[Show abstract][Hide abstract] ABSTRACT: Colistin combination therapy may be required to treat biofilm-associated infections. We evaluated bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against biofilm-embedded and planktonic multidrug-resistant (MDR) Pseudomonas aeruginosa.
One colistin-susceptible reference strain (PAO1) and two colistin-susceptible MDR clinical isolates (HUB1 and HUB2; both carbapenem resistant) were investigated over 72 h in the CDC biofilm reactor, a dynamic biofilm model. Two colistin regimens (constant concentrations of 1.25 and 3.50 mg/L), one doripenem regimen (Cmax 25 mg/L 8 hourly) and their combination were employed. Microbiological response was examined as log changes and absolute bacterial counts.
For biofilm-embedded bacteria, bactericidal activity was only observed with monotherapy with colistin at 3.50 mg/L. The emergence of colistin resistance occurred with colistin monotherapy against two strains (PAO1 and HUB1), but only with the colistin 3.50 mg/L regimen. Colistin 3.50 mg/L plus doripenem resulted in ∼2-3 log10 cfu/cm(2) initial killing against both clinical isolates and remained synergistic at 72 h. The emergence of colistin resistance was not observed in biofilm-embedded bacteria with either combination. For planktonic bacteria, bactericidal activity was not observed with any monotherapy regimen, although enhanced bacterial killing was observed with doripenem plus colistin 3.50 mg/L against all isolates. Colistin resistance was observed with colistin monotherapy against two isolates, but did not emerge with combination regimens.
Doripenem enhanced killing by colistin of biofilm-embedded cells in both carbapenem-susceptible and -resistant strains, and the combination minimized the emergence of colistin resistance.
Journal of Antimicrobial Chemotherapy 05/2014; · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to analyze the efficacy and safety of high doses of daptomycin (10 mg/kg/d) plus rifampin (D10R) for prosthetic joint infection (PJI). This was an observational retrospective multicenter study (2010-12) including all patients with acute PJI by fluoroquinolone-resistant staphylococci managed with implant retention and D10 + R. Twenty cases were included: two (10%) were withdrawn due to toxicity, leaving 18 cases for efficacy evaluation: 13 (72%) women, age 79 years (range 58-90). Clinical failure was observed in nine (50%) patients: in five cases staphylococci were recovered (28% of microbiologicalfailures); no modification of daptomycin-MIC was observed. These 18 cases were compared with 44 matched historical cases: failure rates were similar, but whereas in the historical series failure occurred fundamentally during therapy, in the present series it was recorded after discontinuation of antibiotics. In summary, D10 + R may be the initial treatment of choice for PJI by fluoroquinolone-resistant staphylococci managed with implant retention.
Diagnostic Microbiology and Infectious Disease. 01/2014;
[Show abstract][Hide abstract] ABSTRACT: Abstract Background and Aims. In cirrhotic patients with spontaneous bacterial peritonitis (SBP) higher polymorphonuclear (PMN) count in ascitic fluid have been reported in infections caused by Gram-negative bacilli (GNB) as opposed to Gram-positive cocci (GPC). However, the influence of other associated factors on the PMN count, such as the specific microorganism causing the episode of SBP, has not been well established. Methods. Retrospective observational study of 194 episodes of positive ascitic and/or blood culture SBP in 159 patients with liver cirrhosis (2001-2009). Parameters associated with PMN count in ascitic fluid at diagnosis were evaluated. Results. The multivariate analysis (model 1) showed that a virulent etiology of the infection [coefficient 3.941 (95% confidence interval (95 CI): 0.421-7.461)] and the model for end-stage liver disease (MELD) score [coefficient 0.196 (95 CI: 0.007-0.384)] were positively associated with the PMN count in ascites, while a nosocomial acquisition was inversely associated [coefficient -3.546 (95 CI: -6.855 - -0.238)]. A nonsignificant trend toward higher PMN count was found in GNB versus GPC, but there were differences between groups of microorganisms: pyogenic streptococci [median (p25-p75): 3211 (1615-8004)], Enterobacteriaceae [2958 (917-7690)], Vibrionaceae [9215 (375-17280)], nonfermenting GNB [1384 (565-3865)], viridans group streptococci [1044 (503-2354)] and enterococci [1050 (476-4655)](p = 0.005). No clear cut-offs of ascitic PMN count predicting a particular etiology could be calculated out of these data. Conclusions. In cirrhotic patients with SBP, the causing microorganism, the place of acquisition of the infection and the host liver condition were the main factors determining PMN count in ascitic fluid. Third-generation cephalosporin resistance was associated with low PMN count probably because this group included bacteria with inherent low virulence.
