Integrating animal health surveillance and food safety: the issue of antimicrobial resistance.

Surveillance of antimicrobial resistance in commensal, zoonotic and pathogenic bacteria from humans, animals and food is an essential source of information when formulating measures to improve food safety. International organisations (the World Health Organization, the World Organisation for Animal Health, the Food and Agriculture Organization of the United Nations, and the Codex Alimentarius Commission) have developed a complete set of standards related to resistance surveillance programmes and are calling for the establishment of integrated surveillance programmes. The most important task in establishing an integrated surveillance programme for antimicrobial resistance should be the harmonisation of laboratory testing methodology and antimicrobial-use reporting. Overthe last decade, the integration of surveillance of antimicrobial resistance has been an important step toward addressing the global concern with antimicrobial resistance. However, very few systems are in place and there is still a lot to do before harmonised surveillance systems become the norm.

Antimicrobial resistance: a complex issue.

The discovery of antibiotics represented a turning point in human history. However, by the late 1950s infections that were difficult to treat, involving resistant bacteria, were being reported. Nowadays, multiresistant strains have become a major concern for public and animal health. Antimicrobial resistance is a complex issue, linked to the ability of bacteria to adapt quickly to their environment. Antibiotics, and antimicrobial-resistant bacteria and determinants, existed before the discovery and use of antibiotics by humans. Resistance to antimicrobial agents is a tool that allows bacteria to survive in the environment, and to develop. Resistance genes can be transferred between bacteria by horizontal transfer involving three mechanisms: conjugation, transduction and transformation. Resistant bacteria can emerge in any location when the appropriate conditions develop. Antibiotics represent a powerful selector for antimicrobial resistance in bacteria. Reducing the use of antimicrobial drugs is one way to control antimicrobial resistance; however, a full set of measures needs to be implemented to achieve this aim.

Antimicrobial resistance in animal and public health: introduction and classification of antimicrobial agents.

Bacteria have a remarkable ability to adapt, evolve and survive by developing resistance to therapeutic compounds. This ability is also shared by other pathogenic agents such as viruses, fungi, and parasites. Even when focusing on bacterial resistance only, this phenomenon is quite complex to analyse due to the diversity of animal species, the diversity of rearing environment, the number of antimicrobial classes available and the diversity of pathogenic bacteria involved. This introductory paper includes developments on the place of antiviral compounds in veterinary medicine and a classification of antimicrobials used in food-producing animals.

Antagonism of the antibacterial action of some penicillins by other penicillins and cephalosporins.

There are many examples of two penicillins acting synergistically, usually by one competitively inhibiting beta-lactamase, thus protecting the other from inactivation. There are few reports on penicillins antagonizing each other. Eight strains of three genera (Proteus, Escherichia, Pseudomonas) isolated at Boston City Hospital or Institut Pasteur, Paris, showed antagonism of carbenicillin or ampicillin by cephaloridine, cloxacillin, or 6-aminopenicillanic acid. Broth dilution tests showed that with seven of the eight strains the minimum inhibiting concentration (MIC) of the more active antibiotic was increased by 800-6,400% by low concentrations (often one-tenth the MIC) of the antagonist, whereas higher concentrations of "antagonist" were not as antagonistic, This suggested that two or more receptor sites of action for penicillins were present; the antagonist thus blocks the antibacterial action at the more sensitive site but acts additively with the antagonized antibiotic at the less sensitive site. The possibility that the mechanism of antagonism was induction of inactivating enzymes (beta-lactamase, penicillin acylase) was studied in two strains(one Escherichia coli and one Proteus rettgeri), and two antagonists were studied in detail. With E. coli cephaloridine was a poorer inducer of beta-lactamase than were the antagonized antibiotic and 6-aminopenicillanic acid. From these organisms, the good inducers of a beta-lactamase that acted on benzylpenicillin did not induce enzymes that inactivated carbenicillin. Thus, the mechanism of antagonism was not due to beta-lactamase induction.

Antimicrobial resistance at farm level.

