Optimizing therapy for vancomycin-resistant enterococcal bacteremia in children.

PURPOSE OF REVIEW: Uncertainties exist regarding the optimal treatment for vancomycin-resistant enterococcal (VRE) bloodstream infections, particularly in settings in which ampicillin cannot be used. RECENT FINDINGS: Quinupristin-dalfopristin, linezolid, and daptomycin, all approved between 1999 and 2003, represent the mainstays of therapy for VRE bacteremia, although only linezolid has been specifically approved by the United States Food and Drug Administration for this indication. The main objective of this review is to compare the relative efficacies, dosing strategies, and side-effect profiles of quinupristin-dalfopristin, linezolid, and daptomycin for VRE bacteremia in the pediatric population. A brief description of recently approved broad-spectrum Gram-positive agents that may have a role in the management of VRE bacteremia in upcoming years is also provided. SUMMARY: Linezolid, despite its bacteriostatic activity against VRE, may be the most versatile of the available drugs. It has activity against both Enterococcus faecalis and E. faecium, can be administered orally, and resistance appears to be less of a concern with linezolid compared with the other agents. Additionally, the results of two recent meta-analyses demonstrate more favorable outcomes with linezolid compared with daptomycin for the treatment of VRE bacteremia. The clinical pharmacokinetics of linezolid have been well described in children. The most notable concern with linezolid, however, is toxicities associated with prolonged use. Until more prospective data are available, we favor linezolid as first-line therapy for the treatment of VRE bacteremia in children.

Quinupristin-dalfopristin versus linezolid for the treatment of vancomycin-resistant Enterococcus faecium bacteraemia: efficacy and development of resistance.

Quinupristin-dalfopristin and linezolid are widely used for the treatment of vancomycin-resistant Enterococcus faecium (VREF) infections. Increasing resistance of VREF to quinupristin-dalfopristin and linezolid is a cause for concern. To determine the efficacy of and the rate of development of resistance to quinupristin-dalfopristin and linezolid, we analyzed all episodes of clinically significant VREF bacteraemia at a tertiary-care hospital from January 2003 to June 2007. The main outcomes were rates of 30-day mortality, microbiological response, and development of resistance. Fifty-two patients were treated with quinupristin-dalfopristin and 61 were treated with linezolid. Baseline demographic and clinical characteristics were similar between the 2 groups. There were no significant between-group differences in 30-day mortality (48% in the quinupristin-dalfopristin group vs 41% in the linezolid group; p = 0.45) or microbiological response (60% vs 66%; p = 0.51). However, prolonged bacteraemia (18% of 45 evaluable cases vs 4% of 55 evaluable cases; p = 0.04) and development of resistance in blood isolates (11% vs 0%; p = 0.02) were more frequently observed in the quinupristin-dalfopristin group than in the linezolid group. There was no significant difference between the efficacy of quinupristin-dalfopristin and linezolid. However, prolonged bacteraemia and the development of resistance were more common in quinupristin-dalfopristin-treated patients.

The in vitro effects of quinupristin/dalfopristin, erythromycin and levofloxacin at low concentrations on the expression of different cell adhesion molecules on the surface of endothelial cells (Eahy926).

OBJECTIVES: Infusion phlebitis is a common clinical problem associated with some antimicrobial agents. The pathomechanism of infusion phlebitis has not yet been elucidated, however, it has been proposed that chemical irritation of the endothelium leads to subsequent sterile inflammation with recruitment and migration of leukocytes. In the present study, cultured endothelial cells were exposed to antibiotics at clinically relevant concentrations to detect changes in various cell surface markers. METHODS: Cells from the endothelial hybrid cell line Eahy926 were exposed to quinupristin/dalfopristin, erythromycin and levofloxacin at increasing concentrations (3, 10, 30 and 100 mg/l) for 24 h. After washing, the cells were marked with monoclonal antibodies against different cell surface antigens (intercellular cell adhesion molecule-1 [ICAM-1], platelet-endothelial cell adhesion molecule-1 [PECAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin, L-selectin, CD34, alpha(2), alpha(5), beta(1) and beta(4) integrin chains and analysed by flow cytometry. For comparison, cells were either untreated or incubated with tumor necrosis factor alpha (TNF-alpha) at a concentration of 10 ng/ml and analysed for ICAM-1, VCAM-1 and E-selectin expression. RESULTS: There was an increase in ICAM-1 expression on endothelial cells with increasing concentrations of quinupristin/dalfopristin. VCAM-1, E-selectin, L-selectin and CD34 showed an excursive upregulation at the concentration of 100 mg/l only, while no consistent changes were observed for PECAM-1 and the integrins. Markedly less prominent changes in the expression of these adhesion molecules were seen with erythromycin while no relevant changes at all occurred with levofloxacin. The absolute change in ICAM-1 activation with quinupristin/dalfopristin at 100 mg/l (34.4%) was less pronounced than that observed after stimulation with TNF-alpha (>80%). CONCLUSIONS: The results of this study indicate that antibiotics with a high potential for local cytotoxicity may cause an inflammatory response by endothelial cells even at rather low concentrations. The increase in expression of cell surface markers involved in cell-cell interaction could be an important mechanism in the development of infusion phlebitis.

