Treatment of vancomycin-resistant Enterococcus faecium infections with an investigational streptogramin antibiotic (quinupristin/dalfopristin): a report of fifteen cases

OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.     

Winning the battle but losing the war: methicillin-resistant Staphylococcus aureus (MRSA) infection at a teaching hospital

A methicillin-resistant Staphylococcus aureus (MRSA) control policy, aimed at eradication, was established at a 1000-bed hospital in 1985, applied consistently for 10.5 years, and then relaxed. Its components included screening of high-risk patients, transfer of carriers to exhaust-ventilated isolation rooms, closure of wards to new admissions when local transmission was detected, MRSA screening during outbreaks, and prospective collection of clinical and epidemiological information. During the eradication policy period, every 6 months, a mean of 5.1 patients (range 1-12) already carrying MRSA were admitted, and a mean of 3.6 (range 0-16) acquired carriage in the hospital. The largest outbreak comprised 11 patients despite epidemic MRSA strain EMRSA-16 being introduced six times, and MRSA did not become endemic. MRSA-positive admissions increased progressively from 1993; nursing staff workload increased, areas available for alternative patient accommodation were reduced, the resulting ward closures interfered with clinical services, and hence the control policy was relaxed in mid-1995. Isolation facilities were overwhelmed with 622 new patient-isolates in the next 18 months, and there were 67 clinical infections in 1996. The proportion of blood cultures positive for MRSA rose nearly sevenfold by 1996 and 27-fold by 1997. Thus, repeated eradication of MRSA, even epidemic strains, by use of a stringent policy, is possible given sufficient resources, whereas flexible national guidelines designed to control, but not eradicate, epidemic staphylococci, are currently unlikely to be successful. The costs of eradication policies need to be weighed against those of endemicity.     

Attitudes and beliefs of Canadian infection control decision-makers towards 'borderline' methicillin-resistant Staphylococcus aureus

'Borderline' methicillin-resistant Staphylococcus aureus (MRSA) strains are inhibited by drug concentrations of 2 to 8 micrograms/mL. This type of resistance is usually mediated by 'hyper beta-lactamase' production which is detectable in vitro by susceptibility to combinations of a beta-lactam and a beta-lactamase inhibitor (ie, amoxicillin and clavulanic acid). A survey of Canadian infection control experts was performed to assess the knowledge, attitudes and beliefs regarding the containment requirements for borderline MRSA strains in acute health care facilities. Twenty-three of 38 Canadian infection control experts (61%) (members of the Canadian Hospital Epidemiology Committee [CHEC] or the Society for Healthcare Epidemiology of American [SHEA]) returned a questionnaire about a fictional patient with a postoperative wound infection with such a strain. Eleven respondents (48%) considered the isolate as an MRSA, 11 did not and one was unsure. All who did not believe the strain to be MRSA would not have isolated or cohorted the patient. Four in the latter group would have isolated the patient if he or she were on a neurosurgery or cardiovascular surgery unit, indicating a desire to restrict spread of this isolate on those units. Seven of the 12 individuals who had managed at least one patient with a borderline MRSA did not advocate patient isolation or cohorting, and five did. This survey has supported the belief that there are discrepancies among infection control decision-makers in Canada regarding the approach, precautions and therapy of patients infected with borderline strains of MRSA. Further data on virulence of and effective therapy for these isolates are needed to assess whether the additional cost is warranted in controlling the nosocomial spread of these isolates.     

Reemergence of gentamicin-susceptible strains of methicillin-resistant Staphylococcus aureus: roles of an infection control program and changes in aminoglycoside use