Bacteria that are resistant to antimicrobials are widespread. This article reviews the distribution of resistant bacteria in farm environments. Humans, animals, and environmental sites are all reservoirs of bacterial communities that contain some bacteria that are susceptible to antimicrobials and others that are resistant. Farm ecosystems provide an environment in which resistant bacteria and genes can emerge, amplify and spread. Dissemination occurs via the food chain and via several other pathways. Ecological, epidemiological, molecular and mathematical approaches are being used to study the origin and expansion of the resistance problem and its relationship to antibiotic usage. The prudent and responsible use of antibiotics is an essential part of an ethical approach to improving animal health and food safety. The responsible use of antibiotics during research is vital, but to fully contribute to the containment of antimicrobial resistance 'prudent use' must also be part of good management practices at all levels of farm life.

Functional results 5 years after successful percutaneous mitral commissurotomy in a series of 528 patients and analysis of predictive factors.

OBJECTIVES: This study sought to assess late functional results after successful percutaneous mitral commissurotomy and to determine their predictors. BACKGROUND: Few studies have reported late results of percutaneous mitral commissurotomy or have analyzed their late results regardless of immediate results, despite the fact that late deterioration may well be related either to a decrease in valve area or to poor initial results. METHODS: Between 1986 and 1992, 528 patients underwent successful percutaneous mitral commissurotomy (mean [+/- SD] age 46 +/- 18 years; mean follow-up 32 +/- 18 months). A successful procedure was defined by a mitral valve area > or = 1.5 cm2 and no regurgitation > 2/4. Dilation was performed using a single balloon in 13 patients, a double balloon in 349 and the Inoue balloon in 166. Multivariate analysis was performed with a Cox model. RESULTS: The survival rate for patients in New York Heart Association functional class I or II, with no cardiac-related deaths or need for mitral surgery or repeat dilation, was 76 +/- 6% at 5 years. By multivariate analysis, the independent predictors of good functional results were echocardiographic group (p = 0.01), functional class (p = 0.02) and cardiothoracic index (p = 0.005) before the procedure and valve area after the procedure (p = 0.007). The predictive model derived allowed estimation of the probability of good functional results according to the value of these four predictors for any given patient. CONCLUSIONS: Good functional results were observed 5 years after successful percutaneous mitral commissurotomy in a large series of varied patients. The analysis of predictive factors may provide useful indications for follow-up results in patients undergoing this technique.

Role of antidiuretic hormone in impaired water excretion of patients with congestive heart failure.

Plasma antidiuretic hormone (ADH), PRA, plasma osmolality, and the parameters of renal water excretion were measured after overnight dehydration and for 5 h after an oral load in 14 patients with congestive heart failure (CHF) treated with diuretics (group 1), 8 hypertensive patients without CHF also treated with diuretics (group 2), and 11 patients with coronary artery disease but without CHF who were not treated with diuretics (group 3). Under basal conditions, mean plasma osmolality was lower in group 1 than in group 3, but was not different in groups 1 and 2. Mean plasma ADH was higher in group 1 than in group 2 or 3. In response to the water load, plasma osmolality and plasma ADH levels decreased in the 3 groups. ADH levels remained significantly greater in group 1 than in groups 2 and 3 from 2-4 h after the water load despite more marked hypoosmolality in group 1 compared with that in either of the 2 control groups. Plasma ADH was significantly correlated with plasma osmolality only in the 2 control groups. Mean PRA was greater in patients with CHF and patients without CHF treated with diuretics than in untreated patients. Cumulative water excretion was lower in patients with CHF than in patients in the 2 control groups from 2-5 h after the water load. At 5 h, the mean percentage excretion of the ingested loads was 56.8%, 90.7%, and 91.2% in the patients of groups 1, 2, and 3 respectively. Free water clearance was lower and minimal urinary osmolality was greater in the patients with CHF than in those in the 2 control groups. Two patients with CHF, who excreted more than 75% of the water load, also had low plasma basal ADH levels. These data show that patients with CHF have an inappropriate response of plasma ADH to a marked fall in plasma osmolality. This disorder is not due to the diuretic therapy, since hypertensive patients treated with diuretics behaved similarly to untreated patients without CHF. The reasons for this inappropriate response of plasma ADH during a water load in patients with CHF are probably multifactorial.

Strategies in aminoglycoside use and impact upon resistance.

