Rediscovering the value of fosfomycin trometamol in the era of antimicrobial resistance: A systematic review and expert opinion.

The worldwide prevalence of uncomplicated lower urinary tract infections (uUTIs) caused by multidrug-resistant Escherichia coli is increasing. To address this emergency, international guidelines recommend reducing administration of fluoroquinolones, in the context of growing resistance and the long-lasting and potentially disabling side effects of these drugs. The favoured drug to replace fluoroquinolones is fosfomycin trometamol (FT), a well-known derivate of phosphonic acid with broad-spectrum activity against Gram-negative and Gram-positive bacteria, including multidrug-resistant (MDR) strains. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recently reduced the susceptibility breakpoint for E. coli from 32 mg/L to 8 mg/L regarding FT used for uUTIs. This might lead to increased appropriate use of oral fosfomycin target therapy against E. coli and other microorganisms, and may be associated with a high likelihood of success. For species such as Klebsiella spp, particularly MDR strains, the absence of clinical breakpoints might lead to reduced use of oral fosfomycin, particularly if minimum inhibitory concentration is not available. To address this issue, this review presents an overview of the preclinical evidence on the activity of FT, and a systematic review of the clinical activity of FT in uUTIs in women, and in the prevention of infectious complications after prostate biopsy. The findings indicate that the safety and microbiological and clinical effectiveness of a single oral dose of FT are similar to that for comparator regimens with longer treatment schedules in women with uUTI, and FT can be considered a viable alternative to fluoroquinolones for antimicrobial prophylaxis in prostate biopsy. These observations and a broad clinical experience support the empirical use of FT for treating uUTI and indicate that FT is a promising candidate to effectively counteract antibiotic-resistant uUTIs throughout Europe.

Glutathione: Pharmacological aspects and implications for clinical use in non-alcoholic fatty liver disease.

Glutathione is a tripeptide synthesized at cytosolic level, that exists in cells in a reduced form (thiol-reduced-GSH-) and in an oxidized form (disulfide-oxidized). The antioxidant function of GSH has led to speculation about its therapeutic role in numerous chronic diseases characterized by altered redox balance and reduced GSH levels, including, for instance, neurodegenerative disorders, cancer, and chronic liver diseases. Among these latter, non-alcoholic fatty liver disease (NAFLD), characterized by lipid accumulation in hepatocytes, in the absence of alcohol abuse or other steatogenic factors, is one of the most prevalent. The umbrella term NAFLD includes the pure liver fat accumulation, the so-called hepatic steatosis or non-alcoholic fatty liver, and the progressive form with inflammation, also known as non-alcoholic steatohepatitis, which is related to the increase in oxidative stress and reactive oxygen species, eventually leading to liver fibrosis. Although the pathogenetic role of oxidative stress in these diseases is well established, there is still limited evidence on the therapeutic role of GSH in such conditions. Hence, the aim of this review is to depict the current molecular and pharmacological knowledge on glutathione, focusing on the available studies related to its therapeutic activity in NAFLD.

Prevention of recurrent respiratory infections : Inter-society Consensus.

Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.

Refractory mucocutaneous leishmaniasis resolved with combination treatment based on intravenous pentamidine, oral azole, aerosolized liposomal amphotericin B, and intralesional meglumine antimoniate.

INTRODUCTION: Mucocutaneous leishmaniasis (MCL) is a complication of tegumentary leishmaniasis, causing potentially life-threatening lesions in the ear, nose, and throat (ENT) region, and most commonly due to Leishmania (Viannia) braziliensis. We report a case of relapsing MCL in an Italian traveler returning from Argentina. CASE DESCRIPTION: A 65-year-old Italian male patient with chronic kidney disease, arterial hypertension, prostatic hypertrophy, and type-2 diabetes mellitus was referred for severe relapsing MCL acquired in Argentina. ENT examination showed severe diffuse pharyngolaryngeal edema and erythema, partially obstructing the airways. A nasopharyngeal biopsy revealed a lymphoplasmacytic inflammation and presence of Leishmania amastigotes, subsequently identified as L. (V.) braziliensis by hsp70 PCR-RFLP analysis and sequencing. Despite receiving four courses of liposomal amphotericine B (L-AmB) and two courses of miltefosine over a 2-year period, the patient presented recurrence of symptoms a few months after the end of each course. After the patient was referred to us, a combined treatment was started with intravenous pentamidine 4 mg/kg on alternate days for 10 doses, followed by one dose per week for an additional seven doses, intralesional meglumine antimoniate on the nasal lesion once per week for six doses, oral azoles for three months, and aerosolized L-AmB on alternate days for three months. The treatment led to regression of mucosal lesions and respiratory symptoms. Renal function temporarily worsened, and the addition of insulin was required to maintain glycemic compensation after pentamidine discontinuation. CONCLUSIONS: This case highlights the difficulties in managing a life-threatening refractory case of MCL in an Italian traveler with multiple comorbidities. Even though parenteral antimonial derivatives are traditionally considered the treatment of choice for MCL, they are relatively contraindicated in cases of chronic kidney disease.The required dose adjustment in cases of impaired renal function is unknown, therefore the use of alternative drugs is recommended. This case was resolved with combination treatment, including aerosolized L-AmB, which had never been used before for MCL.