We have tested the effect of stromal cells on the proliferation in long- and short-term cultures of primitive (Thy-1+, CD34+, CD33-, CD38- , HLA-DR , adherent in vitro and quiescent in vivo) progenitors in normal human bone marrow. These primitive cells produce granulocyte-macrophage colony-forming cells (CFU-GM) that are measured in secondary clonogenic assays. Addition of stromal cells to normal adherent haemopoietic progenitor cells reduced CFU-GM production by 80% (P =0.0002) after 1 week of incubation. In long-term culture (LTC), in the presence of stroma. the normal adherent cells did not produce significant numbers of CFU-GM until 3-4 weeks later which suggests that stromal cells reduce the probability of quiescent cell activation. This effect could not be attributed to soluble inhibitory factors and was specific to stroma grown with, rather than without, methylprednisolone. It was blocked by heparanase (H'ase) II treatment of stromal cells, by phosphatidylinositol-specific phospholipase C (PI-PLC) treatment of progenitor cells, by antibody blocking of beta1 integrin molecules or by exposure to glucose/N-acetyl-D-glucosamine/alpha-methyl-D-mannoside, but not by exposure to galactose or fructose. Moreover, these interventions enabled the progenitor cells to respond to stimulatory factors in the culture supernatant. We interpret these results as support for a model involving primitive progenitor cell binding to stroma by PI-CAM/HS, beta1 integrin activation via lectin-like interactions and the transduction of signals which reduce the ability of primitive cells to respond to ambient stimulators. This model provides a mechanism for the maintenance of the quiescent state of stem cells by adhesion to stromal cells.     

Influence of erythromycin resistance, inoculum growth phase, and incubation time on assessment of the bactericidal activity of RP 59500 (quinupristin-dalfopristin) against vancomycin-resistant Enterococcus faecium

RP 59500, a mixture of two semisynthetic streptogramin antibiotics (quinupristin and dalfopristin), is one of a few investigational agents currently in clinical trials with inhibitory activity against multiple-drug-resistant strains of Enterococcus faecium. We evaluated the bactericidal activity of this antimicrobial against 30 recent clinical isolates of vancomycin-resistant E. faecium, including 23 erythromycin-resistant (MIC, >256 microg/ml) and 7 erythromycin-intermediate (MIC, 2 to 4 microg/ml) strains. All isolates were inhibited by RP 59500 at 0.25 to 1.0 microg/ml. The bactericidal activity of RP 59500 was markedly influenced by the erythromycin susceptibility of the strains and by several technical factors, such as inoculum growth phase and time of incubation of counting plates. As determined by time-kill methods, RP 59500 at a concentration of 2 or 8 microg/ml failed to kill erythromycin-resistant organisms under any conditions. Bactericidal activity was observed against all seven erythromycin-intermediate isolates when log-phase inocula were used and the cells were counted after 48 h of incubation (mean reductions in viable bacteria for RP 59500 at concentrations of 2 and 8 microg/ml, 3.45 and 3.50 log10 CFU/ml, respectively), but killing was diminished when the plates were examined at 72 h (mean killing, 3.06 and 2.95 log10, CFU/ml, respectively). No bactericidal activity was observed when stationary-phase cultures were used. On the basis of these data, we expect that bactericidal activity of RP 59500 against the multiple-drug-resistant E. faecium strains currently encountered would be distinctly uncommon.     

Application of an optimized and highly discriminatory method based on arbitrarily primed PCR for epidemiologic analysis of methicillin-resistant Staphylococcus aureus nosocomial infections

The optimization of an arbitrarily primed PCR method for typing 96 methicillin-resistant Staphylococcus aureus (MRSA) isolates was compared with pulsed-field gel electrophoresis. Identical results in the differentiation of MRSA clones and identification of the main cluster that included 82 strains (88% of patients) were obtained by both techniques.     

Influences of type and duration of antimicrobial prophylaxis on an outbreak of methicillin-resistant Staphylococcus aureus and on the incidence of wound infection

Pneumothorax corresponds to the extravasation of air in the pleural cavity. This produces a partial or complete collapse of the adjacent lung. This is a common thorax disease resulting from a leak between the broncho-pulmonary gas compartment and the usually virtual pleural space. Pneumothorax is called spontaneous when no traumatic or iatrogenic factors are present. Spontaneous pneumothorax can be primary (when no radiographic or clinical injuries can be detected) or secondary to an underlying pulmonary disorder. Evolution of spontaneous pneumothorax is usually benign. However, recurrence is frequent. Preventing recurrences is the basis of all the therapeutic controversies which, after drainage, are based on pleurodesia indications. Vital prognosis may be compromised when pneumothorax is compressive, bilateral, or when it results in respiratory failure in patients with chronic respiratory insufficiency.     

