Use of quinolones in osteomyelitis and infected orthopaedic prosthesis.

The present review provides an updated critical analysis of the use of quinolones in osteomyelitis and orthopaedic prosthetic infections. Only papers published in peer-reviewed journals and related to the following areas were selected: experimental osteomyelitis, penetration of quinolones into human bone, and clinical use in comparative and noncomparative studies. Local drug carriers impregnated with quinolones allow high local antibiotic concentrations to be achieved in experimental systems. Considerable clinical experience has been gained mostly with ciprofloxacin and ofloxacin. Cumulated results in clinical trials show clinical success rates of more than 90% in osteomyelitis caused by Enterobacteriaceae. The combination of quinolones and rifampicin for the treatment of staphylococcal osteomyelitis as well as orthopaedic prosthetic infections appears very promising in clinical studies with a small number of patients. However, further comparative studies using quinolones as single agents or in combination (versus standard parenteral therapy) remain necessary in osteomyelitis due to Staphylococcus aureus or Pseudomonas aeruginosa. In particular, studies with the newer quinolones should be strongly encouraged in acute or chronic osteomyelitis and in more complicated situations such as diabetic osteomyelitis or foreign-body infection.

Predictors of inappropriate hospital days in a department of internal medicine.

BACKGROUND: This study aimed to identify predictors of inappropriate hospital days in a department of internal medicine, as a basis for quality improvement interventions. METHODS: The appropriateness of 5665 hospital days contributed by 500 patients admitted to the Department of Internal Medicine, Geneva University Hospitals, Switzerland, was assessed by means of the Appropriateness Evaluation Protocol. Predictor variables included patient's age and sex, manner of admission and discharge, and characteristics of hospital days (weekend, holiday, sequence). RESULTS: Overall, 15% of hospital admissions and 28% of hospital days were rated as inappropriate. In multivariate models, inappropriate hospital days were more frequent among patients whose admission was inappropriate (odds ratio [OR] = 5.3, 95% CI: 3.1-8.4) and among older patients (80-95 years: OR = 3.6, 95% CI: 1.7-7.0, versus <50 years). The likelihood of inappropriateness also increased with each subsequent hospital day, culminating on the day of discharge, regardless of the total length of stay. CONCLUSIONS: This study identified both the admission and the discharge processes as important sources of inappropriate hospital use in a department of internal medicine. The oldest patients were also at high risk of remaining in the hospital inappropriately. Surprisingly, long hospital stays did not generate a higher proportion of inappropriate days than short hospital stays. This information proved useful in developing interventions to improve the hospitalization process.

Risk factors for a medically inappropriate admission to a Department of Internal Medicine.

OBJECTIVE: To identify patient- and admission-related risk factors for a medically inappropriate admission to a department of internal medicine. METHODS: Cross-sectional study of a systematic sample of 500 admissions to the department of internal medicine of an urban teaching hospital. The appropriateness of each admission and reasons for inappropriate admissions were assessed using the Appropriateness Evaluation Protocol. Risk factors included the time (day of week and holidays) and manner (through emergency department or direct admission) of admission, patient age and sex, health status of patient and spouse, living arrangements, formal home care services, and informal support from family or friends. RESULTS: Overall, 76 (15.2%) hospital admissions were rated as medically inappropriate by the Appropriateness Evaluation Protocol. In multivariate analysis, the likelihood of an inappropriate admission was increased by better physical functioning of the patient (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1-2.1 [for 1 SD in Physical Functioning scores]), lower mental health status of the patient's spouse (OR, 2.6; 95% CI, 1.3-5.6), receipt of informal help from family or friends (OR, 3.3; 95% CI, 1.5-7.2), and hospitalization by one's physician (OR, 3.6; 95% CI, 1.7-7.5). Receiving formal adult home care was not associated with inappropriateness of hospitalization. CONCLUSIONS: Inappropriate admissions to internal medicine wards are determined by a mix of factors, including the patient's health and social environment. In addition, the private practitioners' discretionary ability to hospitalize their patients directly may also favor medically inappropriate admissions.

Impact of a public campaign on pre-hospital delay in patients reporting chest pain.

