 12 h. Conventional doses of tigecycline could be used for secondary bacteremia with origin in skin and soft-tissue or abdominal infections in tigecycline-susceptible isolates. Regarding the use of combination therapy, it is fully justified in the empirical regimen. Nevertheless, combination therapy cannot be recommended in the directed therapy for CRAB bacteremia. The decision should be individualized in each patient. However, we consider that combination therapy should be reserved for patients with bad clinical evolution or with infections caused by less-susceptible strains. Although the results of in vitro and in vivo experiments are promising, the combination of colistin plus a glycopeptide in CRAB bacteremia is discouraged in the clinical setting. The clinical efficacy of this combination is doubtful, but there exists an evident risk of increased nephrotoxicity. There are insufficient data to establish the optimal treatment duration in patients with CRAB bacteremia. However, we suggest maintaining antimicrobial therapy for 2 weeks in patients with CRAB bacteremia, especially in those manifested as severe doi: 10.1586/14787210.2015.1032254
Review
´ ndiz-Millon, Dı´az-Martı´n, Lopez-Sa ´ nchez & Gutierrez-Pizarraya Garnacho-Montero, Amaya-Villar, Ferra
sepsis or septic shock. Shorter duration of therapy may be acceptable in patients with less severe infections and adequate empirical therapy.
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Five-year view
Reduction of the time for confirmation of CRAB as the causative pathogen of a bloodstream infection and early appropriate antibiotics to treat this infection is crucial for critical patients. These are the current challenges that may help to improve patient outcome. Development of rapid methods for detection of bacteremia that includes at least certain patterns of susceptibility is an urgent necessity. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry is a modern technology that allows rapid identification of carbapenemase activity directly from bacterial colonies. This methodology has proved to be fast, easy-to-perform, accurate and cost-effective to routinely identify bacterial isolates. Widespread use of this tool may permit the rapid identification of CRAB in blood with the consequent institution of early active therapy. The need of new molecules, especially those with new modes of action, to treat multidrug-resistant Gram-negative bacilli is an urgent need. In the meanwhile, optimal dosing regimen of the available antibiotics using their pharmacokinetic and pharmacodynamic properties is mandatory particularly in organisms
with reduced susceptibilities. Very few molecules active against A. baumannii are in the antibiotic pipeline. BAL30072 is a novel monosulfactam with in vitro activity against Gramnegative pathogens especially against A. baumannii including carbapenem-resistant strains [85]. DS-8587 is a broad-spectrum fluoroquinolone especially effective against A. baumannii [86]. Sitafloxacin, a broad-spectrum oral fluoroquinolone, is active against 92% of CRAB isolated assuming the MIC cut-off value as £2 mg/l [87]. Eravacycline is a novel tetracycline with antimicrobial activity against Gram-positive and Gram-negative bacteria including CRAB [88]. Nevertheless, these compounds are in the pre-clinical phase or in the early stages of the clinical development, and the MIC breakpoints for the majority of these antimicrobials against A. baumannii are not available yet. Hopefully certain of these antibiotics could be an efficacious therapeutic option for CRAB bacteremia in the upcoming years. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
Early institution of appropriate antimicrobial therapy is shown to improve survival of patients with CRAB bacteremia.
.
Carbapanem should not be used at least in monotherapy in the empirical therapy of CRAB bacteremia in areas with high rate of resistance to carbapenems.
.
Colistin is the most appropriate option in the empirical treatment of patients with high suspicion of CRAB bacteremia.
.
A loading dose of 6–9 MU of colistin is necessary in all patients independently of their renal function to achieve adequate plasma levels in the first 24 h.
.
Maintenance dose should be individually adjusted according to creatinine clearance. With creatinine clearance above 50 ml/min, maintenance doses of 9 MU every day (divided in two or three doses) should be administered.
.
For patients undergoing continuous renal replacement therapy, a daily dose of 9 MU of colistin is suggested.
.