Bayesian Monte Carlo uncertainty analysis of human health risks from animal antimicrobial use in a dynamic model of emerging resistance.

Recent qualitative analyses warn of potential future human health risks from emergence of antibiotic resistance in food-borne pathogens due to the use of similar antimicrobial drugs in both food animals and human medicine. While historical data suggest that human health risks from some animal antimicrobials, such as virginiamycin (VM), have remained low (McDonald et al., 2001), there is a widespread concern that "resistance epidemics" or endemics could arise in the future. How reassuring is the past about the future? This article applies quantitative risk assessment methods to help find out, using human health risks from VM and the nearly identical human antimicrobial quinupristin-dalfopristin (QD) as a case study. A dynamic simulation model is used to predict the risks of emerging resistance to human antimicrobials in human populations from given input assumptions. Bayesian Monte Carlo uncertainty analysis allows past data to constrain and inform selection of input parameter values, and thus to predict the possible future resistance patterns that are consistent with historical data. The results show that health risks from VM use in food animals are highly sensitive to the human prescription rate of QD. For realistic prescription rates, quantitative risks are less than 1 x 10(-6) even for members of the most-threatened (ICU patient) population, while societal risks are <1 excess statistical death per year for the whole U.S. population. Such quantitative estimates complement more qualitative assessments that discuss the possibility of future "resistance epidemics" (or endemics) without quantifying their probabilities.

Relationship between myalgias/arthralgias occurring in patients receiving quinupristin/dalfopristin and biliary dysfunction.

OBJECTIVES: To determine whether myalgias/arthralgias occurring in cancer patients who receive quinupristin/dalfopristin are associated with biliary tract dysfunction. METHODS: We studied 56 patients with vancomycin-resistant enterococcal infections who were treated with quinupristin/dalfopristin 7.5 mg/kg every 8 h for a mean duration of 12 days (range 2-52 days). Liver function tests, including a test for alkaline phosphatase, were performed before, during and after the end of therapy. All patients were followed for 1 month after completion of therapy. RESULTS: Thirty-eight (68%) of the 56 patients responded. Myalgias/arthralgias were the leading adverse events occurring in 20 (36%) of the patients. Patients with myalgias/arthralgias had significantly higher levels of alkaline phosphatase (mean 318.7 IU/L) during the mid-term therapy cycle compared with patients without any joint or muscular pain (mean 216.3 IU/L, P = 0.05). In addition, 3/18 (16.6%) patients with myalgias/arthralgias had more than five-fold the normal levels of alkaline phosphatase, which did not occur in any of the other patients who did not develop myalgias/arthralgias (P = 0.04). All myalgias/arthralgias resolved after the discontinuation of quinupristin/dalfopristin. By univariate analysis, other factors associated with myalgias/arthralgias were relapse of haematological malignancy (P = 0.01), receiving tacrolimus within 1 month prior to treatment (P = 0.04) and receiving methotrexate during antimicrobial therapy (P = 0.05). CONCLUSIONS: Myalgias/arthralgias occur frequently in cancer patients receiving quinupristin/dalfopristin and may be associated with biliary tract dysfunction, as measured by alkaline phosphatase or other factors that could lead to intra-hepatic cholestasis, such as relapse of haematological malignancy or treatment with tacrolimus or methotrexate.

