Preoperative decolonization and periprosthetic joint infections-A randomized controlled trial with 2-year follow-up.

Preoperative decolonization, especially of Staphylococcus aureus carriers, has been proposed to reduce periprosthetic joint infections (PJI), but the evidence-based consensus is still lacking and data on long-term outcomes is scarce. In a previous randomized, single-blinded trial, decolonization produced no significant reduction of surgical site infections in overall elective orthopedic surgery at 3-month follow-up. A 2-year follow-up was then performed to specifically detect the impact of decolonization on delayed-onset PJI (3-24 months after surgery). Between November 2015 and September 2017, 613 of 1318 recruited patients underwent prosthetic surgery. Individuals were allocated into either the S. aureus carrier group (34%, 207 of 613 patients) or the noncarrier group (406 of 613 patients), according to nasal swab screening results. Both groups were then randomized into intervention and control arms. In the S. aureus group, the intervention consisted of daily chlorhexidine showers and application of mupirocin nasal ointment twice a day for 5 days before surgery. In noncarriers, only chlorhexidine showers were prescribed. Sample size calculation was based on the initial trial for overall and not for the prosthetic surgery group. No PJI was found at 2 years in either the carrier or in the noncarrier group. Therefore, no definite conclusion about the efficacy of preoperative decolonization to reduce PJI can be drawn. PJI proportions in this study were lower than described in the literature (mostly around 0.3%). Despite the insufficient sample size, this trial is the largest randomized trial on decolonization with a long-term follow-up, and results may be helpful for future meta-analyses.

Does Preoperative Decolonization Reduce Surgical Site Infections in Elective Orthopaedic Surgery? A Prospective Randomized Controlled Trial.

BACKGROUND: Surgical site infections (SSIs) after elective orthopaedic surgery are very stressful for patients due to frequent rehospitalizations with reoperations and poorer functional outcomes. Prevention of such events is therefore crucial. Although an evidence-based consensus is still lacking, preoperative decolonization could decrease SSI. Specifically, more information is needed about the effect of a preoperative decolonization procedure on SSI proportions in both Staphylococcus aureus carriers and non-S. aureus carriers after general orthopaedic surgery. QUESTIONS/PURPOSES: Our study addressed the following questions: (1) Does preoperative decolonization reduce the risk of SSI after general elective orthopaedic surgery in patients colonized with S. aureus? (2) Does preoperative decolonization reduce the risk of SSI among patients who are not colonized with S. aureus? METHODS: In this prospective, randomized, single-blinded trial, we recruited patients undergoing general elective orthopaedic surgery in one tertiary care center in Switzerland. Between November 2014 and September 2017, 1318 of 1897 screened patients were enrolled. Patients were allocated into either the S. aureus carrier group (35%, 465 of 1318 patients) or the noncarrier group (65%, 853 of 1318 patients) according to screening culture results. In the S. aureus group, 232 patients were allocated to the intervention arm and 233 were allocated to the control arm. Intervention was 5 days of daily chlorhexidine showers and mupirocin nasal ointment twice a day. Of the 853 noncarriers, 426 were allocated to the intervention arm and 427 were allocated to the control arm. All patients in both groups were analyzed in an intention-to-treat manner. The primary endpoint was SSI occurrence at 90 days postoperative and the secondary endpoint was SSI occurrence at 30 days postoperative.The initial sample size calculation was made for the S. aureus carrier group. Based on the literature review, a 4% proportion of SSI was expected in the control group. Thus, 726 carriers would have been needed to detect a relative risk reduction of 80% with a power of 80% at a two-sided α-error of 0.048 (adjusted for interim analysis). Assuming carrier prevalence of 27%, 2690 patients would have been needed in total. An interim analysis was performed after including half of the targeted S. aureus carriers (363 of 726). Based on the low infection rate in the control group (one of 179), a new sample size of 15,000 patients would have been needed. This was deemed not feasible and the trial was stopped prematurely. RESULTS: Among carriers, there was no difference in the risk of SSI between the intervention and control arms (decolonized SSI risk: 0.4% [one of 232], control SSI risk: 0.4% [one of 233], risk difference: 0.0% [95% CI -1.2% to 1.2%], stratified for randomization stratification factors; p > 0.999). For noncarriers, there was no difference in risk between the intervention and control arms (decolonized SSI risk: 0.2% [one of 426], control SSI risk: 0.2% [one of 247], stratified risk difference: -0.0% [95% CI -0.7 to 0.6]; p = 0.973). CONCLUSIONS: We found no difference in the risk of SSI between the decolonization and control groups, both in S. aureus carriers and noncarriers. Because of the low event numbers, no definite conclusion about efficacy of routine preoperative decolonization can be drawn. The results, however, may be helpful in future meta-analyses. LEVEL OF EVIDENCE: Level II, therapeutic study.