Fosfomycin trometamol and N-acetyl-L-cysteine as combined oral therapy of difficult-to-treat chronic bacterial prostatitis: Results of a pilot study.

This paper presents the results of a pilot study of difficult-to-treat patients (exhibiting several previous treatment failures or detection of extended-spectrum beta-lactamase [ESBL] strains) with chronic bacterial prostatitis (CBP) who underwent treatment with fosfomycin trometamol (FT) and N-acetyl-L-cysteine (NAC). Twenty-eight patients with clinically- and microbiologically-confirmed CBP who attended a single urological institution between January 2018 and March 2019 were treated with oral administration of 3 g FT once a day for 2 days, followed by a dose of 3 g every 48 h for 2 weeks, in combination with oral administration of NAC 600 mg once a day for 2 weeks. Clinical and microbiological analyses were carried out at the time of admission (T0) and during follow-up at 1 month (T1) and 6 months (T2) after the end of treatment. Symptoms were assessed by the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and International Prostatic Symptom Score (IPSS), and quality of life was assessed by Quality of Well-Being (QoL) questionnaires. Isolated strains were Escherichia coli (23 patients), Enterococcus spp. (3 patients), and Klebsiella oxytoca (2 patients). ESBL strain was found in 19 (67.8%) patients. Microbiological eradication was documented in 21 (75%) patients at the second follow-up visit and clinical cure was achieved in 20 (71.4%) patients. Significant changes on questionnaires were recorded between baseline and follow-up visits. Fifteen of 19 patients (78.9%) with ESBL strains were cured. No significant side effects were reported. FT in combination with NAC is a promising alternative therapy in difficult-to-treat CBP patients.

Fosfomycin Trometamol versus Comparator Antibiotics for the Treatment of Acute Uncomplicated Urinary Tract Infections in Women: A Systematic Review and Meta-Analysis.

PURPOSE: We performed a systematic review and meta-analysis to compare the effectiveness and safety profile of fosfomycin vs comparator antibiotics in women with acute uncomplicated cystitis. MATERIALS AND METHODS: Relevant databases were searched using methods recommended by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. We assessed the risk of bias and confounders. The study primary end point was clinical or microbiological success, defined as complete (cure) and/or incomplete resolution of symptoms at the end of treatment (improvement) and/or microbiological eradication. RESULTS: After screening 539 articles 15 were included which recruited a total of 2,295 adult female patients. Of the studies 14 were used for microbiological eradication analysis. We used 11 of the 15 articles in a total of 1,976 patients for clinical resolution and 11 in a total of 1,816 patients for safety outcome analysis. No difference was found for clinical resolution in all comparators combined in 11 randomized controlled trials in a total of 1,976 patients (OR 1.16, 95% CI 0.91-1.49, p=0.13). No difference was found for microbiological eradication in 14 randomized controlled trials in a total of 2,052 patients (OR 1.03, 95% CI 0.83-1.30, p=0.09) or for safety outcome in 11 randomized controlled trials in a total of 1,816 patients (OR 1.17, 95% CI 0.86-1.58, p=0.33). Most adverse effects reported for fosfomycin were transient and single dose therapy seems to have resulted in better patient compliance. CONCLUSIONS: Single dose oral fosfomycin trometamol is equal to comparator regimens in terms of clinical and microbiological effectiveness and safety in women with microbiologically confirmed and/or clinically suspected, acute uncomplicated cystitis. It is associated with high patient compliance.

Posaconazole oral suspension primary prophylaxis in acute leukemia and allogeneic stem cell transplant patients: can it be used without measurement of plasma concentration?