Scandinavian Journal of Gastroenterology 08/2013; · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: infected hip hemiarthroplasties (HHA) are classically analyzed along with infected total hip arthroplasties (THA), but patients with either one or other device are different. We describe the clinical presentation, etiology and prognosis of infected HHA compared with infected THA.
comparative study of patients with infected HHA and THA from a prospective database of prosthetic joint infection (PJI) cases in our hospital (2003-2011), focusing on patients managed with debridement, antibiotics and implant retention (DAIR).
210 episodes of hip-PJI (age 74 years, 63% women): 62(39%) HHA and 148 (61%) THA. HHA-patients were older and had more comorbidities. Late-chronic and hematogenous infections were more frequent in THA. 123 (59%) patients were managed with DAIR: 72 THA and 51 HHA. Staphylococcus aureus was more frequent in THA (44% vs 26%,p=0.032), while Gram-negative bacilli were more prevalent in HHA (73% vs 51%,p=0.018), with a higher prevalence of fluoroquinolone-resistance in cemented-HHA. Overall failure was 37%, with no significant differences among groups. A higher mortality was observed in HHA cases (21% vs 4%,p=0.005), particularly in cemented-HHA.
infected THA and HHA have different characteristics, etiology and prognosis. Overall failure was similar, probably balanced by different predictors among groups, but mortality was higher among cemented-HHA.
The Journal of infection 08/2013; · 4.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is an urgent need for novel antibiotics to treat life-threatening infections caused by bacterial 'superbugs'. Validated in vitro pharmacokinetic/pharmacodynamic (PK/PD) and animal infection models have been employed to identify the most predictive PK/PD indices and serve as key tools in the antibiotic development process. The results obtained can be utilized for optimizing study designs in order to minimize the cost and duration of clinical trials. This review outlines the key in vitro PK/PD and animal infection models which have been extensively used in antibiotic discovery and development. These models have shown great potential in accelerating drug development programs and will continue to make significant contributions to antibiotic development.
Current opinion in microbiology 07/2013; · 7.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of Streptococcus species as an aetiological microorganism of vertebral osteomyelitis (VO) is considered to be of little relevance. We aimed to describe a large number of cases of streptococcal vertebral osteomyelitis (SVO), to analyze the clinical features associated with different Streptococcus species, and to compare them with a cohort of patients with VO caused by Staphylococcus aureus. An incidence study and a retrospective, multicenter, observational clinical study of cases of SVO (1991-2011) were performed. Statistical comparison of SVO by different species and between them and staphylococcal VO was carried out. Over the whole period there was an increasing incidence in the number of VOs and SVOs per year (p <0.05). Among 58 cases of SVO, those caused by non-viridans streptococcus (Streptococcus pneumoniae, Streptococcus agalactiae and Streptococcus pyogenes; n = 26) mimicked VO by S. aureus, and presented with more fever, neurological symptoms and paravertebral abscesses in comparison with those caused by the viridans group (remaining species). In contrast, the latter have a sub-acute clinical picture and were associated with the presence of endocarditis (p <0.05). Among non-viridans SVOs, concomitant infection was specifically related to S. pneumoniae (p <0.05). In conclusion, SVO presents a wide range of clinical patterns. The relationship between VO and diagnosis of endocarditis was established with SVO caused by the viridans group. Whereas non-viridans SVO mimics acute characteristics of VO caused by S. aureus, cases of viridans SVO are significantly more likely to have a sub-acute clinical presentation. The increased incidence of SVO during the last decades could support a new epidemiological scenario.
Clinical Microbiology and Infection 06/2013; · 4.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Linezolid may be an interesting alternative for prosthetic joint infection (PJI) due to its bioavailability and its antimicrobial spectrum. However, experience in this setting is scarce. The aim of the study was to assess linezolid's clinical and microbiological efficacy, and also its tolerance. This was a prospective, multicenter, open-label, non-comparative study of 25 patients with late-chronic PJI caused by Gram-positive bacteria managed with a two-step exchange procedure plus 6 weeks of linezolid. Twenty-two (88%) patients tolerated linezolid without major adverse effects, although a global decrease in the platelet count was observed. Three patients were withdrawn because of major toxicity, which reversed after linezolid stoppage. Among patients who completed treatment, 19 (86%) demonstrated clinical and microbiological cure. Two patients presented with clinical and microbiological failure, and one showed clinical cure and microbiological failure. In conclusion, linezolid showed good results in chronic PJI managed with a two-step exchange procedure. Tolerance seems acceptable, though close surveillance is required.