Assessment of amikacin resistance over a 10-year period at our institution revealed that the number of resistant strains remained stable. Qualitatively, amikacin-resistant Enterobacteriaceae and Pseudomonas were fairly stable. There was a slight increase in amikacin-resistant Acinetobacter and staphylococci. Different factors influencing the emergence and spread of resistant hospital bacteria have been studied at different periods and compared with similar data on gentamicin-resistant strains. Transmissible plasmids, multiple mechanisms of resistance, and high levels of resistance were more frequent in gentamicin-resistant strains. In the amikacin-resistant strains, the level of resistance was 16 to 32 mg/liter with few autotransferable plasmids. A synergistic or additive effect with cephalosporins, which may be a factor in decreasing the risk of selection of the resistant strains since there is no plasmid-mediated resistance to cephalosporins, was demonstrated in Enterobacteriaceae. To control the development of aminoglycoside resistance in hospitals, it may be necessary to restrict the use of more than the one drug to which resistance is developing; to use the antibiotic at the right dosage and, when necessary, in a combination that may prevent the emergence of resistant organisms and plasmids; and to develop measures to control bacterial and R factor transmission.

Synergism and antagonism in double beta-lactam antibiotic combinations.

Combinations of two beta-lactam antibiotics may be advantageous in certain clinical situations, providing a synergistic activity against specific organisms or a broad spectrum of antibiotic coverage. Depending on the combination and the bacteria, synergism, indifference, or antagonism can be observed. Synergism may occur when two beta-lactam antibiotics, acting on different penicillin-binding proteins, are combined or when a penicillinase-susceptible beta-lactam antibiotic is protected by another beta-lactam antibiotic acting as a beta-lactamase inhibitor in strains producing a penicillinase (chromosomal or plasmidic). With different species, such as Enterobacter, Citrobacter, indole-positive Proteus, Serratia, Aeromonas, and Pseudomonas, which produce an inducible chromosome-encoded cephalosporinase, antagonism will appear if one of the two combined antibiotics causes induction of the beta-lactamase and the other becomes inactivated by the increased amount of the enzyme. Although most combinations of new beta-lactam antibiotics (ureido-penicillins, third-generation cephalosporins, monobactams) appear to be indifferent, antagonism and possible selection of resistant mutants are the drawbacks of such combinations. Nevertheless, highly active compounds, if used at doses above the minimal inhibitory concentrations, especially in the case of potential cephalosporinase-inducers, may be safe in vivo as far as avoiding antagonism is concerned, but not necessarily with respect to the selection of resistant mutants.

Fate of circulating immune complexes in infective endocarditis.

To examine the role of circulating immune complexes (CIC) in infective endocarditis, we studied 64 patients with infective endocarditis for the presence of CIC by the polyethylene-glycol (PEG)-precipitation test and the Clq binding test. This study was repeated during the course of the disease in 23 patients. CIC were found in 84 per cent of patients (66 per cent with acute infective endocarditis, 89 per cent with subacute infective endocarditis) during the active phase of the disease. Higer PEG precipitates were associated with typical cutaneous signs, cryoglobulins and nonstreptococcic culture-positive infective endocarditis. Under appropriate antibiotic treatment, the PEG precipitate levels of 17 patients fell within 1 month to the normal range, with a concomitant drop in cryoglobulinemia and rheumatoid factor. Conversely, uncontrolled sepsis always (six of six) yielded a rising level of CIC. These findings support the hypothesis that CIC may be important in the pathogenesis of peripheral lesions in infective endocarditis.

Thrombolytic therapy: future issues.