Tigecycline is not a suitable option for CRAB primary bacteremia. If no other alternative is available or they are contraindicated due to toxicity, a high-dose regimen (loading dose 200 mg followed by 100 mg every 12 h) should be administered.
.
Combination therapy should not be routinely used in the directed therapy for CRAB bacteremia. The decision should be individualized in each patient depending of the clinical situation and the MIC of the isolated strain.
bloodstream infections. Int J Antimicrob Agents 2009;34:575-9
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doi: 10.1586/14787210.2015.1032254
Review
Optimum treatment strategies for carbapenemresistant Acinetobacter baumannii bacteremia Expert Rev. Anti Infect. Ther. Early online, 1–9 (2015)
Jose Garnacho-Montero*1–3, Rosario Amaya-Villar1–3, Carmen Ferra´ndiz-Millon1, Ana Dı´az-Martı´n1,2, Jose Marı´a Lopez-Sa´nchez1 and Antonio Gutierrez-Pizarraya2,3
Carbapenem-resistant Acinetobacter baumannii (CRAB) constitutes an increasing problem worldwide. CRAB bacteremia is associated with a high fatality rate and its optimal treatment has not been established. Early institution of appropriate therapy is shown to improve survival of patients with CRAB bloodstream infection. Regrettably, treatment options are limited. Little information exists about the efficacy of sulbactam for the treatment of CRAB bacteremia. Colistin and tigecycline possess good in vitro activity and represent in many cases the only therapeutic options although clinical data are scarce. The need for a loading dose of colistin has been recently demonstrated to rapidly achieve therapeutic levels. The use of combination therapy is also a matter of debate but current evidence do not support its routine use. KEYWORDS: Acinetobacter baumannii . bacteremia . carbapenem-resistant . colistin . polymyxin . tigecycline .
treatment
1
Unidad Clı´nica de Cuidados Crı´ticos, Hospital Universitario Virgen del Rocı´o, Sevilla, Spain 2 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocı´o/CSIC/Universidad de Sevilla, Sevilla, Spain 3 Red Espan˜ola de Investigacion en Patologı´a Infecciosa (REIPI), Hospital Universitario Virgen del Rocı´o, Sevilla, Spain *Author for correspondence: [email protected]
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Acinetobacter baumannii has gained increasing attention in recent decades because of its potential to cause severe infections and by its ability to develop resistance to practically all the available antimicrobials. Bacteremia is probably with pneumonia, the most significant infection caused by this Gram-negative bacterium. Clinical manifestation of A. baumannii bloodstream infections range from transient bacteremia to severe diseases manifested as septic shock with high mortality. Regarding the origin of bacteremia, the lower respiratory tract is the most frequent source of infection, followed by intravascular catheters. Of note, inappropriate empirical antimicrobial therapy is associated with mortality even after adjustment with confounders [1,2]. Traditionally, carbapenems have been considered the drug of choice for empirical treatment of A. baumannii infections and they are still the first-line agents for the empirical therapy in areas with high rates of susceptibility. However, carbapenem-resistant A. baumannii (CRAB) has emerged as a serious threat for healthcare systems worldwide. Optimal management of infections caused by CRAB represents a real challenge given the paucity of 10.1586/14787210.2015.1032254
alternatives and the uncertainties about their efficacy and safety. This problem is especially pressing in severe infections such as bacteremia. In fact, carbapenem resistance has been identified as an independent variable associated with mortality in patients with A. baumannii bacteremia [3,4]. The inadequate antimicrobial empirical therapy rate is higher in bacteremias caused by carbapenem resistant A. baumannii than in carbapenem susceptible A. baumannii bacteremia cases. Moreover, the use of inactive empirical therapy was an independent predictor for death [5,6]. Very recently, in a cohort of patients with CRAB bacteremia, active antibiotic treatment was identified as a protective factor for 14-day mortality after adjusting with a multivariate Cox analysis that included the propensity score as covariate [7]. Consequently, carbapenems cannot be considered the treatment of choice in those areas with high rate of infections by CRAB. Nowadays, polymyxins are the antimicrobials with the greatest level of in vitro activity against A. baumannii [8–10]. However, polymyxins have been used with caution because they constitute frequently the last resort and their use is
2015 Informa UK Ltd
ISSN 1478-7210
1
Review
´ ndiz-Millon, Dı´az-Martı´n, Lopez-Sa ´ nchez & Gutierrez-Pizarraya Garnacho-Montero, Amaya-Villar, Ferra
Box 1. Risk factors for development of CRAB bacteremia. . . . .