Posaconazole oral suspension (PCZ-susp) can display a variable degree of inter and intra-individual absorption. However, there is no agreement on the need of plasma-posaconazole-concentration (PPC) monitoring as a routine practice in patients receiving PCZ-susp. In this prospective, multicenter study we evaluated the variability of PPCs in hematologic patients receiving PCZ-susp prophylaxis with the aim to define conditions at different risk of subtherapeutic PPCs. Overall, 103 acute leukemia (AL) patients submitted to intensive chemotherapy (115 courses) and 46 allogeneic stem cell transplant (allo-SCT) recipients (47 courses) receiving PCZ-susp prophylaxis were considered. The adequacy of PPC pattern after the steady state (≥day 7 of treatment) in courses with two or more PPC measurements was defined as follows: inadequate pattern: PPC < 0.5 mcg/ml at least once; borderline pattern: PPC always ≥0.5mcg/ml but < 0.7 mcg/ml at least once; adequate pattern: PPC always ≥0.7 mcg/ml. The PPC pattern was evaluable in 83 and 37 AL and allo-SCT patients, respectively. It was adequate, borderline and inadequate in 63.9%, 14.5%, and 21.7% of courses, respectively, in AL, and in 62.2%, 10.8%, and 27.0% of courses, respectively, in allo-SCT. In both groups, an inadequate PPC pattern was associated with the development of diarrhea. In absence of diarrhea, the probability of an inadequate PPC pattern was 11.9% in AL and 17.2% in allo-SCT patients. PCZ-susp might be used without stringent need of PPC monitoring in patients without diarrhea.

Management of Meningitis Caused by Multi Drug-Resistant Acinetobacter Baumannii: Clinical, Microbiological and Pharmacokinetic Results in a Patient Treated with Colistin Methanesulfonate.

This paper reports on a 71- year-old Caucasian male who underwent neurosurgery for an oligodendroglioma, followed by a cranial-sinus fistula and cerebrospinal fluid rhinorrhea. The clinical course was complicated due to an extensively drug-resistant Acinetobacter baumannii meningitis. The patient was treated with colistin methanesulfonate, intrathecal for 24 days and intravenous for 46 days. In addition, the patient received meropenem and teicoplanin to treat a urinary tract infection and a bacterial aspiration pneumonia. Cerebrospinal fluid trough colistin levels resulted above the MIC of A. baumannii. Colistin cerebrospinal fluid concentration did not increase over the treatment period. Meningitis was cured and A. baumannii eradicated. No side effects from the antimicrobial therapy were observed. In conclusion, this case highlights the issues in treating infections caused by resistant Gram negative bacteria and supports previous findings on the efficacy, pharmacokinetic and tolerability of intravenous and intrathecal colistin treatments.

Cost of care and antibiotic prescribing attitudes for community-acquired complicated intra-abdominal infections in Italy: a retrospective study.

INTRODUCTION: Complicated intra-abdominal infections (cIAIs) are a common cause of morbidity worldwide, and in spite of improvements in patient care, therapeutic failure still occurs, impacting in-hospital resource consumption. This study aimed to assess the costs associated with the treatment of community-acquired cIAIs, from the Italian National Health Service perspective. METHODS: This retrospective study analyzed the charts of patients who were discharged from four Italian university hospitals between January 1 and December 31, 2009 with a primary diagnosis of community-acquired cIAIs. Patient characteristics, diagnosis, surgical procedure, antibiotic therapy, and length of hospital stay were all recorded and the cost of total hospital care was estimated. Costs were calculated in Euros at 2009 values. RESULTS: The records of 260 patients (mean age 48.9 years; 57% males) were analyzed. The average cost of care for a patient hospitalized due to cIAI was €4385 (95% CI 3650-5120), with an average daily cost of €419 (95% CI 378-440). Antibiotic therapy represented just under half (44.3%) of hospitalization costs. The strongest predictor of the increase in hospital costs was clinical failure: patients who clinically failed received an average of 8.2 additional days of antibiotic therapy and spent 11 more days in hospital compared with patients who responded to first-line therapy (both p < 0.05 vs. patients who were successfully treated). Furthermore, they incurred €5592 in additional hospitalization costs (2.88 times the cost associated with clinical success) with 53% (€2973) of the additional costs attributable to antibiotic therapy. Overall, antibiotic appropriateness rate was 78.8% (n = 205), and was significantly higher in patients receiving combination therapy compared with those treated with monotherapy (97.3% vs. 64.6%). CONCLUSION: The results of this study suggest that hospitals need to be aware of the clinical and economic consequences of antibiotic therapy of cIAIs and to reduce overall resource use and costs by improving the rate of success with appropriate initial empiric therapy.