Genetic linkage and cotransfer of a novel, vanB-containing transposon (Tn5382) and a low-affinity penicillin-binding protein 5 gene in a clinical vancomycin-resistant Enterococcus faecium isolate

Mechanisms for the intercellular transfer of VanB-type vancomycin resistance determinants and for the almost universal association of these determinants with those for high-level ampicillin resistance remain poorly defined. We report the discovery of Tn5382, a ca. 27-kb putative transposon encoding VanB-type glycopeptide resistance in Enterococcus faecium. Open reading frames internal to the right end of Tn5382 and downstream of the vanXB dipeptidase gene exhibit significant homology to genes encoding the excisase and integrase of conjugative transposon Tn916. The ends of Tn5382 are also homologous to the ends of Tn916, especially in regions bound by the integrase enzyme. PCR amplification experiments indicate that Tn5382 excises to form a circular intermediate in E. faecium. Integration of Tn5382 in the chromosome of E. faecium C68 has occurred 113 bp downstream of the stop codon for the pbp5 gene, which encodes high-level ampicillin resistance in this clinical isolate. Transfer of vancomycin, ampicillin, and tetracycline resistance from C68 to an E. faecium recipient strain occurs at low frequency in vitro and is associated with acquisition of a 130- to 160-kb segment of DNA that contains Tn5382, the pbp5 gene, and its putative repressor gene, psr. The interenterococcal transfer of this large chromosomal element appears to be the primary mechanism for vanB operon spread in northeast Ohio. These results expand the known family of Tn916-related transposons, suggest a mechanism for vanB operon entry into and dissemination among enterococci, and provide an explanation for the nearly universal association of vancomycin and high-level ampicillin resistance in clinical E. faecium strains.     

Treatment of vancomycin-resistant Enterococcus faecium with RP 59500 (quinupristin-dalfopristin) administered by intermittent or continuous infusion, alone or in combination with doxycycline, in an in vitro pharmacodynamic infection model with simulated endocardial vegetations

Quinupristin-dalfopristin is a streptogramin antibiotic combination with activity against vancomycin-resistant Enterococcus faecium (VREF), but emergence of resistance has been recently reported. We studied the activity of quinupristin-dalfopristin against two clinical strains of VREF (12311 and 12366) in an in vitro pharmacodynamic model with simulated endocardial vegetations (SEVs) to determine the potential for resistance selection and possible strategies for prevention. Baseline MICs/minimal bactericidal concentrations (microg/ml) for quinupristin-dalfopristin, quinupristin, dalfopristin, and doxycycline were 0.25/2, 64/>512, 4/512, and 0.125/8 for VREF 12311 and 0.25/32, 128/>512, 2/128, and 0.25/16 for VREF 12366, respectively. Quinupristin-dalfopristin regimens had significantly less activity against VREF 12366 than VREF 12311. An 8-microg/ml simulated continuous infusion was the only bactericidal regimen with time to 99.9% killing = 90 hours. The combination of quinupristin-dalfopristin every 8 h with doxycycline resulted in more killing compared to either drug alone. Quinupristin-dalfopristin-resistant mutants (MICs, 4 microg/ml; resistance proportion, approximately 4 x 10(-4)) emerged during the quinupristin-dalfopristin monotherapies for both VREF strains. Resistance was unstable in VREF 12311 and stable in VREF 12366. The 8-microg/ml continuous infusion or addition of doxycycline to quinupristin-dalfopristin prevented the emergence of resistance for both strains over the 96-h test period. These findings replicated the development of resistance reported in humans and emphasized bacterial factors (drug susceptibility, high inoculum, organism growth phase) and infectious conditions (penetration barriers) which could increase chances for clinical resistance. The combination of quinupristin-dalfopristin with doxycycline and the administration of quinupristin-dalfopristin as a high-dose continuous infusion warrant further study to determine their potential clinical utility.     