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. . . .
Length of stay Prior colonization with CRAB Admission to the ICU Previous use of antibiotics: carbapenems and third-generation cephalosporins Medical underlying conditions Immunosuppression Unscheduled admission Respiratory failure at admission Older age
Adapted from references [5,7,11].
not absent of side effects. Thus, selection of patients who should receive empirical treatment covering CRAB is essential. The most frequently reported risk factors for CRAB bacteremia are listed in BOX 1 [5,7,11]. Several studies have reported a direct relation between colonization pressure and the acquisition of this pathogen [12,13]. Therefore, infections occurring during an outbreak or in a patient previously colonized by CRAB are the most powerful reasons for CRAB empirical coverage [14]. Therapeutic options for CRAB bacteremia
Most data regarding therapy for CRAB invasive infections including bacteremia come from case series and retrospective studies, though some clinical trials have been finished. These trials enrolled patients with different infections caused by difficult-to-treat Gram-negative bacteria and not exclusively CRAB. Pneumonia is the most frequent source of infection in these clinical trials. We summarize the most current knowledge regarding pharmacokinetic and pharmacodynamic properties, optimum dosing, clinical efficacy and safety of the available antimicrobial options for CRAB bacteremia. Sulbactam
Sulbactam is a potent b-lactamases inhibitor but possesses bactericidal activity against A. baumannii. In the majority of the studies, sulbactam has been used with ampicillin, although this association is not necessary given that ampicillin/sulbactam activity against A. baumannii is exclusively due to sulbactam. Regrettably, a steady increase in the resistance to sulbactam in A. baumannii clinical isolates has been reported in the last decade [15]. Sulbactam is a drug with undetermined breakpoints for Acinetobacter strains, but isolates with a MIC £4 mg/l are considered as susceptible [15]. Ampicillin/sulbactam was more effective than polymyxins in a retrospective study that included CRAB infections of diverse origins (although up to 30% of the patients in both groups were also treated with a carbapenem). Bloodstream infections were the most common infection site (62%) and urinary tract infections were not excluded from this analysis [16]. The lack of a loading dose of colistin and of the use of the current dosages to optimize the antimicrobial properties of polymyxins could explain these results. doi: 10.1586/14787210.2015.1032254
Valuable information about efficacy of sulbactam and the optimal dosing for severe infections have been obtained in two studies carried out in patients with ventilator-associated pneumonia (VAP). A randomized study evaluated the efficacy and safety of sulbactam (administered as ampicillin–sulbactam 2:1) in high doses (18/9 g vs 24/12 g every 24 h) in patients with VAP caused by multidrug-resistant strains of A. baumannii. The clinical and bacteriological cure was similar with both regimens and with excellent tolerance [17]. This same group compared in 28 patients with multidrug-resistant A. baumannii VAP, ampicillin–sulbactam (9 g every 8 h) with colistin (3 MIU every 8 h). Clinical and microbiological response was similar in both groups. The rate of renal impairment was higher with the use of colisitin (33 vs 15.3%), although this difference did not achieve statistical significance due to the low number of patients enrolled [18]. A recent study performed in healthy volunteers concluded that a 4-h infusion of 3 g of sulbactam every 8 h constitutes the best treatment option for lesssusceptible strains (MIC 8 mg/l) (TABLE 1) [19]. Polymyxins