Prospective phase II single-center study of the safety of a single very high dose of liposomal amphotericin B for antifungal prophylaxis in patients with acute myeloid leukemia.

Some preclinical and pharmacokinetic studies suggested the variable safety and the potential efficacy of an antifungal prophylaxis with a single high dose of liposomal amphotericin B (L-AmB) in high-risk patients. An open-label, prospective study was conducted with 48 adults receiving induction chemotherapy for acute myeloid leukemia (AML). Patients received a single infusion of 15 mg/kg of body weight L-AmB and, eventually, a second dose after 15 days of persistent neutropenia. The primary objective was tolerability and safety. Efficacy was also evaluated as a secondary endpoint. A pharmacokinetic study was performed with 34 patients in order to evaluate any association of plasma L-AmB levels with toxicity and efficacy. Overall, only 6 patients (12.5%) reported Common Toxicity Criteria (CTC) grade 3 hypokalemia, which was corrected with potassium supplementation in all cases, and no patient developed clinically relevant nephrotoxicity. Mild infusion-related adverse events occurred after 6 of 53 (11.3%) total infusions, with permanent drug discontinuation in only one case. Proven invasive fungal disease (IFD) was diagnosed in 4 (8.3%) patients. The mean AmB plasma levels at 6 h, 24 h, and 7 days after L-AmB administration were 160, 49.5, and 1 mg/liter, respectively. The plasma AmB levels were higher than the mean values of the overall population in 3 patients who developed CTC grade 3 hypokalemia and did not significantly differ from the mean values of the overall population in 3 patients who developed IFD. Our experience demonstrates the feasibility and safety of a single 15-mg/kg L-AmB dose as antifungal prophylaxis in AML patients undergoing induction chemotherapy.

Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary?

Pharmacokinetic studies of daptomycin in septic patients indicate that pharmacokinetic parameters may be altered. The purpose of this clinical investigation is to determine the pharmacokinetics of daptomycin in a population of hospitalized patients with clinically significant gram-positive infections and receiving daptomycin. Daptomycin was measured using an isocratic HPLC technique. Thirty-five patients suffering from gram-positive severe infections and receiving daptomycin were included in the study. Patients were divided into two groups, depending on the dose of daptomycin received: group A, including 24 patients receiving 6 mg/kg/day daptomycin and group B, 11 patients receiving 8 mg/kg/day. Patients receiving a daptomycin dosage of 8 mg/kg/day had significantly higher values of mean C max and AUC0-24. Each group was further divided into three subgroups, according to the creatinine clearance (CrCl) values: (1) patients with a CrCl >80 ml/min, (2) patients with CrCl ranging between 80 and 40 ml/min, and (3) patients with CrCl <40 ml/min. Compared to patients with normal renal function, those with CrCl <40 ml/min had higher mean values of minimum concentration (C min) (p < 0.001), AUC0-24 (p = 0.03), and prolonged plasma half-time (p < 0.001). These differences were present both in patients receiving 6 and those with 8 mg/kg/day. However, in each of the three subgroups with different degrees of renal function a marked variability of pharmacokinetics parameters was observed. The factors associated with increased mortality were an infection acquired in the ICU, hypoalbuminemia, and AUC/MIC <666. The marked variability that characterizes daptomycin pharmacokinetics in these patients suggest the monitoring of the main pharmacokinetic parameters in this clinical setting.

Candida glabrata prosthetic hip infection.

We present a case of a 60-year-old Caucasian woman carrying a 2-year-old hip prosthesis infected by Candida glabrata dose-dependent susceptible to fluconazole and voriconazole. Resection arthroplasty was performed. Six weeks of caspofungin plus liposomal amphotericin combination therapy achieved joint sterilization and allowed a successfully reimplantation arthroplasty. In addition we review 9 cases of C. glabrata prosthetic joint infection described to date in the literature.

Conventional and long-circulating liposomes of artemisinin: preparation, characterization, and pharmacokinetic profile in mice.