OBJECTIVE: To decrease pre-hospital delay in patients with chest pain. DESIGN: Population based, prospective observational study. SETTING: A province of Switzerland with 380000 inhabitants. SUBJECTS: All 1337 patients who presented with chest pain to the emergency department of the Hôpital Cantonal Universitaire of Geneva during the 12 months of a multimedia public campaign, and the 1140 patients who came with similar symptoms during the 12 months before the campaign started. MAIN OUTCOME MEASURES: Pre-hospital time delay and number of patients admitted to the hospital for acute myocardial infarction (AMI) and unstable angina. RESULTS: Mean pre-hospital delay decreased from 7h 50 min before the campaign to 4 h 54 min during it, and median delay from 180 min to 155 min (P < 0.001). For patients with a final diagnosis of AMI, mean delay decreased from 9 h 10 min to 5 h 10 min and median delay from 195 min to 155 min (P < 0.002). Emergency department visits per week for AMI and unstable angina increased from 11.2 before the campaign to 13.2 during it (P < 0.02), with an increase to 27 (P < 0.01) during the first week of the campaign; visits per week for non-cardiac chest pain increased from 7.6 to 8.1 (P = NS) during the campaign, with an increase to 17 (P < 0.05) during its first week. CONCLUSIONS: Public campaigns may significantly reduce pre-hospital delay in patients with chest pain. Despite transient increases in emergency department visits for non-cardiac chest pain, such campaigns may significantly increase hospital visits for AMI and unstable angina and thus be cost effective.

Quinolones and osteomyelitis: state-of-the-art.

The present review provides a critical quantitative analysis of the use of quinolones in osteomyelitis. Only papers published in peer-reviewed journals and related to the following areas were selected: experimental osteomyelitis, penetration of quinolones into human bone and clinical use in comparative and non-comparative studies. Cumulated results show clinical success rates of more than 90% in osteomyelitis caused by Enterobacteriaceae, after prolonged oral use of ciprofloxacin. However, further comparative studies using oral quinolones as single agents or in combination (versus standard parenteral therapy) are required in osteomyelitis due to S. aureus or P. aeruginosa, or in more complicated situations such as diabetic osteomyelitis or foreign body infection.

Teicoplanin alone or combined with rifampin compared with vancomycin for prophylaxis and treatment of experimental foreign body infection by methicillin-resistant Staphylococcus aureus.

The prophylactic and therapeutic activities of teicoplanin were evaluated in two different experimental models of foreign body infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In a guinea pig model of prophylaxis, subcutaneously implanted tissue cages were infected at a > 90% rate by 10(2) CFU of MRSA in control animals. A single dose of 30 mg of teicoplanin per kg of body weight administered intraperitoneally 6 h before bacterial challenge was as effective as vancomycin in preventing experimental infection in tissue cages injected with either 10(2), 10(3), or 10(4) CFU of MRSA. In a rat model evaluating the therapy of chronic tissue cage infection caused by MRSA, the efficacy of a 7-day high-dose (30 mg/kg once daily) regimen of teicoplanin was compared with that of vancomycin (50 mg/kg twice daily). Whereas high levels of teicoplanin were found in tissue cage fluid, continuously exceeding its MBC for MRSA by 8- to 16-fold, no significant reduction in the viable counts of MRSA occurred during therapy. In contrast, either vancomycin alone or a combined regimen of high-dose teicoplanin plus rifampin (25 mg/kg twice daily) could significantly decrease the viable counts in tissue cage fluids. Whereas the bacteria recovered from tissue cage fluids during therapy showed no evidence of teicoplanin resistance, they failed to be killed even by high levels of this antimicrobial agent. The altered susceptibility of in vivo growing bacteria to teicoplanin killing might in part explain the defective activity of this antimicrobial agent when used as monotherapy against chronic S. aureus infections. These data may indicate the need for a combined regimen of teicoplanin with other agents such as rifampin to optimize the therapy of severe staphylococcal infections.

Comparative efficacies of imipenem, oxacillin and vancomycin for therapy of chronic foreign body infection due to methicillin-susceptible and -resistant Staphylococcus aureus.