Polymyxins are a group of polypeptide cationic antibiotics. Only polymyxin B and polymyxin E (colistin) are available for clinical use. It is noteworthy that the precise determination of in vitro activity for polymyxins is challenging because their physical–chemical properties can be influenced by the medium composition. Dilution methods are clearly preferred over disc susceptibility testing methods [20]. The addition of a surfactant (polysorbate 80) to the broth microdilution panels improves their accuracy for MIC determination [21]. Major errors have also been described with the E-test that cannot be considered as an accurate alternative [22]. Over the last decade, our knowledge on the clinical pharmacokinetic of colistin has increased considerably. Colistin is administered as an inactive form, colistimethate sodium (CMS) that undergoes rapid hydrolysis to colistin. Several studies have pointed out that intravenous administration of CMS may lead to inappropriately low plasma concentrations and is associated with higher mortality. Thus, low daily dosage of colistin was identified as an independent predictor of mortality (OR: 0.81; 95% CI: 0.68–0.96) in patients with VAP [23]. Plachouras et al. [24] has recently determined the need of a colistin loading dose for rapid achievement of the target serum concentrations. In 18 critically ill patients receiving 3 million IU of CMS 8-hourly, plasma drug levels were insufficient for the first 2–3 days. The authors recommended a loading dose of 9 million IU and 4.5 million IU 12-hourly because colistin exhibited a half-life that was relatively long in relation to the dosing interval. The target of colistin should be based on MIC, site of infection and severity of infection. However, it can be complicated to obtain therapeutic levels for A. baumannii with MIC >1 mg/l [25]. The clinical efficacy and the lack of toxicity of this regimen have been confirmed in a series of critically ill patients with bacteremia or VAP caused by multidrug-resistant Expert Rev. Anti Infect. Ther.
Optimum treatment strategies for CRAB bacteremia
Review
Table 1. Recommended doses of antimicrobials for CRAB A. baumannii bacteremia in patients with normal renal function. Antibiotic
Loading dose
Daily dose
Observations
Meropenem
Not required
2 g/8 h
Extended infusion (3–4 h) is recommended. In this case, first dose should be administered in 30 min. Always in combination therapy for CRAB
Sulbactam†
Not required
9–12 g/day (in three or four doses)
4-h infusion is recommended
Colistin (administered as the pro-drug CMS)†
6–9 UI of CMS
9 UI/day in two or three doses
Loading dose is necessary including patients with renal dysfunction. No dose adjustment in patients on CRRT§
Polymyxin B
Not established
1.5–3 mg/kg/day in two doses
Continuous infusion may be suitable. Same dose in patients on CRRT
Minocycline
200 mg
100 mg/12 h
The manufacturer recommends dosage adjustment in patients with renal dysfunction (clearance of creatinine 12 l/kg), penetrating well into different tissues but with low serum concentration declining rapidly after intravenous administration. This characteristic makes this drug not initially appropriate for the treatment of primary bacteremia. In fact, the steady-state peak concentration of tigecycline in serum after intravenous administration of the standard dosification was 0.72 ± 0.24 mg/l [47]. Therefore, treatment with tigecycline at the standard dosing regimen for bloodstream infections caused by A. baumannii strains with a MIC close to the breakpoint (£2 mg/l) may be insufficient. More recently, peak tigecycline serum concentrations were highly variable and concentrations increased with dose reaching serum levels above 1 mg/l after administration of a loading dose of 200 mg and a maintenance dose of 100 mg every 12 h [48]. Small non-comparative series have reported relatively poor clinical and microbiological outcomes with tigecycline for tigecycline-susceptible CRAB bacteremia [49–51]. The high severity of illness and the notable delays in initiation of effective antimicrobial therapy could also explain these results. Recently, a high-dose regimen (loading dose 200 mg followed by 100 mg every 12 h) has been successfully and safely used in critically ill patients with severe infections due to multidrugresistant bacteria although the number of primary bacteremia was anecdotal [52]. Fosfomycin