Drug skin tests in cutaneous adverse drug reactions to pristinamycin: 29 cases with a study of cross-reactions between synergistins.

The present study was made to determine the value of drug skin tests in patients with cutaneous adverse drug reactions (CADRs) due to a synergistin (pristinamycin) and to determine the frequency of cross-reactions between synergistins. 29 patients were referred during the onset of the CADR due to pristinamycin: 18 with maculopapular rash, 9 erythrodermas, 1 angioedema and 1 Stevens-Johnson syndrome. They all had patch tests with pristinamycin and, in most cases, with other synergistins [virginiamycin and dalfopristin-quinupristin (DQ)], prick tests (10 cases) and intradermal tests (IDT) (5 cases). Skin tests with synergistins were positive in 27 cases, patch tests with pristinamycin in 20/29 cases (69%), prick tests with pristinamycin in 3/9 cases on immediate (1 case) or on delayed (2 cases) readings, and IDT with DQ in 4/5 cases. Cross-reactions between synergistins occurred in 9/22 with virginiamycin and in 7/8 cases with DQ. Skin tests with synergistins are useful in investigating CADR due to pristinamycin. Synergistins are composed of 2 chains (1 depsipeptide and 1 macrocyclic lactone) with many structural analogies between all synergistins. According to the chemical structures and our results, it seems advisable to avoid all synergistins in patients with CADR due to pristinamycin.

Quantifying human health risks from virginiamycin used in chickens.

The streptogramin antimicrobial combination Quinupristin-Dalfopristin (QD) has been used in the United States since late 1999 to treat patients with vancomycin-resistant Enterococcus faecium (VREF) infections. Another streptogramin, virginiamycin (VM), is used as a growth promoter and therapeutic agent in farm animals in the United States and other countries. Many chickens test positive for QD-resistant E. faecium, raising concern that VM use in chickens might compromise QD effectiveness against VREF infections by promoting development of QD-resistant strains that can be transferred to human patients. Despite the potential importance of this threat to human health, quantifying the risk via traditional farm-to-fork modeling has proved extremely difficult. Enough key data (mainly on microbial loads at each stage) are lacking so that such modeling amounts to little more than choosing a set of assumptions to determine the answer. Yet, regulators cannot keep waiting for more data. Patients prescribed QD are typically severely ill, immunocompromised people for whom other treatment options have not readily been available. Thus, there is a pressing need for sound risk assessment methods to inform risk management decisions for VM/QD using currently available data. This article takes a new approach to the QD-VM risk modeling challenge. Recognizing that the usual farm-to-fork ("forward chaining") approach commonly used in antimicrobial risk assessment for food animals is unlikely to produce reliable results soon enough to be useful, we instead draw on ideas from traditional fault tree analysis ("backward chaining") to reverse the farm-to-fork process and start with readily available human data on VREF case loads and QD resistance rates. Combining these data with recent genogroup frequency data for humans, chickens, and other sources (Willems et al., 2000, 2001) allows us to quantify potential human health risks from VM in chickens in both the United States and Australia, two countries where regulatory action for VM is being considered. We present a risk simulation model, thoroughly grounded in data, that incorporates recent nosocomial transmission and genetic typing data. The model is used to estimate human QD treatment failures over the next five years with and without continued VM use in chickens. The quantitative estimates and probability distributions were implemented in a Monte Carlo simulation model for a five-year horizon beginning in the first quarter of 2002. In Australia, a Q1-2002 ban of virginiamycin would likely reduce average attributable treatment failures by 0.35 x 10(-3) cases, expected mortalities by 5.8 x 10(-5) deaths, and life years lost by 1.3 x 10(-3) for the entire population over five years. In the United States, where the number of cases of VRE is much higher, a 1Q-2002 ban on VM is predicted to reduce average attributable treatment failures by 1.8 cases in the entire population over five years; expected mortalities by 0.29 cases; and life years lost by 6.3 over a five-year period. The model shows that the theoretical statistical human health benefits of a VM ban range from zero to less than one statistical life saved in both Australia and the United States over the next five years and are rapidly decreasing. Sensitivity analyses indicate that this conclusion is robust to key data gaps and uncertainties, e.g., about the extent of resistance transfer from chickens to people.

