Management of carbapenem-resistant Enterobacteriaceae infections.

BACKGROUND: Carbapenem resistance is defined as in vitro non-susceptibility to any carbapenem and/or documented production of a carbapenemase. This feature has rapidly spread worldwide among clinical isolates of Enterobacteriaceae, mostly Klebsiella spp., and is associated with diverse molecular mechanisms. Carbapenem resistance is often associated with resistance to all traditional ß-lactams and other classes of antibiotics, denoting a typical example of an extensively drug-resistant phenotype. OBJECTIVES: To summarize and interpret in a balanced manner the most clinically relevant data in terms of carbapenem-resistant Enterobacteriaceae (CRE) infection management. SOURCES: Data were extracted by PubMed and clinicaltrials.gov search and manual scrutiny among references of analysed articles. CONTENT: Features of newer and older, rediscovered antimicrobial options for CRE are described. Observational studies and randomized clinical trials (RCT) of CRE treatment are summarized, with a specific focus on the effects of monotherapy compared with combination treatment. IMPLICATIONS: The available evidence on the current management of CRE mostly comes from observational, non-comparative, retrospective, small studies, with a high risk of selection bias. Very little evidence comes from RCT. Conflicting results of RCT and observational studies call for caution before combination therapies are deemed superior to monotherapy. Data on newer agents have spurred enthusiasm but remain limited as concerns severe CRE infections. A balanced approach should guide the clinician in the choice of old or new drugs, and of monotherapies or combination regimens. Efforts should be made to perform adequately sized clinical trials answering well-defined research questions.

Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli: an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals.

OBJECTIVES: To explore contemporary antibiotic management of infections caused by carbapenem-resistant Gram-negative bacteria in hospitals. METHODS: Cross-sectional, internet-based questionnaire survey. We contacted representatives of all hospitals with more than 800 acute-care hospital beds in France, Greece, Israel, Italy, Kosovo, Slovenia, Spain and selected hospitals in the USA. We asked respondents to describe the most common actual practice at their hospital regarding management of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa through close-ended questions. RESULTS: Between January and June 2017, 115 of 141 eligible hospitals participated (overall response rate 81.6%, country-specific rates 66.7%-100%). Most were tertiary-care (99/114, 86.8%), university-affiliated (110/115, 89.1%) hospitals and most representatives were infectious disease specialists (99/115, 86.1%). Combination therapy was prescribed in 114/115 (99.1%) hospitals at least occasionally. Respondents were more likely to consider combination therapy when treating bacteraemia, pneumonia and central nervous system infections and for Enterobacteriaceae, P. aeruginosa and A. baumannii similarly. Combination of a polymyxin with a carbapenem was used in most cases, whereas combinations of a polymyxin with tigecycline, an aminoglycoside, fosfomycin or rifampicin were also common. Monotherapy was used for treatment of complicated urinary tract infections, usually with an aminoglycoside or a polymyxin. The intended goal of combination therapy was to improve the effectiveness of the treatment and to prevent development of resistance. In general, respondents shared the misconception that combination therapy is supported by strong scientific evidence. CONCLUSIONS: Combination therapy was the preferred treatment strategy for infections caused by carbapenem-resistant Gram-negative bacteria among hospital representatives, even though high-quality evidence for carbapenem-based combination therapy is lacking.

Influence of vancomycin minimum inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus left-sided infective endocarditis treated with antistaphylococcal ß-lactam antibiotics: a prospective cohort study by the International Collaboration on Endocarditis.