Miliary tuberculosis with atypical presentation in an immunocompetent young African man.

We present an atypical case of tuberculosis in an immunocompetent man from west Africa living in Europe. The patient entered the hospital with a painful lump of 3 cm on his right clavicule which he noticed 2 weeks before and back pain. During the examinations for further evaluation his condition deteriorated within short time. Tuberculosis was diagnosed, treatment started but he needed mechanical ventilation at the intensive care unit and had kidney failure. The further evolvement was favourable in the end but needed intensive treatment for over 4 weeks. Tuberculosis cases with such severe evolution are rather known with immunodeficient patients. Extrapulmonary tuberculosis, especially skeletal tuberculosis is seen more frequent in young immunocompetent migrants. The migrating persons seem to be more at risk to get sick than the ones staying in their origin country. We suppose the course of our patient's disease is miliary or septic, of which both are rather rare entities.

Efficacy of doripenem against Escherichia coli and Klebsiella pneumoniae in experimental meningitis.

OBJECTIVES: In this study the efficacy of doripenem, a new broad-spectrum carbapenem, was tested against an Escherichia coli strain and a Klebsiella pneumoniae strain in an experimental animal model. The comparator was cefepime monotherapy. METHODS: The rabbit meningitis model was used in this study and the penetration of doripenem through uninflamed and inflamed meninges was determined. RESULTS: Doripenem, injected three times (75 mg/kg), led to serum peak levels around 100 mg/L and trough levels around 5 mg/L, resulting in a penetration rate of 14% through inflamed meninges and 7% through uninflamed meninges. Against K. pneumoniae, doripenem was slightly but not significantly more efficacious than cefepime over 8 h (5.40 ± 1.37 log(10) cfu/mL versus 3.59 ± 0.89 log(10) cfu/mL for cefepime). Also against the E. coli strain doripenem was slightly superior to the comparator (5.55 ± 0.87 log(10) cfu/mL versus 3.80 ± 1.10 log(10) cfu/mL for cefepime), although the difference was not significant. CONCLUSIONS: Doripenem is a potential monotherapy for the treatment of meningitis due to Gram-negative microorganisms.

Daptomycin: a new treatment for insidious infections due to gram-positive pathogens.

Daptomycin, a new lipopeptide antibiotic, is highly bactericidal against the majority of Gram-positive human pathogens, including methicillin-resistant (MRSA) and vancomycin-resistant enterococci. Its mechanism of action is unique resulting in the destruction of the membrane potential without lysing the cell wall. The mechanism of action of daptomycin, its antibacterial spectrum, the development of resistance and pre- and clinical studies are discussed in this review.

Unexpected metastatic pheochromocytoma - an unusual presentation.