A considerable amount of work has been devoted to thrombolytic therapy (about 3000 references from 1991 to 1995 in a Medline search). The most important and well established indication of thrombolytic treatment is acute myocardial infarction (MI). Megatrials have evidenced a significant 30 to 40% reduction in hospital mortality in the treated patients. However, lack of sufficient thrombolysis in approximately 25% of patients, reocclusion in 6 to 16% of patients and intracranial hemorrhage in about 0.5% of patients are the main concerns regarding thrombolysis. Three approaches should improve the results of thrombolytic therapy in acute MI: earlier medical treatment, use of more efficacious thrombolytic agents in combination with more active antithrombotic agents and reduction of severe bleeding with safer combination of drugs. An improved of laboratory monitoring may also reduce the incidence of severe hemorrhagic events. In acute pulmonary embolism (PE), a change of indication for treatment based on echocardiography and high probability ventilation-perfusion lung scan results (without requiring pulmonary angiography) could broaden the use of thrombolysis. However, thus far, there has not been a demonstration of a reduction in mortality in large controlled studies. Thrombolysis in acute ischemic stroke is an attractive treatment but thrombolytic treatment is still at an experimental stage. However, the successful use of rt-PA in acute MI has renewed the interest in thrombolysis for focal cerebro-vascular ischaemia. Large controlled studies with SK, rt-PA or UK locally or intravenously administered have been recently undertaken to evaluate the benefit/risk ratio of treatment which seems surprisingly variable in different subgroups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of percutaneous mitral commissurotomy on left atrial spontaneous contrast of mitral stenosis.

To assess the influence of percutaneous mitral commissurotomy (PMC) on left atrial spontaneous echo contrast of mitral stenosis, transesophageal echocardiography was performed before and 24 to 48 hours after the procedure, and on average, 6 months later in 82 patients. Fifty-nine patients (72%) were in stable sinus rhythm and 23 in permanent atrial fibrillation. Eleven patients (13%) had history of embolism, and 31 were on long-term anticoagulant therapy. The intensity of spontaneous contrast was graded as follows: 0 = no contrast; 1 = slight contrast; and 2 = intense contrast with the typical aspect of "smoke." PMC resulted in a twofold increase in the valve area irrespective of the method of evaluation used (2 cm2 after vs 1.05 before; p < 0.0001). Severe mitral regurgitation occurred in 3 patients who were operated on within 3 months after PMC. Left atrial spontaneous contrast was noted before the procedure in 53 patients (65%). Multivariate analysis showed left atrial size and cardiac index to be predictive factors of its presence (both p < 0.05). At early post-PMC investigation, the incidence of contrast was 50%, and at 6 months, only 28%. Sinus rhythm appeared to be the only independent predictive factor of the disappearance of contrast by multivariate analysis. In patients in atrial fibrillation, the prevalence of spontaneous contrast was 100% before PMC, 91% at early post-PMC investigation (p = NS), and 89% at the late study (p = NS); the rates were 51, 34 (p < 0.005) and 4% (p < 0.0001), respectively, in patients in sinus rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and delayed hormonal changes in mitral stenosis treated by balloon valvulotomy.

The role of left atrial and aortic pressures on the secretion of the main hormones controlling blood volume is still subject to debate in humans. Because of increased mean left atrial pressure and decreased mean aortic pressure produced by balloon inflation in patients with mitral stenosis treated with balloon valvulotomy, the hormonal changes occurring acutely (group II of patients) were measured. The same studies (group I patients) were also performed 48 hours after this treatment, a period at which left atrial pressure permanently diminished. Inflation of the balloon resulted in a decrease in plasma renin activity and increases in plasma atrial natriuretic factor (ANF) and plasma arginine vasopressin (AVP). Forty-eight hours after balloon valvulotomy, which had produced a decrease in left atrial pressure, plasma ANF was lower (58.9 +/- 7.9 vs 95.3 +/- 11.9 pg/ml; p < 0.001), and plasma renin activity (2,575 +/- 533 vs 960 +/- 113 pg/ml/hour; p < 0.01), plasma angiotensin II (25.0 +/- 4.1 vs 9.3 +/- 1.3 pg/ml; p < 0.001) and plasma aldosterone (181.7 +/- 36.7 vs 139.9 +/- 19.8 pg/ml; p < 0.05) were higher than their respective control levels 24 hours before treatment of the stenosis. In contrast, plasma AVP (3.7 +/- 0.25 vs 4.4 +/- 0.31 pg/ml; p = 0.001) diminished moderately along with plasma osmolality (282.4 +/- 0.1 vs 286.2 +/- 0.6 mOsm/kg; p < 0.001). Urinary sodium excretion was also examined before and after balloon valvulotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Early assessment by transesophageal echocardiography of left atrial appendage function after percutaneous mitral commissurotomy.