The efficacies of imipenem when directed against methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains of Staphylococcus aureus were compared with those of oxacillin and vancomycin in a subcutaneous rat model, using chronically infected tissue cages. At three weeks after inoculation, stable chronic infections were established with average bacterial counts exceeding 10(6) cfu/mL tissue cage fluid for both strains. Intraperitoneal administration (twice a day for 7 days) of imipenem (80 mg/kg) or oxacillin (200 mg/kg) produced peak levels of 23 or 45 mg/L and through levels of < 0.1 and 5.7 mg/L, respectively. The therapeutic regimens of either imipenem (P < 0.001) or oxacillin (P < 0.02) administered for 7 days led to significant reductions in bacterial counts in the tissue cage fluids of animals chronically infected with MSSA. In contrast, imipenem was not effective against chronic MRSA tissue cage infections, despite the relatively low MIC of the infecting strain and the use of high dose (120 mg/kg) therapy. In-vitro susceptibility testings of MRSA performed before and after imipenem therapy demonstrated the emergence of a highly resistant subpopulation.

[Delay in management and treatment of patients with suspected acute myocardial infarction: role of the public, of extra- and intra-hospital structures and transportation methods]. / Délais dans la prise en charge et le traitement des patients avec suspicion d'infarctus aigu du myocarde: le rôle du public, des structures extra- et intra-hospitalières et des moyens de transports.

The potential impact of thrombolytic agents on mortality and morbidity from coronary artery disease is weakened by in- and out-of-hospital delays occurring in the management of acute myocardial infarction. The goals of this study were to review the situation 5 years after the publication of the GISSI study. From October 1, 1991 to March 31, 1992, all the events occurring between symptom onset and in-hospital treatment were analyzed for 620 consecutive patients with suspected myocardial infarction seen in the emergency ward of the University Hospital, Geneva. Among them, 189 (30.5%) had myocardial infarction and 144 (23%) unstable angina. Mean and median delay between symptom onset and hospital arrival for the 620 patients were 10 h 02 min and 2 h 55 min respectively; 117 (19%) patients came straight to the hospital alone, with the risk of arrhythmic complications en route to the emergency ward but with shorter time delays (mean delay: 6 h 13 min; median delay: 2 h 30 min) than the 503 (81%) patients who called out-of-hospital services (mean delay: 10 h 55 min; median delay: 3 h; p < 0.04). The latter patients accounted for 47% of mean out-of-hospital delay and the out-of-hospital services for 53%. Minimization or ignorance of symptoms, waiting for relief from medication and attempts to reach relatives were responsible for long patients' decision times.(ABSTRACT TRUNCATED AT 250 WORDS)

Susceptibility of Staphylococcus aureus growing on fibronectin-coated surfaces to bactericidal antibiotics.

Several recent studies have shown that bacteria either grown in vitro as adherent biofilms or recovered from infected prosthetic devices have decreased susceptibilities to antimicrobial killing. To further study the microbial and environmental factors responsible for this decreased antibiotic susceptibility, we developed an in vitro model of surface-adherent Staphylococcus aureus growing on polymethylmethacrylate coverslips coated with pure fibronectin. After exponential growth for 4 h, the population of fibronectin-attached S. aureus remained constant for a further 48-h period, as evaluated by CFU counts of organisms quantitatively removed from the coverslips. At selected time points, surface-bound organisms were exposed to bactericidal concentrations of either oxacillin, vancomycin, fleroxacin, or gentamicin in short-term (0.5 to 2 h) or long-term (24 h) killing assays. Whereas at 2 h surface-growing organisms were still optimally killed by all antimicrobial agents, at 4 and 24 h attached bacteria expressed markedly altered susceptibilities to these agents. The decrease in susceptibility was moderate for fleroxacin, more important for oxacillin and vancomycin, and extensive for gentamicin. When surface-attached S. aureus was compared with bacteria grown in a fluid phase, both populations showed a parallel time-dependent decrease in their susceptibilities to either oxacillin, vancomycin, or fleroxacin. In contrast, attached organisms became considerably more resistance to gentamicin than suspended bacteria did. Subpopulations of organisms spontaneously released from coverslips during antibiotic exposure also showed markedly reduced susceptibilities to antimicrobial killing. This simple model of S. aureus colonization of in vitro fibronectin-coated surfaces might represent a useful approach to the study of the physiological and biochemical changes that underlie the decreased antibiotic susceptibilities of biomaterial-attached organisms.