The classic triad of pheochromocytoma consists of episodic headache, sweating, and tachycardia. General clinicians should be aware, however, that this rare entity might present with a wide spectrum of clinical symptoms. We recently observed a noteworthy case of malignant pheochromocytoma where there was a lack of specific symptoms despite an advanced tumor stage. Malignancy is an important cause of mortality. Reliable diagnosis of malignancy depends upon evidence of local invasion, distant metastases, or recurrence. As in our case, new scintigraphic methods, such as 111-In-pentetreotide scintigraphy (Octreoscan), may occasionally reveal 123-I-metaiodobenzylguanidine-negative distant metastases and help to establish an early diagnosis of malignancy. Tumor size, and perhaps even biochemical profile, may be factors increasing the likelihood of a malignant process and may contribute to early identification of patients at risk.

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model.

OBJECTIVES: To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF. METHODS: The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro. RESULTS: In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an i.v. injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays. CONCLUSIONS: EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspected.

Prevention of brain injury by the nonbacteriolytic antibiotic daptomycin in experimental pneumococcal meningitis.

Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ceftriaxone in experimental pneumococcal meningitis, and the treatments were evaluated for their effects on inflammation and brain injury. Eleven-day-old rats were injected intracisternally with 1.3 x 10(4) +/- 0.5 x 10(4) CFU of Streptococcus pneumoniae serotype 3 and randomized to therapy with ceftriaxone (100 mg/kg of body weight subcutaneously [s.c.]; n = 55) or daptomycin (50 mg/kg s.c.; n = 56) starting at 18 h after infection. The cerebrospinal fluid (CSF) was assessed for bacterial counts, matrix metalloproteinase-9 levels, and tumor necrosis factor alpha levels at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection. Daptomycin cleared the bacteria more efficiently from the CSF than ceftriaxone within 2 h after the initiation of therapy (log(10) 3.6 +/- 1.0 and log(10) 6.3 +/- 1.4 CFU/ml, respectively; P < 0.02); reduced the inflammatory host reaction, as assessed by the matrix metalloproteinase-9 concentration in CSF 40 h after infection (P < 0.005); and prevented the development of cortical injury (cortical injury present in 0/30 and 7/28 animals, respectively; P < 0.004). Compared to ceftriaxone, daptomycin cleared the bacteria from the CSF more rapidly and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis. Further research is needed to investigate whether nonbacteriolytic antibiotic therapy with daptomycin represents an advantageous alternative over current bacteriolytic antibiotic therapies for the treatment of pneumococcal meningitis.

Testing strategies and follow-up for coeliac disease in a general internal medicine outpatient department from 2000 to 2005.

PRINCIPLES: Coeliac disease (gluten sensitive enteropathy) is a genetically determined disorder with an incidence in the general population that is comparable to type 2 diabetes mellitus. Awareness of this fact and of the often atypical and oligosymptomatic manifestations is only now gaining ground in the medical profession. A high index of suspicion is important in order to minimise diagnostic and therapeutic delay. METHODS: Testing patterns and follow-up for coeliac disease in our institution have been analysed retrospectively for the past five years. The current literature was reviewed with respect to recommendations for clinical practice. RESULTS: A total of 271 patients were tested for coeliac disease over a period of five years. Only in 24 patients were positive results found; after further work-up, the final number of cases with certain or presumed coeliac disease was four. Followup was often difficult, many patients being lost after a single visit. CONCLUSIONS: This study showed that the number of tests ordered in our institution, more often for abdominal than atypical symptoms, has started to increase in the past two years. It also showed that screening tests have found their place in general clinical practice, while the final choice of tests needs to be determined in accordance with available guidelines and local resources. Upper endoscopy with small bowel biopsy remains the gold standard for diagnosis, but its place in follow-up is less certain. Coeliac disease is a disorder for which there is a definite treatment (gluten free diet); if it is left untreated diminished quality of life and potentially serious complications may ensue. Further education of the medical profession regarding coeliac disease, its incidence, presentation and treatment, is clearly indicated..

Daptomycin is more efficacious than vancomycin against a methicillin-susceptible Staphylococcus aureus in experimental meningitis.