Insertion possibility of 16S-23S space amplification and random amplified polymorphic DNA analysis for typing of methicillin-resistant Staphylococcus aureus strains in the context of nosocomial infections

Within the scope of the present study n = 183 MRSA isolates from the extended area of Düsseldorf and n = 93 international MRSA strains from seven different countries were typed by pulsed-field gel electrophoresis and two PCR methods (RAPD and 16S-23S-spacer amplification). The isolates could be subdivided into 30 different types by PFGE, into 21 by means of RAPD and 18 by 16S-23S-spacer amplification. PFGE had the highest discriminatory potential, however, a combined use of the three typing methods allows a more detailed differentiation even of those isolates with identical PFGE pattern. Both amplification procedures were rapid, easy in handling with reproductable results. For a temporary epidemiological analysis within 24 hours, both amplification methods could be combined. In case the investigated isolates were still suspected of showing a "clonal identity", they should be analysed by additional PFGE (lasting about four days). Although the international isolates were chosen by random selection, several MRSA strains with identical pattern could be found in different countries of the world. Some RAPD-, spacer- and PFGE pattern were constant over many years. This reflects a high genetic stability of single strains.     

Randomized prospective trial of gentian violet with dibutyryl cAMP and povidone-iodine with sugar as treatment for pressure sores infected with methicillin-resistant Staphylococcus aureus in elderly patients

A randomized prospective study was done to evaluate the two treatments for pressure sores infected with methicillin-resistant Staphylococcus aureus in elderly patients: Gentian violet plus dibutyryl cAMP (GVcAMP, n = 8) and povidone-iodine plus sugar (IS, n = 11). Age, underlying diseases, and nutritional status did not differ between the two groups. Specimens were obtained biweekly from the pressure sores and were cultured. The percentage of culture dishes with no methicillin-resistant S. aureus was 93% for the patients given GVcAMP, but only 74% for those given IS (p < 0.01). By the 14th week after the start of treatment, the mean area of the pressure sores in the GVcAMP group had decreased to 45% of the area at the start of treatment. In the IS group, the decrease was smaller to 56% of the area before treatment. No local or systemic adverse effects occurred in either group. GVcAMP is useful to treat pressure sores infected with methicillin-resistant S. aureus.     

School-based intervention for adolescent obesity: Analysis of treatment, randomly selected control, and self-selected control subjects.

55 junior high school students were assigned from stratified blocks of percentage overweight to a comprehensive behavioral program or to a no-treatment condition. The average S in treatment declined in percentage overweight 5.71%; controls gained 2.41%. Parental participation was correlated with weight change among Ss in the treatment group. Comparison of controls with a group of children who refused treatment revealed similar patterns of weight change, suggesting that self-selected controls may be appropriate in this kind of research. (5 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Association between decreased susceptibility to a new antibiotic for treatment of human diseases, everninomicin (SCH 27899), and resistance to an antibiotic used for growth promotion in animals, avilamycin

Guinea-pigs were maintained for 5 weeks on a diet containing three different concentrations of vitamin C: a) traces (none added), b) medium (0.05% w/w) and high (0.5% w/w). Twenty-four hours before killing the animals received one i.p. dose of 3 g ethanol per kg body weight (a model of short-term acute intoxication). In a parallel experiment which lasted 5 weeks, the animals were treated every week with two i.p. doses of 1 g ethanol per kg body weight followed by the final acute intoxication (3g ethanol/kg) (a model of long-term chronic alcoholization). In both experiments, the guinea-pigs with the highest tissue concentration of vitamin C proved to have significantly decreased residual levels of ethanol and acetaldehyde in the liver and the brain, a decreased activity of alanine- and aspartate aminoacyl transferases in the serum and decreased contents of triacylglycerols and cholesterol in the serum and liver in comparison with the vitamin C-unsupplemented group. The regression curve expressing vitamin C levels versus residual ethanol and acetaldehyde concentrations in the liver confirmed the highly significant negative correlation between them. Administration of the guinea-pigs with large amounts of vitamin C appears to accelerate ethanol and acetaldehyde metabolism and reduce some of their adverse health effects.     