Diagnostic microbiology and infectious disease 03/2013; · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Efficacy of daptomycin, imipenem or rifampin with fosfomycin was evaluated and compared with daptomycin-rifampin in a tissue-cage model infection caused by MRSA.Strain HUSA 304 was used; MIC/MBC (μg/ml): fosfomycin 4/8, daptomycin 1/4, imipenem 0.25/32 and rifampin 0.03/0.5.Daptomycin-rifampin was confirmed as the most effective therapy against MRSA foreign-body infections. Fosfomycin combinations with high doses of daptomycin and rifampin were efficacious alternative therapies in this setting. Fosfomycin-imipenem was relatively ineffective and did not protect against resistance.
Antimicrobial Agents and Chemotherapy 10/2012; · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Several series predicting the prognosis of staphylococcal prosthetic joint infection (PJI) managed with debridement, antibiotics and implant retention (DAIR) have been published, but some of their conclusions are controversial. Little is known at present of the influence of the antibiotics used or of the influence of methicillin-resistant S. aureus (MRSA).Methods. Retrospective multicenter observational study of cases of PJI by S.aureus managed with DAIR (2003-2010). Failure: infection persistence/relapse, death, need for salvage therapy or prosthesis removal. Analysis of parameters predicting failure was performed with logistic and Cox regression.Results. 345 episodes (41% men, 73 years). MRSA caused 81 episodes. Fifty-two were hematogenous, with poorer prognosis and 88% caused by methicillin-susceptible S.aureus (MSSA). Median of 93 days of antibiotics, with similar use of rifampin-based combinations in MSSA- and MRSA-PJI. Failure was recorded in 45% of episodes, often early after debridement. Median survival time was 1257 days. There were no overall prognostic differences between MSSA- and MRSA-PJI, but MRSA-cases failed more during the period of treatment (HR 2.34), while MSSA-PJI failed more after therapy. Rifampin-based combinations showed an independent protective effect. Other independent predictors of outcome were immunosuppressive therapy, polymicrobial, inflammatory and bacteremic infections needing more than one debridement, and the exchange of removable components of the prosthesis.Conclusions. This is the largest series of PJI by S.aureus managed with DAIR reported to date. Success rate was 55%. The use of rifampin may have contributed to homogenizing MSSA and MRSA prognoses, although the specific rifampin-combinations may have had different efficacy.
[Show abstract][Hide abstract] ABSTRACT: Despite the use of daptomycin alone at high doses (greater than 6 mg/kg of body weight/day) against difficult-to-treat infections, clinical failures and resistance appeared. Recently, the combination daptomycin-cloxacillin showed enhanced efficacy in clearing bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to evaluate the efficacy of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg/day in humans, respectively) in combination with cloxacillin in a rat tissue cage infection model by MRSA and to compare its efficacy to that of daptomycin-rifampin. We used MRSA strain ATCC BAA-39. In the log- and stationary-phase kill curves, daptomycin-cloxacillin improved the bactericidal activity of daptomycin, especially in log phase. For in vivo studies, therapy was administered intraperitoneally for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day (daptomycin 100 and daptomycin 45), daptomycin 100-cloxacillin at 200 mg/kg/12 h, daptomycin 45-cloxacillin, and daptomycin 100-rifampin at 25 mg/kg/12 h. Daptomycin-rifampin was the best therapy (P < 0.05). Daptomycin 45 was the least effective treatment and did not protect against the emergence of resistant strains. There were no differences between the two dosages of daptomycin plus cloxacillin in any situation, and both protected against resistance. The overall effect of the addition of cloxacillin to daptomycin was a significantly greater cure rate (against adhered bacteria) than that for daptomycin alone. In conclusion, daptomycin-cloxacillin enhanced modestly the in vivo efficacy of daptomycin alone against foreign-body infection by MRSA and was less effective than daptomycin plus rifampin. The benefits of adding cloxacillin to daptomycin should be especially evaluated against infections by rifampin-resistant MRSA and for protection against the emergence of daptomycin nonsusceptibility.
Antimicrobial Agents and Chemotherapy 05/2012; 56(7):3806-11. · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The recent emergence of third-generation cephalosporin resistance in spontaneous bacterial peritonitis is of great concern, although neither the risk factors for resistance nor its real impact on mortality have been well defined.
