Biotherapeutics and biotherapy of surgical enteropathies.

Probiotic agents are living micro-organisms that, upon ingestion, exert health benefits beyond inherent general nutrition. In this context, we must differentiate between biotherapeutics as approved drugs and dietary supplements and food products containing prebiotic bacteria that are not considered drugs. At present, the only biotherapeutic agent which is prescribable in some European countries, indicated to relieve specific diseases, is the yeast Saccharomyces boulardii. In this review, we consider the various pre-clinical and clinical aspects of biotherapeutics as basic drugs and the biotherapeutic powers of their use in the treatment of some surgical enteropathies.

Classification of oral cephalosporins. A matter for debate.

There are many cephalosporins available and various ways of classifying them for clinical use. Oral cephalosporins probably need a classification of their own. This informal discussion was prompted by the appearance of the recommendations of an expert committee of the Paul Ehrlich Gesellschaft. The views of several other commentators are included. There is considerable individual variation in preference for different styles of classification depending on what the classification is for.

Preclinical and clinical pharmacology of biotherapeutic agents: Saccharomyces boulardii.

Probiotic agents are living microorganisms that, upon ingestion, exert health benefits beyond inherent general nutrition. In this context, we must differentiate between biotherapeutics as approved drugs and dietary supplements and food products containing probiotic bacteria that are not considered drugs. At present the only biotherapeutic agent which is prescribable in some European countries, indicated to relieve specific diseases, is the yeast Saccharomyces boulardii. In this review we consider the various preclinical and clinical aspects of biotherapeutics as basic drugs and the biotherapeutic powers of their use in the treatment of some surgical enteropathies.

Preliminary results of a survey of the use of antimicrobial agents as prophylaxis in orthopedic surgery.

An epidemiological survey of the use of antimicrobial prophylaxis in Italian hospitals was carried out under the auspices of the Journal of Chemotherapy. Out of 500 Italian orthopedic centers queried, 225 agreed to participate in this study. A total of 136,321 surgical procedures were reported in the 166 centers reporting complete answers on type of surgery. They comprised hip and knee prosthesis (13.9%), spine surgery (4%), hip endoprosthesis (5.2%), osteosynthesis (26.9%), arthroscopy (24.4%), and others (25.5%). Perioperative antimicrobial prophylaxis was used in 75% of operations (ranging from 57.1% to 99.4% in arthroscopy and joint prosthesis, respectively). Short term (<24 h) antimicrobial prophylaxis was performed in 38.4% of the 206 centers answering this question correctly. 61.1% of centers employed single agent prophylaxis and 70.8% of these prescriptions were betalactam antibiotics. Bacteriological analysis revealed gram-positive isolates in 73.3% of cases. Methicillin resistance was present in 45% of 915 tested strains. Out of 4221 patients with high risk of infectious complications (joint prosthesis surgery) given antimicrobial prophylaxis in 46 centers, the percentage of surgical wound infections was overall 2.1%, while that of non-surgical wound infections was 3.6%. The total infection rate was decreased by about half in association with long-term (>24 h) as compared to short-term (<24 h) antibiotic treatment (3.7% vs 7.6%, respectively), and with use of antibiotic drug combinations vs single antibiotic drugs (3.9 vs 6.6%, respectively). The incidence of surgical-site infection was not decreased by extending the chemoprophylaxis for more than the first 24 h after surgery, while it was reduced from 2.5 to 1.4% by use of combination antibiotic therapy.

Does surgical prophylaxis with teicoplanin constitute a therapeutic advance?

Antibiotic prophylaxis has become standard care not only in operations characterized by high infection rates but also in the vast majority of clean surgical procedures, including those that use foreign materials, grafts or prosthetic devices as well as non-implant surgery. While use of antibiotics in clean implant surgery is undisputed, it is still controversial in clean non-implant surgery. As antibiotic prophylaxis should be directed against expected pathogens, the glycopeptides are considered suitable alternative antibiotics to first and second generation cephalosporins in clean surgical procedures associated with a high risk of wound infections due to Gram-positive bacteria, including methicillin-resistant, and for patients allergic to beta-lactam antibiotics. In deciding whether to use a glycopeptide for prophylaxis, the current wound infection rates with methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis at single institutions need to be considered, to limit the use of glycopeptides to wards where the incidence of methicillin resistance is high. Of the two available glycopeptides, teicoplanin may be preferable to vancomycin for peri-operative prophylaxis because of its excellent tissue penetration, as indicated by the large volume of distribution, lower toxicity, and particularly long half-life, allowing single-dose administration in several surgical procedures. Clinical trials with teicoplanin prophylaxis in several types of clean surgical procedures including orthopedic, cardiac, vascular and dental operations, have shown it to be efficacious. This review focuses on results from clinical studies with this glycopeptide as prophylaxis in clean surgery.