OBJECTIVES: To test the efficacy of daptomycin, a cyclic lipopeptide antibiotic, against a methicillin-susceptible Staphylococcus aureus strain in experimental rabbit meningitis and to determine its penetration into non-inflamed and inflamed meninges RESULTS: Over a treatment period of 8 h, daptomycin (15 mg/kg) was significantly superior to the comparator regimen vancomycin (-4.54 +/- 1.12 log(10)/mL for daptomycin versus -3.43 +/- 1.17 log(10)/mL for vancomycin). Daptomycin managed to sterilize 6 out of 10 CSFs compared with 4 out of 10 for vancomycin. The penetration of daptomycin into inflamed meninges was approximately 5% and approximately 2% into non-inflamed meninges. CONCLUSIONS: The superior bactericidal activity of daptomycin was confirmed in vivo and in time-killing assays in vitro.

Efficacy of telavancin against penicillin-resistant pneumococci and Staphylococcus aureus in a rabbit meningitis model and determination of kinetic parameters.

The penetration of telavancin was 2% into inflamed meninges and ca. 1 per thousand into noninflamed meninges after two intravenous injections (30 mg/kg of body weight). In experimental meningitis, telavancin was significantly superior to vancomycin combined with ceftriaxone against a penicillin-resistant pneumococcal strain. Against a methicillin-sensitive staphylococcal strain, telavancin was slightly but not significantly superior to vancomycin.

A rare cause of fatal right heart failure.

Microscopic pulmonary tumor embolism (MPTE) is an uncommon cause of dyspnea in patients with cancer and one of the most difficult to diagnose. MPTE is a syndrome that is pathologically characterized by the occlusion of small pulmonary arteries and arterioles by aggregates of tumor cells. Because the clinical picture resembles that of thromboembolic disease, it is rarely recognized before death. The most common clinical symptom is subacute progressive dyspnea over weeks to months. We recently observed a case of MPTE of exceptional interest as the patient was under aggressive anticoagulant treatment and developed fulminant pulmonary hypertension with fatal right heart failure.

Preincubation of pneumococci with beta-lactams alone or combined with levofloxacin prevents quinolone-induced resistance without increasing intracellular levels of levofloxacin.

Preincubation of pneumococci with sub-MIC concentrations of ceftriaxone (1/16x MIC), cefotaxime (1/8x MIC), and meropenem (1/4x MIC) alone or combined with levofloxacin (1/8x MIC) over 6 h prevents the emergence of levofloxacin-resistant mutants after 96 h of incubation but does not affect the intracellular accumulation of levofloxacin in two penicillin-resistant pneumococcal strains, suggesting a link between the mechanism of action of beta-lactams and the emergence of quinolone-induced resistance in pneumococci.

Daptomycin is highly efficacious against penicillin-resistant and penicillin- and quinolone-resistant pneumococci in experimental meningitis.

The penetration of daptomycin, a new lipopeptide antibiotic, into inflamed meninges ranged between 4.37 and 7.53% (mean, 5.97%). Daptomycin was very efficacious in the treatment of experimental pneumococcal meningitis, producing a decrease of -1.20 +/- 0.32 Deltalog(10) CFU/ml. h in the bacterial titer of Streptococcus pneumoniae against a penicillin-resistant strain and of -0.97 +/- 0.32 Deltalog(10) CFU/ml. h against a penicillin- and quinolone-resistant strain found in cerebrospinal fluid (CSF). For both strains, daptomycin was significantly superior to the standard regimen of a combination of ceftriaxone with vancomycin, sterilizing 9 of 10 CSF samples after 4 h. In vitro, daptomycin produced highly bactericidal activity in concentrations above the MIC.

Fluoroquinolones in the Treatment of Meningitis.