Duration of antibiotic treatment in surgical infections of the abdomen. Forum statement: a plea for selective and controlled postoperative antibiotic administration

Excessive duration of antibiotics appears to be the principal reason for their inappropriate use in current surgical practice. The main factors to blame are the inability of the clinician to distinguish between contamination and infection, infection and inflammation, and failure to stratify the latter. Consequently, and unnecessarily, prophylactic drugs are carried through into the postoperative period and treatment is continued for long periods. Most experts who contributed to this Discussion Forum favour a trend away from the use of therapeutic courses of fixed duration, and towards attempts to stratify the infective processes, minimising administration by tailoring the duration to the clinical findings. As a consensus of this forum specific recommendations are: Contamination (gastroduodenal peptic perforations operated within 12 hours, traumatic enteric perforations operated with 12 hours, peritoneal contamination with bowel contents during elective or emergency procedures, early or phlegmonous appendicitis or phlegmonous cholecystitis): single dose prophylaxis. Resectable infection (appendicectomy for gangrenous appendicitis, cholecystectomy for gangrenous cholecystitis, bowel resection for ischaemic or strangulated dead bowel without frank perforation): 24 hours postoperative antibiotics. Advanced infection (intra-abdominal infection from diverse sources): 48 hours to 5 days, based on operative findings and patient's condition. Severe intra-abdominal infection with the source not easily controllable (infected pancreatic necrosis, postoperative intra-abdominal infection): longer courses may be necessary.     

Antibacterial activity of gatifloxacin (AM-1155, CG5501, BMS-206584), a newly developed fluoroquinolone, against sequentially acquired quinolone-resistant mutants and the norA transformant of Staphylococcus aureus

Alternate mutations in the grlA and gyrA genes were observed through the first- to fourth-step mutants which were obtained from four Staphylococcus aureus strains by sequential selection with several fluoroquinolones. The increases in the MICs of gatifloxacin accompanying those mutational steps suggest that primary targets of gatifloxacin in the wild type and the first-, second-, and third-step mutants are wild-type topoisomerase IV (topo IV), wild-type DNA gyrase, singly mutated topo IV, and singly mutated DNA gyrase, respectively. Gatifloxacin had activity equal to that of tosufloxacin and activity more potent than those of norfloxacin, ofloxacin, ciprofloxacin, and sparfloxacin against the second-step mutants (grlA gyrA; gatifloxacin MIC range, 1.56 to 3.13 microg/ml) and had the most potent activity against the third-step mutants (grlA gyrA grlA; gatifloxacin MIC range, 1.56 to 6.25 microg/ml), suggesting that gatifloxacin possesses the most potent inhibitory activity against singly mutated topo IV and singly mutated DNA gyrase among the quinolones tested. Moreover, gatifloxacin selected resistant mutants from wild-type and the second-step mutants at a low frequency. Gatifloxacin possessed potent activity (MIC, 0.39 microg/ml) against the NorA-overproducing strain S. aureus NY12, the norA transformant, which was slightly lower than that against the parent strain SA113. The increases in the MICs of the quinolones tested against NY12 were negatively correlated with the hydrophobicity of the quinolones (correlation coefficient, -0.93; P < 0.01). Therefore, this slight decrease in the activity of gatifloxacin is attributable to its high hydrophobicity. Those properties of gatifloxacin likely explain its good activity against quinolone-resistant clinical isolates of S. aureus harboring the grlA, gyrA, and/or norA mutations.     

Host response to initial and challenge infections, following treatment, of Gyrodactylus bullatarudis and G. turnbulli (Monogenea) on the guppy (Poecilia reticulata)

Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether F alpha 1AT was dysfunctional, the inhibitory activity of F alpha 1AT against human neutrophil elastase (HNE) was compared with that of common alpha 1AT phenotypes. Time-dependent inhibition of HNE by alpha 1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S alpha 1AT phenotypes in human sera. The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M-1s-1 respectively. F was found to have reduced activity much like that of Z, the alpha 1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate alpha 1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ, indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals. In conclusion, F alpha 1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema. The disease risk for F homozygotes remains to be determined.