Cefodizime in skin suction blister fluid and serum following a single intravenous or intramuscular dose in adult patients.

Cefodizime is a third generation cephalosporin for parenteral use. The pharmacokinetics of this cephem antibiotic were determined in serum and skin suction blister fluid (SBF) after intravenous (i.v.) or intramuscular (i.m.) administration of a single 1 g dose in 8 adult patients with normal renal and hepatic function who volunteered for the study. The concentration versus time curve showed a slower elimination rate from the extravascular compartment: the half-lives were 4.4+/-0.5 and 5.4+/-0.4 hours after i.v. and i.m. route respectively. The relatively long elimination half-life in SBF with a mean residence time of about 8 hours allows the use of cefodizime once-a-day for the treatment of infections due to sensitive pathogens.

New insight into the clinical pharmacokinetics of cefaclor: tissue penetration.

The serum pharmacokinetic data presented are generally in agreement with those obtained by other authors with both the cefaclor IR (immediate release) and AF (advanced formulation) or MR (modified release) formulations. With the new sustained-release formulation, the time of peak (Tmax) and mean residence time (MRT) values are significantly longer than those observed with the standard cefaclor IR. For the first time the penetration of the MR formulation of cefaclor was determined both in suction blister fluid (SBF) and alveolar epithelial lining fluid (ELF). Cefaclor demonstrated a high tissue distribution, with a high penetration index (PI) into blister fluid, which is at least representative of a relatively large volume of fluid-filled spaces and in part of highly vascularized tissues. SBF and ELF concentrations were higher than blood levels starting at the 4th-6th hour after dose, with longer elimination half-lives from the extravascular compartment than from serum. Cefaclor has a favorable pharmacokinetic profile, especially the new sustained-release formulation, which maintains effective concentrations for a longer time than the IR preparation. The MR formulation improves the kinetic properties of the cefaclor molecule with a prolonged MRT which allows a daily dosage of 750 mg every 12 h.

[Antibiotic prophylaxis of postoperative infection in orthopedics. Results of an epidemiologic survey in Italy conducted by the Journal of Chemotherapy]. / Profilassi antimicrobica della infezione chirurgica in ortopedia. Risultati della indagine epidemiologica promossa per l'Italia dal Journal of Chemotherapy.

An epidemiological survey of the use of antimicrobial prophylaxis in Italian hospitals was carried out under the auspices of the Journal of Chemotherapy. Out of 500 Italian orthopedic centers requested, 225 have participated in this study. A total of 136,321 surgical procedures were reported in the 166 centers reporting complete answers on type of surgery. They comprised hip and knee prosthesis (13.9%), spine surgery (4%), hip endoprosthesis (5.2%), osteosynthesis (26.9%), arthroscopy (24.4%), and others (25.5%). Perioperative antimicrobial prophylaxis was used in 75% of operations (ranging from 57.1% to 99.4% in arthroscopy and joint prosthesis, respectively). Short term (< 24 h) antimicrobial prophylaxis was performed in 38.4% of the 206 Centers answering this question correctly. 61.1% of Centers employed single agent prophylaxis. 70.8% of these prescriptions were betalactam antibiotics. Bacteriological analysis of the wound in 86 Centers (total number of isolates 2013) revealed the presence of Gram-positive isolates in 73.7% of cases. Methicillin resistance was expressed in 45% of 915 tested strains. Out of 4221 patients with high risk of infectious complications (joint prosthesis surgery) given antimicrobial prophylaxis in 46 Centers, the percentage of surgical wound infections was overall 2.1%, while that of non-surgical wound infections was 3.6%. A decrease in the total infection rate by about half was associated with long-term (> 24 h) as compared to short-term (< 24 h) antibiotic treatment (3.7 vs 7.6%, respectively), and with the use of antibiotic drug combinations vs single antibiotic drugs (3.9 vs 6.6%, respectively). The incidence of surgical-site infection is not decreased by extending the chemoprophylaxis for more than the first 24 h after surgery, while it is reduced from 2.5 to 1.4% by use of combination antibiotic therapy.

Current treatment of sepsis and endotoxaemia.