Thirty-seven consecutively admitted patients with severe mitral stenosis underwent percutaneous mitral commissurotomy with a transthoracic and biplane or multiplane transesophageal echocardiographic examination before and between 24 and 48 hours after percutaneous mitral commissurotomy. Thirty patients (81%) were in sinus rhythm and 7 were in atrial fibrillation. Left atrial appendage (LAA) function was evaluated in both the transverse and the longitudinal planes by planimetry and pulsed Doppler echocardiographic interrogation at the LAA outlet. Percutaneous mitral commissurotomy resulted in a twofold increase in mitral valve area, and no severe mitral regurgitation occurred. With use of the planimetry method, there was no significant improvement in LAA ejection fraction, except in the transverse plane for patients in sinus rhythm (p = 0.03). With use of Doppler method, 3 distinct flow patterns were observed before the procedure: a "sinus pattern" in patients in sinus rhythm, and a "fibrillatory pattern" (n = 3) or a "no-flow pattern" (n = 4) in patients in atrial fibrillation. After commissurotomy, there was a marked increase in LAA peak Doppler velocity (+62%) and in LAA velocity time integral (+31%). Of the 4 patients in atrial fibrillation with a no-flow pattern, 2 had recovery of a typical effective fibrillatory flow pattern after the procedure. The increase in peak Doppler velocity after commissurotomy was related to the decrease or regression in left atrial spontaneous echo contrast, and correlated with the increase in mitral valve area, the decrease in tranmitral pressure gradient, and the increase in cardiac index; improvement in valve function after successful percutaneous mitral commissurotomy is associated with early improvement in LAA function.

Results of percutaneous mitral commissurotomy in 200 patients.

To assess the feasibility and efficacy of percutaneous mitral commissurotomy (PMC), the procedure was attempted in 200 patients with severe mitral stenosis. There were 154 women and 46 men, their mean age was 43 +/- 16 years (range 13 to 79) and 15 were older than 70 years of age. Forty-four had had previous surgical commissurotomy. Forty were in New York Heart Association class II, 152 in class III and 8 in class IV. In regard to valvular anatomy, 67 had calcified valves, 58 had pliable valves and only mild subvalvular disease, and 75 had flexible valves but extensive subvalvular disease. Grade 1+ mitral regurgitation was present in 62 and grade 2+ in 2. In 11 patients the procedure was discontinued because of complications in 3 and technical failure in 8. Six of the 8 technical failures occurred during the first 15 attempts. Effective PMC was performed in 189 patients using 1 balloon in 23 and 2 balloons in 166. After PMC, there was a significant improvement in mean left atrial pressure (21 +/- 7 to 12 +/- 5 mm Hg, p less than 0.0001), mean mitral gradient (16 +/- 6 to 6 +/- 2 mm Hg, p less than 0.0001), cardiac index (2.6 +/- 0.8 to 3.1 +/- 0.8 liters/min/m2, p less than 0.001) and valve area assessed by hemodynamics (1.1 +/- 0.3 to 2.2 +/- 0.5 cm2, p less than 0.0001) and 2-dimensional echocardiography (1 +/- 0.3 to 1.9 +/- 0.4 cm2, p less than 0.0001). No patient died. Embolism occurred in 8 (4%), with no further sequelae. Sixteen (8%) had atrial septal defect detected by oxymetry.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidemiology of quinolone resistance: Europe and North and South America.

After nearly 10 years of fluoroquinolone usage for a wide range of bacterial infections, a striking difference has been observed in the incidence of bacterial resistance to fluoroquinolones between bacteria responsible for community- and hospital-acquired infections, respectively. Resistance is only rarely encountered among common pathogens. In most studies, 97 to 100% of all pathogens are fully susceptible to fluoroquinolones. In contrast, resistance to fluoroquinolones has emerged and increased among bacteria responsible for nosocomial infections. The incidence of resistance to fluoroquinolones varies between bacterial species, clinical settings and countries, and is related to local epidemic spread of a few clones. The highest incidence of resistance is observed in Pseudomonas aeruginosa, Acinetobacter spp., Serratia marcescens and, particularly, methicillin-resistant Staphylococcus aureus (MRSA): some investigators have reported 95 to 100% fluoroquinolone resistance among MRSA. Follow-up of trends in the resistance to fluoroquinolones based upon surveillance programmes are needed.