Prospective, randomized study comparing quinupristin-dalfopristin with linezolid in the treatment of vancomycin-resistant Enterococcus faecium infections.

OBJECTIVES: Quinupristin-dalfopristin and linezolid have been shown to be efficacious in the treatment of vancomycin-resistant Enterococcus faecium (VREF) infections. However, the two antibiotics have not been compared in terms of safety and efficacy in a prospective randomized study. The objective of this study was to compare the safety and efficacy of the two drugs in the treatment of VREF infections in cancer patients. PATIENTS AND METHODS: Forty cancer patients with VREF infection were randomized to receive linezolid 600 mg every 12 h or quinupristin-dalfopristin 7.5 mg/kg every 8 h. All patients were followed up for 30 days after discontinuation of study drugs. RESULTS: Linezolid and quinupristin-dalfopristin had comparable clinical responses (58% and 43%, respectively, P = 0.6). Myalgias and/or arthralgias occurred at a frequency of 33% in patients who received quinupristin-dalfopristin, but were not observed in the linezolid group (P = 0.03). In contrast, drug-related thrombocytopenia occurred in 11% of patients who received linezolid, but was not observed in the quinupristin-dalfopristin group (P = 0.2). CONCLUSION: In cancer patients, quinupristin-dalfopristin treatment is associated with a relatively high frequency of myalgias/arthralgias; however, profound thrombocytopenia might limit the choice of linezolid in a subpopulation of cancer patients.

Relations between the consumption of antimicrobial growth promoters and the occurrence of resistance among Enterococcus faecium isolated from broilers.

The present study investigates, at farm level, the effect of the time-span between sampling and the last time a particular antimicrobial growth promoter (AGP) was included in the feed on the probability of selecting an AGP-resistant Enterococcus faecium isolate from a broiler flock. The probability that a randomly selected E. faecium isolate was resistant to avilamycin, erythromycin or virginiamycin was 0.91, 0.92 and 0.84, respectively if the isolate originated from a broiler flock fed either avilamycin- or virginiamycin-supplemented feed. As the time-span between sampling and the last AGP consumption increased, the probability of isolating an E. faecium isolate resistant to a particular AGP decreased (probability <0.2 within 3-5 years after last exposure to AGPs). The decrease in probability over time showed little farm-to-farm variation. The number of times a particular AGP was given to previous flocks reared in the same house had no effect on the probability of isolating a resistant isolate.

Quinupristin/dalfopristin-induced Sweet's syndrome.

Quinupristin/Dalfopristin is a new combination of streptogramin antibiotics designed specifically to treat clinically significant infections due to Vancomycin-resistant Enterococcus Faecium. Sweet's syndrome is characterized by painful skin plaques, which is associated with dermal neutrophilic infiltration, fever and peripheral blood leukocytosis. Drug-induced Sweet's syndrome has a temporal relationship between drug ingestion, clinical presentation and the temporally-related resolution of lesions following drug withdrawal or on treatment with systemic corticosteroids. A 63-year-old woman received Quinupristin/Dalfopristin for acute pyelonephritis developed fever, arthralgia, vomiting, and painful erythematous skin plaques. A skin biopsy showed neutrophilic dermatosis, and there was rapid resolution of the symptoms and cutaneous lesions after discontinuation of Quinupristin/Dalfopristin, consistent with drug-induced Sweet's syndrome. To date, there has been no reported case of Sweet's syndrome associated with the use of Quinupristin/Dalfopristin.

Linezolid and quinupristin/dalfopristin: novel antibiotics for gram-positive infections of the skin.

With the continuing development of clinical drug resistance among bacteria, the need for new, effective agents to treat multi-drug-resistant Gram-positive infections remains important. With treatment options limited, it has become critical to identify antibiotics with novel mechanisms of activity. Several new drugs have emerged as possible therapeutic alternatives. This review focuses on agents newly introduced and FDA-approved for the treatment of skin and skin structure infections: linezolid and quinupristin/dalfopristin.

Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy.