We conducted a retrospective study of all spontaneous bacterial peritonitis episodes with positive blood and/or ascitic culture at our center (2001-2009). Episodes were classified according to the place of acquisition: community, healthcare system, or nosocomial.
Two hundred and forty-six episodes were analyzed in 200 patients (150 males, 57.3 years): 34.6% community-acquired, 38.6% healthcare system-acquired, and 26.8% nosocomially-acquired. Third-generation cephalosporin resistance occurred in 21.5% (7.1% community-acquired, 21.1% healthcare system-acquired, 40.9% nosocomially-acquired). These resistant cases were categorized as extended-spectrum β-lactamase-producing Gram-negative bacilli, other resistant Gram-negative bacilli, and Enterococci. Risk factors for resistance were previous use of cephalosporins, diabetes mellitus, upper gastrointestinal bleeding, nosocomial acquisition, and a low polymorphonuclear count in ascites. Regarding third-generation cephalosporin resistance, adequate empirical treatment was 80.7%. Independent predictors of mortality were nosocomial acquisition, poor hepato-renal function, immunosuppressive therapy, a marked inflammatory response during the episode and either third-generation cephalosporin-resistance or low rates of adequate empirical treatment.
The risk of third-generation cephalosporin resistance was particularly high in nosocomially-acquired episodes of spontaneous bacterial peritonitis, but also occurred in healthcare system-acquired cases. The extent of resistance and the adequacy of empirical antibiotics had a significant effect on mortality along with the patient's hepato-renal function. These data can help determine the most suitable empirical antimicrobial treatments in these patients.
Journal of Hepatology 12/2011; 56(4):825-32. · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The observed higher incidence of pyogenic vertebral osteomyelitis (PVO) may entail an increasing number of patients with no microbiologic diagnosis. The true incidence of these cases, how exhaustive the etiologic diagnostic efforts must be, and the usefulness of an empirical antibiotic therapy are not well defined.
Retrospective analysis of all cases of vertebral osteomyelitis in our center (1991-2009) and retrospective analysis of cases of PVO (2005-2009). Clinical data, diagnostic procedures, treatment, and outcome were reviewed. A comparative analysis between microbiologically confirmed PVO (MCPVO) and probable PVO (PPVO) was performed.
Increasing incidence of PVO (+0.047 episodes/100,000 inhabitants-year). During the last decade, there was an increase of PPVO (+0.059 episodes/100,000 inhabitants-year) with stable incidence of MCPVO. During 2005-2009, there were 72 patients [47 (65%) MCPVO and 25 (35%) PPVO]. 60% men; mean age was 66 years. Bacteremia was found in 59%. Computed tomographic guided vertebral biopsy, positive in 7/36 (19%), was more successful among patients with bacteremia. Among MCPVO, there was an increasing proportion of less virulent bacteria. Cases of MCPVO presented more frequently with sepsis, fever, and high acute-phase reactants, and PPVO cases were mostly treated with oral fluoroquinolones plus rifampin. No differences were found between both groups in outcome (93% success, 22% sequelae).
An epidemiologic change of PVO is suggested by a higher incidence of PPVO and the isolation of less virulent microorganisms among MCPVO. In this setting, the availability of an oral and effective empirical antibiotic therapy may challenge an exhaustive prosecution of the etiology.
Seminars in arthritis and rheumatism 06/2011; 41(2):247-55. · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the clinical features, risk factors, molecular epidemiology and outcome of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) bacteraemia in hospitalized cancer patients.
Episodes of ESBL-EC bacteraemia were compared with a susceptible control group in a 3 year prospective study. ESBL-EC strains were studied by PCR and isoelectric focusing, and molecular typing was performed by PFGE.
Out of 531 episodes of bacteraemia, 135 were caused by E. coli. Seventeen of these cases involved ESBL-EC-producing strains (12.6%). In the multivariate analysis, female gender [odds ratio (OR) 3.43; 95% confidence interval (CI) 1.03-11.4] and previous antibiotic therapy (OR 3.22; 95% CI 1.00-10.3) were found to be independent risk factors for ESBL acquisition. An analysis of ESBL-EC isolates revealed a polyclonal distribution with CTX-M predominance (59%). Patients with ESBL-EC bacteraemia were more likely to have received an inadequate empirical antibiotic therapy (65% versus 6%; P = 0.000), and the time to adequate therapy was longer in this group (0 versus 1.50 days; P = 0.000). The overall mortality rate was 22%, ranging from 20% to 35% (P = 0.20). Risk factors for mortality were solid tumour (OR 19.41; 95% CI 4.66-80.83), corticosteroid therapy (OR 3.04 95% CI 1.05-8.81) and intensive care unit admission (OR 248.24, 95% CI 18.49-3332.14). In neutropenic patients, ESBL-EC bacteraemia was associated with poorer outcome and a higher overall mortality rate (37.5% versus 6.5%; P = 0.01).