Beta-lactamases in clinical isolates. Spectrum implications of sulbactam/ampicillin.

Combining ampicillin with an irreversible beta-lactamase inhibitor such as sulbactam is a promising technique for controlling infections due to resistant organisms. The combination not only restores the effectiveness of ampicillin against species that have acquired resistance to it, but it can extend the antimicrobial spectrum to species that have never exhibited susceptibility to ampicillin. However, the inhibition of beta-lactamases and the evaluation of inhibitors are still complicated by numerous factors known collectively as 'the epidemiology of beta-lactamases'. This refers to the distribution of enzymes in different bacterial species and in different geographical locations, the numerous types of enzymes, the variable number and amount of beta-lactamases that may exist in the same cell, and, of course, the potential for transfer of beta-lactamase resistance from one species to another.

The epidemiology of bacterial resistance to quinolones.

The new fluoroquinolones have been in use for nearly 10 years in the treatment of community- and nosocomially-acquired infections. Resistant clones may be selected during therapy and disseminate if favourable epidemiological conditions prevail. Resistance to the fluoroquinolones is still rare in common pathogens with 97 to 100% of strains remaining susceptible. Resistance has been reported in methicillin-susceptible Staphylococcus aureus, Campylobacter jejuni/coli, Salmonella, Shigella and Escherichia coli. Among nosocomial pathogens, the incidence of fluoroquinolone resistance varies between bacterial species, countries and periods of study, and is dependent on local epidemiological factors and antibiotic policies. The highest incidence of resistance is observed in Serratia and Acinetobacter spp., and particularly in methicillin-resistant S. aureus. Surveillance programmes are needed to follow up trends in resistance to the fluoroquinolones and their possible association with clinical failures.

Biological study of intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction.

An anisoylated plasminogen streptokinase activator complex (APSAC) has been administered as a bolus intravenous injection of 30U to 14 patients with acute myocardial infarction. Systemic effects on coagulation and fibrinolysis were studied. In 1 patient, the treatment produced no biological modification, which could be explained by an increased streptokinase resistance in this patient, apparent from the sample collected before treatment. In the other patients, as expected, fibrinogen, plasminogen, alpha 2-antiplasmin and factors V and VIIIc fell dramatically, while there was an increase in serum fibrinogen degradation product concentrations. In addition, plasma fibrin derivatives increased during APSAC therapy, both in patients who had occluded or patent coronary arteries. Discrepancies were found between methods used to measure fibrinogen: with the Ellis and Stransky method, concentrations were higher than with the Clauss method; and for plasminogen, automated methods using different analysers may give higher results in some patients.

[beta-Lactamases of Branhamella catarrhalis and their phenotypic implications]. / beta-Lactamases de Branhamella catarrhalis et leurs implications phénotypiques.

Of the 50 strains of beta-lactamase-producing Branhamella catarrhalis isolated at Saint Joseph's Hospital (Paris) that were studied, 94% produced BRO-1 type beta-lactamase and 6% produced the BRO-2 type. We examined the transfer of BRO-1 and BRO-2 genes and found that, among 7 donor strains producing BRO-1, all were able to transfer the gene for BRO-1 production by conjugation. Of the 4 donor strains producing BRO-2, 2 were able to transfer the gene for BRO-2 production by conjugation. Three BRO-1 beta-lactamase-producing transformants were obtained from total DNA extracted from 3 strains producing BRO-1. Plasmid bands were demonstrated in strains of B. catarrhalis, but no change in plasmid profiles was seen in beta-lactamase-positive recombinants, supporting previous studies that suggested the beta-lactamases are chromosomal. In vitro activity of oral beta-lactams was tested for 67 strains of B. catarrhalis (56 beta-lactamase-producing strains). Cefixime, cefpodoxime and the combination ampicillin-clavulanic acid were very active against the beta-lactamase-producing strains. BRO-1 beta-lactamase appears to affect the activity of cefaclor, cefuroxime and loracarbef. BRO-2 beta-lactamases have no effect on the activity of these cephalosporins. Cefixime and cefpodoxime seemed the least affected by beta-lactamase production.