This article reviews the new criteria for selecting the proper antimicrobial agent and dosage regimen for standard treatment of severe sepsis, with the intention of preventing septic shock. After introducing new concepts on the pathogenesis of sepsis and septic shock, the authors analyse the parameters of beta-lactam antibacterial activity, the antibiotic-induced release of bacterial endotoxin and the interrelationships between pharmacokinetics and pharmacodynamics of antibiotics in the search for an optimum dosage regimen of antimicrobial mono- or polytherapy for severely ill septic patients admitted to the intensive care unit. The mortality rate resulting from severe bacterial sepsis, particularly that associated with shock, still approaches 50% in spite of appropriate antimicrobial therapy and optimum supportive care. Bacterial endotoxins that are part of the cell wall are one of the cofactors in the pathogenesis of sepsis and septic shock and are often induced by antimicrobial chemotherapy, even if administered rationally. Not all antimicrobial agents are equally capable of inducing septic shock; this is dependent on their mechanism of action rather than on the causative pathogen species. The quantity of endotoxin released depends on the drug dose and whether filaments or spheroplast formation predominate. Some antibiotics, such as carbapenems, ceftriaxone, cefepime, glycopeptides, aminoglycosides and quinolones, do not have the propensity to provoke septic shock because their rapid bacterial activity induces mainly spheroplast or fragile spheroplast-like bacterial forms.

New criteria for selecting the proper antimicrobial chemotherapy for severe sepsis and septic shock.

The mortality rate resulting from severe bacterial sepsis, particularly that associated with shock, still approaches 50% in spite of appropriate antimicrobial therapy and optimum supportive care. Bacterial endotoxins that are part of the cell wall are one of the cofactors in the pathogenesis of sepsis and septic shock and are often induced by antimicrobial chemotherapy even if it is administered rationally. Not all antimicrobial agents are equally capable of inducing septic shock; this is dependant on their mechanism of action rather than on the causative pathogen species. The quantity of endotoxin released depends on the drug dose and whether filaments or spheroplast formation predominates. Some antibiotics such as carbapenems, ceftriaxone, cefepime, glycopeptides, aminoglycosides and quinolones do not have the propensity to provoke septic shock because their rapid bactericidal activity induces mainly spheroplast or fragile spheroplast-like bacterial forms.

Comparative multicenter trial of teicoplanin versus cefazolin for antimicrobial prophylaxis in prosthetic joint implant surgery. Italian Study Group for Antimicrobial Prophylaxis in Orthopedic Surgery.

A randomized multicenter study was carried out in 12 centers in Italy to compare administration of a single dose of teicoplanin (400 mg i.v. bolus at time of anesthesia) versus that of five doses of cefazolin over a 24-h period (2 g at induction of anesthesia and 1 g every 6 h postoperatively, i.v. bolus) as antimicrobial prophylaxis in patients undergoing hip or knee arthroplasty. Of 860 patients enrolled, 427 received teicoplanin and 433 cefazolin. A total of 846 patients (422 teicoplanin and 424 cefazolin) were evaluable for safety and 826 patients for efficacy. Six patients (1.5%) in the teicoplanin group and seven patients (1.7%) in the cefazolin group developed a surgical wound infection during their postoperative hospital stay: this difference was not significant. Proven or suspected infections involving other body systems occurred in 114 patients (57 in each group). Seven hundred ninety-two patients completed a 3-month evaluation and 738 patients a 12-month evaluation: the success rates in evaluable patients at these observation times were 99.2% and 99.7% for teicoplanin and 99.2% and 99.7% for cefazolin, respectively. Adverse events occurred in three (0.7%) teicoplanin patients and nine (2.1%) cefazolin patients (P = 0.083). A single preoperative dose of teicoplanin ensures adequate surgical antisepsis, with results comparable to a standard multiple-dose regimen of cefazolin.

Clarithromycin: pharmacokinetic and pharmacodynamic interrelationships and dosage regimen.

In the last decade three important pharmacodynamic parameters: T>MIC, Cmax/MIC and AUC/MIC, have been shown to correlate well with in-vitro antimicrobial efficacy and that found in animal models, differentiating among groups of antibiotics with diverse mechanisms of action such as exposure time or concentration-dependent effect. The macrolide antimicrobial agents display variable concentration-dependent killing, indicating the increasing importance of the Cmax parameter. Clarithromycin, whose T>MIC and AUC influence its clinical efficacy, is in an intermediate position between its progenitor, erythromycin, and the azalides. This paper reviews pharmacokinetic and pharmacodynamic characteristics of clarithromycin, examining the potential impact of these properties on the dose and the optimal interval between administrations.