In our centre, ESBL-EC bacteraemia is frequent among cancer patients, especially in those exposed to antibiotic pressure. All ESBL-EC strains were unrelated and most of them carried a CTX-M group enzyme. Patients with ESBL-EC bacteraemia received inadequate empirical antibiotic therapy more frequently than patients carrying a susceptible strain, but significant differences in mortality could not be demonstrated.
Journal of Antimicrobial Chemotherapy 12/2009; 65(2):333-41. · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serious Enterococcus faecalis infections usually require combination therapy to achieve a bactericidal effect. In orthopedic infections, the prognosis of enterococcal etiology is considered poor, and the use of aminoglycosides is questioned. The ampicillin-ceftriaxone combination has recently been accepted as alternative therapy for enterococcal endocarditis. After one of our patients with endocarditis and vertebral osteomyelitis was cured with ampicillin-ceftriaxone, we started a pilot study of orthopedic infections. Patients with infections due to E. faecalis (with two or more surgical samples or blood cultures) diagnosed during 2005 to 2008 were recruited. Polymicrobial infections with ampicillin- and ceftriaxone-resistant microorganisms were excluded. Patients received ampicillin (8 to 16 g/day)-ceftriaxone (2 to 4 g/day) and were followed up prospectively. Of 31 patients with E. faecalis infections, 10 received ampicillin-ceftriaxone. Including the first patient, 11 patients were treated with ampicillin-ceftriaxone: 3 with prosthetic joint infections, 3 with instrumented spine arthrodesis device infections, 2 with osteosynthesis device infections, 1 with foot osteomyelitis, and 2 with vertebral osteomyelitis and endocarditis. Six infections (55%) were polymicrobial. All cases except the vertebral osteomyelitis ones required surgery, with retention of foreign material in six cases. Ampicillin-ceftriaxone was given for 25 days (interquartile range, 15 to 34 days), followed by amoxicillin (amoxicilline) being given to seven patients (64%). One patient with endocarditis died within 2 weeks (hemorrhagic stroke) and was not evaluable. For one patient with prosthesis retention, the infection persisted; 9/10 patients (90%) were cured, but 1 patient was superinfected. Follow-up was for 21 months (interquartile range, 14 to 36 months). Ampicillin-ceftriaxone may be a reasonable synergistic combination to treat orthopedic infections due to E. faecalis. Our experience, though limited, shows good outcomes and tolerability and may provide a basis for further well-designed comparative studies.
Antimicrobial Agents and Chemotherapy 08/2009; 53(10):4305-10. · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hyperammonemic encephalopathy is a rarely reported complication of multiple myeloma (MM). We describe an illustrative case of hyperammonemia in the setting of an immunoglobulin (Ig) D-lambda MM, and perform a systematic review of the English-written literature. Our search yielded 26 more cases. Median age was 64 years, and 54% of patients were male. All presented with progressive impairment of their level of consciousness. Median ammonium concentration was 109 micromol/L (interquartile range, 73-149 micromol/L). Most were IgA type (10 cases), and there were 2 cases of IgD type. Most cases were aggressive or chemotherapy-resistant forms of MM. Eight patients were diagnosed with MM at the same time as the episode of hyperammonemia. Only 1 patient had signs of portal hypertension as a result of concomitant hyperdynamic heart failure. Determination of amino acid in 10 patients showed high levels of glycine, low levels of tyrosine, and a low Fischer ratio. Two patients did not receive chemotherapy and died. Twenty-two out of 25 patients who received chemotherapy against MM showed a decrease in ammonium blood concentration, and of those, 15 survived the episode (68%). Overall mortality was 44%. In conclusion, hyperammonemia is a severe complication of MM, associated with a high mortality. It should be considered in any patient with MM and a low level of consciousness. Chemotherapy directed against MM seems to be the most effective measure in order to achieve normal ammonium levels and clinical improvement.