The continuous increase of resistant pathogens causing meningitis has limited the efficacy of standard therapeutic regimens. Due to their excellent activity in vitro and their good penetration into the cerebrospinal fluid (CSF), fluoroquinolones appear promising for the treatment of meningitis caused by gram-negative microorganisms, ie, Neisseria meningitidis and nosocomial gram-negative bacilli. The newer fluoroquinolones (moxifloxacin, gemifloxacin, gatifloxacin, and garenoxacin) have excellent activity against gram-positive microorganisms. Studies in animal models and limited clinical data indicate that they may play a future role in the treatment of pneumococcal meningitis. Analysis of pharmacodynamic parameters suggests that CSF concentrations that produce a C(peak)/minimal bactericidal concentration (MBC) ratio of at least 5 and concentrations above the MBC during the entire dosing interval are a prerequisite for maximal bactericidal activity in meningitis. Of interest, newer fluoroquinolones act synergistically with vancomycin and beta-lactam antibiotics (ceftriaxone, cefotaxime, meropenem) against penicillin-resistant pneumococci in experimental rabbit meningitis, potentially providing a new therapeutic strategy. Clinical trials are needed to further explore the usefulness of quinolones as single agents or in combination with other drugs in the therapy of pneumococcal meningitis.

Modeling of transfer kinetics at the serum-cerebrospinal fluid barrier in rabbits with experimental meningitis: application to grepafloxacin.

The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CL(diff)) and active efflux clearance (CL(active)) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CL(diff), and efflux clearance is the sum of CL(diff), CL(active), and bulk flow clearance (CL(bulk)). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CL(bulk) of 0.01 ml/min, CL(active) was estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.

Gemifloxacin is efficacious against penicillin-resistant and quinolone-resistant pneumococci in experimental meningitis.

In experimental rabbit meningitis, gemifloxacin penetrated inflamed meninges well (22 to 33%) and produced excellent bactericidal activity (change in log(10) [Deltalog(10)] CFU/ml/h, -0.68 +/- 0.30 [mean and standard deviation]), even superior to that of the standard regimen of ceftriaxone plus vancomycin (-0.49 +/- 0.09 deltalog(10) CFU/ml/h), in the treatment of meningitis due to a penicillin-resistant pneumococcal strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, gemifloxacin showed good bactericidal activity (-0.48 +/- 0.16 deltalog(10) CFU/ml/h). The excellent antibacterial activity of gemifloxacin was also confirmed by time-kill assays over 8 h in vitro.

Cefepime is efficacious against penicillin- and quinolone-resistant pneumococci in experimental meningitis.

In experimental rabbit meningitis, cefepime given at a dose of 100 mg/kg was associated with concentrations in the cerebrospinal fluid of between 5.3 and 10 mg/L and a bactericidal activity of -0.61 +/- 0.24 Delta log(10) cfu/mL x h, similar to the standard regimen of ceftriaxone combined with vancomycin (-0.58 +/- 0.14 Delta log(10) cfu/mL x h) in the treatment of meningitis due to a penicillin- and quinolone-resistant pneumococcal mutant strain (MIC 4 mg/L). Compared with the penicillin-resistant parental strain, the penicillin- and quinolone-resistant mutant was killed more slowly by cefepime and ceftriaxone in time-killing assays in vitro over 8 h.

Efficacies of BMS 284756 against penicillin-sensitive, penicillin-resistant, and quinolone-resistant pneumococci in experimental meningitis.

BMS 284756 penetrated well into inflamed meninges (44% +/- 11%) and produced good bactericidal activity (-0.82 +/- 0.22 Delta log(10) CFU/ml. h) in the treatment of experimental meningitis in rabbits due to a penicillin-sensitive strain. BMS 284756 monotherapy had a greater potency than the standard regimen of ceftriaxone and vancomycin (-0.49 +/- 0.08 Delta log(10) CFU/ml. h) against a penicillin-resistant strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, BMS 284756 showed good bactericidal activity (-0.52 +/- 0.12 Delta log(10) CFU/ml. h). The antibacterial activity of BMS 284756 was confirmed by time-killing assays over 8 h in vitro.