Classification of betalactam antibiotics according to their pharmacodynamics.

Considerable information on the pharmacodynamics of betalactams has accumulated throughout the past 20 years demonstrating a time-dependent killing and some pharmacodynamic differences in the type of activity in-vitro and in animal models that should have clinical significance. Unfortunately few clinical studies have directly examined the effects of different dosages that might be predicted to result in failure or success of the outcome, particularly in serious sepsis. Thus on the basis of a long preclinical and clinical experience we propose a pharmacodynamic classification of betalactam antibiotics. Three classes are delineated by the extent of PBP pattern saturation, biomass increase, PAE length and initial killing power.

Efficacy and safety of high dose intravenous ciprofloxacin in the treatment of bacterial pneumonia. Italian Ciprofloxacin Study Group.

One hundred and fifty three hospitalized patients were enrolled in an open, prospective, multi-center study on the efficacy and safety of intravenous ciprofloxacin (400 mg i.v., b.i.d.) for acute bacterial pneumonia: 93 (63%) patients were valid for efficacy out of 148 valid for intention-to-treat analysis. The most commonly isolated organisms from 93 valid-for-efficacy patients were Pseudomonas aeruginosa (17%), Haemophilus influenzae and parainfluenzae (17%), Streptococcus aureus (14%) and Streptococcus pneumoniae (11%). Cure was achieved in 89/93 (95.7%) valid-for-efficacy patients; effective eradications were obtained in 42 (45%) and presumed eradications in 48 (52%) of the 93 patients. Mild or moderate adverse events (AE) occurred in 13/153 (8.5%) patients assessable for safety; all but one AE were rapidly reversible and only one treatment-stop (0.65%) was decided. The treatment of acute bacterial pneumonias with high-dose parenteral ciprofloxacin appears to be efficacious and well tolerated.

Antimicrobial prophylaxis in orthopaedic surgery: the role of teicoplanin.

Orthopaedic joint replacement is generally considered 'clean' surgery characterized by a low incidence of infection. In recent years the use of a clean theatre environment, high local concentrations of antibiotic in the cement and systemic antibiotic prophylaxis have been recognized as important measures to reduce infection rates significantly, and this has been supported by clinical trials. Staphylococcus aureus and Staphylococcus epidermidis cause at least half of all orthopaedic surgical infections. Gram-negative bacilli are involved to a much lesser extent (10-30%). First- and second-generation cephalosporins are currently considered by most authors as standard prophylaxis in elective orthopaedic surgery. In the light of the increasing incidence of methicillin resistance in coagulase-positive and -negative staphylococci, it is becoming more important for antibiotics to act efficiently against such organisms if they are to be of value in prophylaxis in orthopaedic surgery. A combined, single-dose of vancomycin/gentamicin has been used successfully in an open, controlled study in patients undergoing total joint arthroplasty but, given the disadvantages associated with the use of vancomycin, teicoplanin may be an alternative choice in such procedures. This review analyses four comparative trials of the efficacy and safety of teicoplanin, two with cefamandole, one with cefuroxime and one with cephazolin, as prophylaxis in orthopaedic total joint replacement surgery.

Selecting antibacterial agents for the control of surgical infection: mini-review.

An analysis of the recent literature on the control of surgical infections confirms the role of antimicrobial agents which guarantee valid perioperative antisepsis in both clean and clean-contaminated surgery. Current chemotherapy is able to check serious postoperative infectious complications by reducing the risk of septic shock with use of a glycopeptide-aminoglycoside-betalactam combination together with anti-inflammatory drugs.

Immunopharmacology of oral betalactams.

Among the oral beta-lactam antibiotics only cefaclor has demonstrated a consistent in vitro and in vivo immunopharmacological effect which favors phagocytic chemotaxis and antimicrobial potential by inducing a T-helper 1 or pro-inflammatory response. Together with cefpimizole, cefaclor significantly reduces the minimum bactericidal concentration (MBC) against some bacterial species when cultured together with a suspension of polymorphonuclear leukocytes, as opposed to some other oral beta-lactams, co-amoxiclav and cefixime, which do not show this effect. The pro-inflammatory component of cefaclor's activity explains the clinical success of this antibiotic in a high percentage of cases, even when laboratory tests indicate in vitro resistance by the pathogen.