Fosfomycin is a broad-spectrum agent that inhibits the first step of peptidoglycan synthesis. Unfortunately, resistance doi: 10.1586/14787210.2015.1032254
frequently occurs when used in monotherapy; therefore, it should be used in combination with another antimicrobial. Although fosfomycin exhibits poor activity against A. baumannii, the combination of colistin plus fosfomycin exhibits synergistic activity against A. baumannii. A recent open trial evaluated monotherapy with colistin compared to the combination of colistin plus fosfomycin in CRAB. Microbiological response was significantly higher in the combination group, and a nonsignificant trend toward higher clinical cure and lower mortality was observed in this group. Bacteremia represents a small proportion of the cases included in this trial [53]. Other alternatives
Minocycline is a tetracycline antibiotic that retains good activity against multidrug-resistant A. baumannii including isolates resistant to carbapenemsref1. Interpretative criteria supported by international societies establish isolates with MIC £4 mg/l as susceptible, 8 mg/l as intermediate and ‡16 mg/l as resistant [54,55]. Clinical experience with minocycline for A. baumannii infections is scarce. However, clinical cure rate was around 80%, although only a small number of these patients had A. baumannii bloodstream infections. Even though monotherapy with minocycline is theoretically possible, it should be avoided to lessen the risk for drug resistance [54,56]. Interestingly, minocycline could be a valid alternative for strains resistant to tigecycline. Trimethoprim-sulfamethoxazole also exhibits in vitro activity against multidrug-resistant A. baummannii. In a recent study, accepting the Clinical and Laboratory Standards Institute breakpoint of sulfamethoxazole for Enterobacteriaceae (256 mg/l), 70% of the A. baumannii isolates were considered susceptible to trimethoprim-sulfamethoxazole [57]. Unfortunately, clinical information about its clinical utility is lacking. Combination therapy
Animal models suggest that infections caused by CRAB could be treated with a carbapenem in combination with another antibiotic (rifampicin or sulbactam) [58–60]. However, clinical experience in patents with CRAB bacteremia has produced disappointing results [61,62]. Synergy of colistin with diverse antibiotics such as imipenem, rifampin, fosfomycin, sulbactam or tigecycline has also been proved in experimental models [63–65]. Although MDR-A strains are supposed to be colistin-sensitive, in vitro heteroresistance has been reported [66]. This fact constitutes an undeniable argument for the use of combination therapy. However, clinical studies have not generally confirmed the theoretical beneficial effects of combination therapy in patients with severe infections. The combination of colistin plus rifampin has been evaluated in observational studies and clinical trials. Retrospective series concluded that this combination could be associated with a higher rate of clinical cure without apparent side effects [67–69]. Nevertheless, a recent randomized clinical trial did not find clinical superiority of the combination of colistin plus rifampicin over monotherapy with colistin in patients with severe infections (20.1% with bacteremia) caused by extensively drug-resistant Expert Rev. Anti Infect. Ther.