OBJECTIVES: Left-sided methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis treated with cloxacillin has a poorer prognosis when the vancomycin minimum inhibitory concentration (MIC) is ≥1.5 mg/L. We aimed to validate this using the International Collaboration on Endocarditis cohort and to analyse whether specific genetic characteristics were associated with a high vancomycin MIC (≥1.5 mg/L) phenotype. METHODS: All patients with left-sided MSSA infective endocarditis treated with antistaphylococcal ß-lactam antibiotics between 2000 and 2006 with available isolates were included. Vancomycin MIC was determined by Etest as either high (≥1.5 mg/L) or low (<1.5 mg/L). Isolates underwent spa typing to infer clonal complexes and multiplex PCR for identifying virulence genes. Univariate analysis was performed to evaluate the association between in-hospital and 1-year mortality, and vancomycin MIC phenotype. RESULTS: Sixty-two cases met the inclusion criteria. Vancomycin MIC was low in 28 cases (45%) and high in 34 cases (55%). No significant differences in patient demographic data or characteristics of infection were observed between patients with infective endocarditis due to high and low vancomycin MIC isolates. Isolates with high and low vancomycin MIC had similar distributions of virulence genes and clonal lineages. In-hospital and 1-year mortality did not differ significantly between the two groups (32% (9/28) vs. 27% (9/34), p 0.780; and 43% (12/28) vs. 29% (10/34), p 0.298, for low and high vancomycin MIC respectively). CONCLUSIONS: In this international cohort of patients with left-sided MSSA endocarditis treated with antistaphylococcal ß-lactams, vancomycin MIC phenotype was not associated with patient demographics, clinical outcome or virulence gene repertoire.

In vitro activity of multiple antibiotic combinations against Nocardia: relationship with a short-term treatment strategy in heart transplant recipients with pulmonary nocardiosis.

BACKGROUND/OBJECTIVES: Pulmonary nocardiosis (PN) chiefly affects immunocompromised patients, particularly transplant recipients. Cotrimoxazole is still the mainstay of treatment, but it is associated with nephro- and myelo-toxicity, and can show unpredictable activity against Nocardia isolates. METHODS: Over a 20-year period, Nocardia isolates were identified from 12 heart transplant (HTx) recipients with PN. The in vitro activity of various antibacterials, alone or in combination, was assessed using disk-diffusion, minimal inhibitory concentration (MIC), and time-kill methodology. The in vitro results were compared with the clinical outcome of the patients. RESULTS: Seven different Nocardia strains were identified. Disk diffusion and MIC determinations showed that all isolates were susceptible to amikacin, netilmicin, and linezolid, and that moxifloxacin was the most active of the fluoroquinolones. All but 1 of the isolates were susceptible to imipenem. Time-kill studies showed that imipenem/amikacin and imipenem/moxifloxacin combinations were bactericidal for most isolates. Of 12 patients who received 3-4 weeks' intravenous (IV) treatment with amikacin or ciprofloxacin in combination with a beta-lactam, followed by 1-3 months' oral cotrimoxazole, moxifloxacin, or linezolid, 11 were cured; 1 patient died, but not related to Nocardia. CONCLUSION: Initial PN treatment in HTx recipients can be successfully carried out with bactericidal combinations such as imipenem plus amikacin or moxifloxacin, administered IV for 3-4 weeks. Within 1 month, a significant clinical and radiological improvement may be observed. In our experience, a <3 month oral regimen with cotrimoxazole, moxifloxacin, or doxycycline may then be used. This may allow a reduction of side effects and treatment-related burden, without any recurrence.

Treatment of pulmonary nocardiosis in heart-transplant patients: importance of susceptibility studies.

Pulmonary nocardiosis is an infrequent but insidious disease in transplant patients. It has occurred in our centre in 3 out of 233 heart-transplant recipients since 1988. Common clinical features were mild symptoms and a severe nodular lung involvement. Early diagnosis was based upon cultures of bronchoalveolar lavage or fine-needle aspirate specimens of the lung lesions. Susceptibility studies and tests of antibiotic synergism guided the therapy. Two patients were treated with a combination of piperacillin-tazobactam and ciprofloxacin, and one with imipenem and amikacin, for 3-4 wk followed by a 3-month course of trimethoprim-sulphamethoxazole. The nocardial disease was successfully treated in the 3 patients; however, one died of subsequent invasive pulmonary aspergillosis. In the absence of consensus on the length of therapy, this experience suggests that a synergistic combination of a beta-lactam/beta-lactamase inhibitor with ciprofloxacin or amikacin followed by a short course of trimethoprim-sulphamethoxazole may be effective in eradicating nocardial disease and may reduce the need for long-term treatment.