STUDY OBJECTIVE: To evaluate risk factors for the development of arthralgias or myalgias associated with quinupristin-dalfopristin. DESIGN: Retrospective chart review and case-control analysis. SETTING: An 850-bed tertiary care medical center. PATIENTS: All adult and pediatric patients who had received quinupristin-dalfopristin through either a compassionate-use protocol (February 1996-October 1999) or in the year after quinupristin-dalfopristin was added to the hospital formulary (November 1999-October 2000) were included in this study. Case patients were those who developed arthralgias or myalgias while receiving quinupristin-dalfopristin therapy; control patients were those who received quinupristin-dalfopristin but did not develop arthralgias or myalgias. INTERVENTION: Medical records, pharmacy dispensing information, and microbiology data were reviewed by a physician and a pharmacist, both of whom specialized in infectious diseases. Presence or absence of arthralgias or myalgias was the primary outcome assessed. MEASUREMENTS AND MAIN RESULTS: Quinupristin-dalfopristin was administered to 68 patients during the period defined by the study. Arthralgias and myalgias could not be assessed in 18 of the 68 patients because they were sedated and paralyzed, or they were young children who could not communicate the presence of pain. Univariate analysis demonstrated that significant risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin were female sex, chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, major surgery, and receipt of either mycophenolate or cyclosporine. Multivariate analysis demonstrated a strong association with chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, and receipt of either cyclosporine or mycophenolate. Of 50 evaluable patients receiving quinupristin-dalfopristin, 25 had pain that may have been associated with this antimicrobial agent. CONCLUSION: The mechanism for development of arthralgias or myalgias associated with quinupristin-dalfopristin remains unknown, but these adverse events are more likely to occur in patients with chronic liver disease and those who have received a liver transplant or are receiving cyclosporine or mycophenolate.

Clinical experience with quinupristin-dalfopristin as rescue treatment of critically ill patients infected with methicillin-resistant staphylococci.

OBJECTIVES: To describe the efficacy and safety of quinupristin-dalfopristin (Q-D) as rescue therapy in critically ill patients with severe infections caused by methicillin-resistant staphylococci unresponsive to vancomycin treatment. DESIGN: Observational study in the context of the compassionate use programme for Q-D. METHODS: Twelve mechanically ventilated patients suffering from severe staphylococcal infections, pretreated unsuccessfully with vancomycin despite in vitro sensitivity, were included. Patients received, intravenously, Q-D 7.5 mg/kg body weight 3 times daily. The duration of Q-D therapy averaged 11.8 days (range: 1-26 days). The outcome variables were clinical efficacy and bacteriological eradication. RESULTS: Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were isolated in three patients each, and both bacteria were isolated from six patients. Eradication of pathogen(s) was achieved in 7 of 12 patients (66%). Five patients (42%) died due to severe co-morbidity. Adverse events related to Q-D were not observed and neither renal nor liver function was adversely affected. CONCLUSIONS: Quinupristin-dalfopristin appears to be an efficient and safe antimicrobial drug for the rescue treatment of staphylococcal infections in critically ill patients. It may be considered as a treatment option in cases of vancomycin treatment failure.

Two new treatment options for infections due to drug-resistant gram-positive cocci.

Gram-positive cocci, including enterococci and Staphylococcus aureus, have become the leading cause of hospital-acquired infections, and their resistance to antibiotics is increasing. Two important new drugs-quinupristin/dalfopristin (Synercid) and linezolid (Zyvox)-were designed specifically to treat infections due to drug-resistant gram-positive cocci. But their use must be tempered by their cost, toxicity, and concerns about further development of resistant strains.

Synercid plus vancomycin for the treatment of severe methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections: evaluation of 5 cases.

Synercid (quinupristin/dalfopristin), the first semi-synthetic injectable streptogramin, is a promising alternative to glycopeptides against many Gram-positive multiresistant bacteria. Vancomycin is still considered an effective agent for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections but therapeutic failures with glycopeptides have been observed, even for the treatment of infections caused by S. aureus strains sensitive to vancomycin. Synercid, in combination with a glycopeptide, may address this problem without causing significant side effects due to the different toxicity patterns of the 2 antimicrobials. This study reports our experience with the combination of Synercid and vancomycin in 5 patients with severe infection caused by MRSA or methicillin-resistant coagulase-negative Staphylococcus.