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Optimum treatment strategies for CRAB bacteremia
A. baumannii, although microbiological eradication was significantly higher in the combination group [70]. Another clinical trial that compared colistin plus rifampicin with colistin in patients with VAP caused by CRAB reported similar cure rates and mortality in both study arms [71]. A recent systematic review has confirmed the lack of clinical efficacy using the combination of colistin plus rifampin in severe A. baumannii infections. Furthermore, rifampicin use was associated with a higher incidence of liver toxicity than monotherapy with colistin [72]. The combination of colistin plus sulbactam has not provided better clinical results that the monotherapy with colistin [73]. It is worth mentioning a retrospective study that compared monotherapy with colistin with patients that received combination therapy (colistin plus carbapenem, sulbactam, tigecycline or other agents) in 250 patients with extensively resistant A. baumannii bacteremia. Rates of 14-day survival and microbiological cure were significantly higher in the combination group but without differences in the hospital survival [74]. An observational study that included 101 patients with A. baumannii infection failed to demonstrate clinical benefit of combination therapy after adjusting for confounding variables. Colistin plus tigecycline (27.3%) and carbapenem plus tigecycline (12.1%) were the most frequently used combinations [75]. Conversely, a recent systematic review concludes that combination is superior to monotherapy in severely ill patients with A. baumannii infections. Nevertheless, the small sample sizes and the retrospective design impede to find robust evidence that would lead to a firm recommendation [76]. Diverse in vitro studies have documented the existence of an unforeseen potent synergism of the combination of colistin with a glycopeptide against CRAB [77,78]. In a retrospective series, clinical benefit of the combination of colistin plus vancomycin was not documented in 57 patients (29 treated with combination therapy and 28 with monotherapy with colistin) with CRAB pneumonia and bacteremia (14% of the patients had primary bacteremia). In addition, the rate of renal failure was significantly higher in patients on combination therapy compared with those on monotherapy with colistin [79]. Conversely, a multicenter study that included 166 infections caused by different GNBs concluded that therapy with colistin plus a glycopeptide for at least 5 days was a protective factor for 30-day mortality [80]. In this series, A. baumannii represented only 60% of the patients, and the advantage of combination therapy in terms of cure rate could not be demonstrated in patients with A. baumannii infections. A strong synergy against A. baumannii has also been reported with another glycopeptide (teicoplanin) and with other anti-Gram-positive antibiotics such as telavancin (a new lipoglycopeptide) or daptomycin. Nevertheless, the utility of these combinations against colistin-resistant strain is limited [81–84]. Of note, the combination of daptomycin plus low doses of colistin is active against A. baumannii but is not useful against pathogenic Gram-negative bacilli [83]. Well-designed clinical studies are urgently needed to determine the clinical utility of these observations. informahealthcare.com
Review
Duration of therapy
There are neither observational studies nor clinical trials that have assessed the duration of antimicrobial therapy for A. baumannii bacteremia. Therefore, no specific recommendations about the length of therapy for CRAB bacteremia can be performed. The optimal duration must balance sufficient time to cure the infection and not promoting resistance emergence. Expert commentary
Adequate empirical therapy of severe infections caused by CRAB bacteremia is crucial in terms of survival. Due to the increasing antimicrobial resistance and the lack of well-designed studies, empirical treatments for A. baumannii infections often represent a challenge. Traditionally, carbapenems have been the drug of choice for the empirical treatment of A. baumannii infections and they are still the first-line agents for the empirical therapy in areas with high rates of susceptibility. Colistin may be administered empirically in institutions with a high rate of infections due to CRAB. It is suggested as part of the empirical treatment in patients with high suspicion of CRAB bacteremia, such as in outbreaks or in patients colonized with this pathogen. We do recommend the use of a loading dose of 6–9 MU in all patients independently of their renal function. Maintenance dose should be individually adjusted according to creatinine clearance. With creatinine clearance above 50 ml/min, maintenance doses of 9 MU every day (divided in two or three doses) should be administered. For patients undergoing continuous renal replacement therapy, a daily dose of 9 MU is suggested. In the directed therapy, colistin should be preserved for treating infections produced by A. baumannii strains showing resistance to all beta-lactams and sulbactam. Due to its pharmacokinetic/pharmacodynamic characteristics, tigecycline is not a suitable option for CRAB primary bacteremia. If no other alternative is available or they are contraindicated due to toxicity, we recommend high doses of tigecycline: loading dose 200 mg followed by 100 mg every 12 h. Conventional doses of tigecycline could be used for secondary bacteremia with origin in skin and soft-tissue or abdominal infections in tigecycline-susceptible isolates. Regarding the use of combination therapy, it is fully justified in the empirical regimen. Nevertheless, combination therapy cannot be recommended in the directed therapy for CRAB bacteremia. The decision should be individualized in each patient. However, we consider that combination therapy should be reserved for patients with bad clinical evolution or with infections caused by less-susceptible strains. Although the results of in vitro and in vivo experiments are promising, the combination of colistin plus a glycopeptide in CRAB bacteremia is discouraged in the clinical setting. The clinical efficacy of this combination is doubtful, but there exists an evident risk of increased nephrotoxicity. There are insufficient data to establish the optimal treatment duration in patients with CRAB bacteremia. However, we suggest maintaining antimicrobial therapy for 2 weeks in patients with CRAB bacteremia, especially in those manifested as severe doi: 10.1586/14787210.2015.1032254
Review
´ ndiz-Millon, Dı´az-Martı´n, Lopez-Sa ´ nchez & Gutierrez-Pizarraya Garnacho-Montero, Amaya-Villar, Ferra
sepsis or septic shock. Shorter duration of therapy may be acceptable in patients with less severe infections and adequate empirical therapy.