Artemisinin (qinghaosu), a unique endoperoxide sesquiterpene lactone isolated from Artemisia annua L., is a very active antimalarial drug, including severe and cerebral malaria. However, its therapeutical efficacy is limited due to its scarce bioavailability. In this article, artemisinin-loaded conventional and polyethylene glycol (PEGylated) liposomes were proposed as carriers to increase biopharmaceutical properties of the drug. Encapsulation efficacy was determined by high-performance liquid chromatography/diode array detection/electrospray ionization-mass spectrometry, dimensional analysis was performed by dynamic light scattering, and morphology was performed by trasmission electron microscopy. After dialysis, both liposomal formulations showed an encapsulation efficacy of more than 70%; mean diameter of all the artemisinin-loaded vesicles was approximately 130-140 nm. The polydispersity index of the formulations ranged from 0.2 to 0.3 and resulted as suitable for intraperitoneal (i.p.) administration. Pharmacokinetic profile and the main pharmacokinetic parameters of the carriers were evaluated in healthy mice i.p. Free artemisinin was rapidly cleared from plasma and hardly detected 1 hour after administration. Conversely, both liposomal formulations showed much longer blood-circulation time than free artemisinin; artemisinin was still detectable after 3 and 24 hours of administration, respectively, for conventional and PEGylated liposomes. AUC(0-24 h) values were increased by approximately 6 times in both of the liposomal formulations, in comparison with free artemisinin. A strong effect of formulation on the half-life of artemisinin was enhanced by more than 5-fold by the incorporation of PEG into liposomes. Liposomes loaded with artemisinin, especially the long-circulating vesicles, could really represent a new strategy for developing smart, well-tolerated, and efficacious therapeutic nanocarriers to treat tumors, but could also be very useful to treat parasitic disease.

Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer.

INTRODUCTION: Although some studies have suggested that gemcitabine delivered as a fixed dose rate (FDR) infusion of 10 mg/m(2)/min could be more effective than when administered as the standard 30-min infusion, the available pharmacokinetic data are still too limited to draw definitive conclusions. This study is aimed to investigate the plasmatic and intracellular pharmacokinetics of gemcitabine given as FDR at doses of 600 and 1,200 mg/m(2) in combination with 75 mg/m(2) of cisplatin in advanced non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHOD: The patients were divided into two groups receiving different initial doses of the drug: 4 patients received 600 mg/m(2) gemcitabine 60-min i.v. infusion and 4 patients 1,200 mg/m(2) gemcitabine 120-min i.v. infusion both as a FDR of 10 mg/m(2)/min on days 1 and 8 of a 21-day cycle (at first cycle). At the second cycle, all patients were treated with gemcitabine at 1,200 mg/m(2) 120-min i.v. infusion (FDR of 10 mg/m(2)/min) on days 1 and 8 of a 21-day cycle. At each cycle, gemcitabine was administered alone on day one, and in combination with 75 mg/m(2) of cisplatin on day 8. Plasmatic and intracellular pharmacokinetic analyses were performed on blood samples collected at defined time points before, during and after gemcitabine infusion. RESULTS: The plasmatic pharmacokinetic parameters were clearly different when the patients received a higher gemcitabine dose in the second cycle compared to the lower dose of the first course; in the same time, the intracellular drug levels were not modified. Comparing the pharmacokinetic parameters of different patients treated at different dose levels, the results appeared to be quite similar. CONCLUSIONS: A substantially higher accumulation of metabolites in peripheral blood mononuclear cells was observed when the longer infusion time was employed, suggesting a pharmacological advantage for this treatment schedule.

Ertapenem peritoneal fluid concentrations in adult surgical patients.

Ertapenem, a novel carbapenem, is approved for the treatment of mild to severe intra-abdominal infections (IAIs), although its in vivo concentrations in peritoneal fluid are unknown. The purpose of this study was to determine the peritoneal fluid concentration of ertapenem after a single 1 g intravenous dose. After informed consent, 21 patients (9 females and 12 males; mean+/-standard deviation (S.D.) age 50.2+/-17.7 years) requiring intra-abdominal surgery were enrolled. Plasma and peritoneal fluid samples were taken at fixed times during surgery. Drug concentrations were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection. Mean+/-S.D. ertapenem peritoneal fluid concentrations were 64.3+/-23.4 mg/L at 1h and 31.3+/-26.5 mg/L at 3 h after administration. The mean tissue/plasma ratio ranged from 46.7% to 83.1%. The mean peritoneal fluid concentrations were well above the MIC(90) (minimum inhibitory concentration for 90% of the organisms) for susceptible bacteria found in IAIs, especially Escherichia coli, viridans streptococci, Enterobacteriaceae, Klebsiella spp. and Bacteroides fragilis, during the entire sampling time. These pharmacokinetic results support the assumption that ertapenem might be suitable for the treatment of IAIs.