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Five-year view
Reduction of the time for confirmation of CRAB as the causative pathogen of a bloodstream infection and early appropriate antibiotics to treat this infection is crucial for critical patients. These are the current challenges that may help to improve patient outcome. Development of rapid methods for detection of bacteremia that includes at least certain patterns of susceptibility is an urgent necessity. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry is a modern technology that allows rapid identification of carbapenemase activity directly from bacterial colonies. This methodology has proved to be fast, easy-to-perform, accurate and cost-effective to routinely identify bacterial isolates. Widespread use of this tool may permit the rapid identification of CRAB in blood with the consequent institution of early active therapy. The need of new molecules, especially those with new modes of action, to treat multidrug-resistant Gram-negative bacilli is an urgent need. In the meanwhile, optimal dosing regimen of the available antibiotics using their pharmacokinetic and pharmacodynamic properties is mandatory particularly in organisms
with reduced susceptibilities. Very few molecules active against A. baumannii are in the antibiotic pipeline. BAL30072 is a novel monosulfactam with in vitro activity against Gramnegative pathogens especially against A. baumannii including carbapenem-resistant strains [85]. DS-8587 is a broad-spectrum fluoroquinolone especially effective against A. baumannii [86]. Sitafloxacin, a broad-spectrum oral fluoroquinolone, is active against 92% of CRAB isolated assuming the MIC cut-off value as £2 mg/l [87]. Eravacycline is a novel tetracycline with antimicrobial activity against Gram-positive and Gram-negative bacteria including CRAB [88]. Nevertheless, these compounds are in the pre-clinical phase or in the early stages of the clinical development, and the MIC breakpoints for the majority of these antimicrobials against A. baumannii are not available yet. Hopefully certain of these antibiotics could be an efficacious therapeutic option for CRAB bacteremia in the upcoming years. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues .
Early institution of appropriate antimicrobial therapy is shown to improve survival of patients with CRAB bacteremia.
.
Carbapanem should not be used at least in monotherapy in the empirical therapy of CRAB bacteremia in areas with high rate of resistance to carbapenems.
.
Colistin is the most appropriate option in the empirical treatment of patients with high suspicion of CRAB bacteremia.
.
A loading dose of 6–9 MU of colistin is necessary in all patients independently of their renal function to achieve adequate plasma levels in the first 24 h.
.
Maintenance dose should be individually adjusted according to creatinine clearance. With creatinine clearance above 50 ml/min, maintenance doses of 9 MU every day (divided in two or three doses) should be administered.
.
For patients undergoing continuous renal replacement therapy, a daily dose of 9 MU of colistin is suggested.
.
Tigecycline is not a suitable option for CRAB primary bacteremia. If no other alternative is available or they are contraindicated due to toxicity, a high-dose regimen (loading dose 200 mg followed by 100 mg every 12 h) should be administered.
.
Combination therapy should not be routinely used in the directed therapy for CRAB bacteremia. The decision should be individualized in each patient depending of the clinical situation and the MIC of the isolated strain.
bloodstream infections. Int J Antimicrob Agents 2009;34:575-9
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doi: 10.1586/14787210.2015.1032254