Relaxin inhibits the activation of human neutrophils: involvement of the nitric oxide pathway.

In animal models of inflammation, the pregnancy hormone relaxin was shown to reduce the recruitment of leukocytes, especially neutrophils, in inflamed tissues. The current study was designed to clarify whether relaxin could inhibit activation of isolated human neutrophils and, if so, whether the nitric oxide (NO) biosynthetic pathway was involved, as occurs in other relaxin targets. Human neutrophils were preincubated with 1, 10, and 100 nmol/liter porcine relaxin for 1 h before activation with N-formyl-Met-Leu-Phe (10 micromol/liter) or phorbol-12-myristate-13-acetate (0.1 micromol/liter). In selected experiments, the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 100 micromol/liter) was added to the samples 30 min before relaxin. In other experiments, chemically inactivated relaxin (10 nmol/liter) was substituted for authentic relaxin. Untreated, nonactivated neutrophils were the controls. Relaxin reduced significantly and in a concentration-dependent fashion the expression of the surface activation marker CD11b, as well as the generation of superoxide anion, the rise of intracellular Ca(2+), the release of cytoplasmic granules, and the chemotactic migration. These effects of relaxin were blunted by N(G)-monomethyl-L-arginine and could not be reproduced by inactivated relaxin. Relaxin also increased neutrophil inducible NO synthase expression and NO generation. This study provides evidence that relaxin inhibits the activation of human neutrophils stimulated by different proinflammatory agents. This novel property of relaxin could be of relevance in toning down maternal neutrophil activation during pregnancy, thereby counteracting the occurrence of pregnancy-related disorders such as preeclampsia, which is regarded as an excess maternal inflammatory response to pregnancy.

Regional and systemic prophylaxis with teicoplanin in total knee arthroplasty: a tissue penetration study.

Five patients undergoing total knee arthroplasty (TKA) received 800 mg intravenous teicoplanin systemically 2.5 hours before surgery and 15 patients received 200 mg teicoplanin into a foot vein in the leg to be treated. Samples of bone, synovia, subcutaneous tissue, and skin were collected at 20, 40, and 60 minutes after tourniquet inflation and at the end of surgery. None of the study subjects experienced adverse effects, adverse events, or infections during the postoperative and follow-up period. Mean teicoplanin concentration in the collected tissue ranged from 1.52 to 5.81 mg/L after regional prophylaxis and from 0.9 to 2.94 mg/L after systemic prophylaxis. Bone and soft tissue penetration of teicoplanin after regional prophylaxis with 200 mg is at least comparable with that achieved after systemic prophylaxis with 800 mg. Regional prophylaxis in TKA appears to be safe and valuable. Higher dosages of teicoplanin seem to be needed to ensure coverage against coagulase negative staphylococci.

[Antibiotic prophylaxis in surgery: news and controversies]. / Profilassi antibiotica in chirurgia: attualità e controversie.

Preoperative administration of antibiotics to prevent possible post-surgical infections represents a cornerstone of modern medicine. Although the general principles of surgical prophylaxis have been quite clearly defined during the last few decades, advenaces in surgical techniques, the changes in bacterial ecology in hospital, the spread of bacterial resistance and the substantial increase in the surgical population at risk, suggest that several aspects of surgical prophylaxis should be reviewed and new controlled studies should be carried on. The American guidelines for surgical prophylaxis, worked out recently by the CDC, have not modified their general structure, and have strongly influenced the protocols and the prescriptive behaviour of other countries, including Italy. The following points suggest that these guidelines are probably no longer adeguate for the situation in question: evidence from several sources would extend the advisability of antibiotic prophylaxis to other clean surgeries; the current classification of surgical procedures does not consider the "new" population of risk patients; the duration of prophylaxis and its role in preventing post-surgical infections "at a distance" infections has not been carefully defined; the evolution of bacterial epidemiology and bacterial resistance and the contemporary availability of new antibiotics has moved the fear of a post-antibiotic era In the clinical practice, according to these considerations and whilst awaiting the results of new clinical trials, in some cases and for some at risk patients it would appear justified to use third generation cephalosporins and especially ceftriaxone that, because of its peculiar pharmacokinetcs characteristics, guarantees with a single dose the same efficacy of three doses of other cephalosporins.