Fibronectin is more active than fibrin or fibrinogen in promoting Staphylococcus aureus adherence to inserted intravascular catheters.

To further define the role of fibrin(ogen) and fibronectin in Staphylococcus aureus adherence to central venous catheters, the amount, chemical integrity, and biologic activity of these proteins adsorbed on lines inserted in hospitalized patients were prospectively studied. Polyurethane cannulas promoted a significantly lower adherence of S. aureus than polyvinyl chloride (P < .01) or Hickman (P < .001) cannulas and contained the lowest amount of immunologically assayed fibronectin but not of fibrin(ogen). Fibrinogen showed an extensive loss of adherence-promoting activity on inserted cannulas, which was related to its proteolytic breakdown, as detected by SDS-PAGE and immunoblots with antifibrinogen antibodies and confirmed by in vitro studies with purified protein fragments. In contrast, either intact or fragmented fibronectin, although present in much lower amounts than fibrin(ogen), could actively promote S. aureus adherence onto intravenous catheters.

Effect of cyclosporin A and zidovudine on immune abnormalities observed in the murine acquired immunodeficiency syndrome.

Two therapeutic modalities, zidovudine (targeting retroviral replication) and cyclosporin A (targeting immunopathologic consequences of retroviral expression) were evaluated in a murine model of AIDS. In previous studies, cyclosporin A treatment (40 or 60 mg/kg/day) before and after infection with LP-BM5 murine leukemia viruses protected against the development of immunodeficiency disease. The present study extends these findings. First, a low dose of cyclosporin A (20 mg/kg/day) was ineffective, and treatment initiated 5 days after infection did not protect against virus-induced lymphoproliferation and hypergammaglobulinemia. Second, zidovudine added to drinking water (0.1 mg initiated 5 days after infection and continued for 8 weeks) was more effective than 0.2 mg/mL given day 5-12 after infection. This treatment reduced lymph node size, disease severity as determined histologically, retrovirus-induced gp70 expression, and IgE (but not IgM and IgG) levels. Third, combined treatment had an additive, protective effect on lymphocyte proliferative capacity. This successful dual therapeutic strategy in a mouse model has potential applicability for similar approaches in treating human immunodeficiency virus infection.

Contribution of tumor necrosis factor to host defense against staphylococci in a guinea pig model of foreign body infections.

The contribution of the cytokine tumor necrosis factor (cachectin; TNF) to host defenses against staphylococcal foreign body infections was studied in vivo. In tissue cages subcutaneously implanted into guinea pigs, progressive infection was initiated by a very low inoculum (100 cfu) of Staphylococcus aureus with a success rate of 100%, as is frequently encountered in related clinical situations. Locally injected autologous bacterial components derived from the cell wall of S. aureus, in particular peptidoglycan, were very active in raising TNF levels in tissue cage fluid and in preventing the development of infection by the 100% infective dose of the test strain. Furthermore, injection of murine recombinant TNF into tissue cages could substitute for the bacterial components in preventing experimental infection by S. aureus. The protective effect of TNF-eliciting bacterial components could be neutralized by anti-TNF antibodies. A local increase in TNF levels might improve host defenses against staphylococcal foreign body infections.

Epidermal and splenic antigen-presenting cell function in a retrovirally induced murine immunodeficiency syndrome (MAIDS).

Since alterations of epidermal Langerhans cells (LC) have been observed in humans infected with HIV, we investigated the morphology and function of these cells in murine acquired immunodeficiency syndrome (MAIDS), a murine model closely resembling human AIDS. The number as well as the shape of dendritic MHC class II+ cells from ear skin of C57BL/6 mice were similar in normal and infected animals. In mixed epidermal cell (EC) lymphocyte cultures, EC from infected mice and from normal mice stimulated allogeneic T cell proliferation to the same extent. In contrast to T cells from normal mice, however, T cells from infected mice did not respond to allogeneic spleen cells, confirming the presence of a T-cell defect in MAIDS. Subcutaneous injection of syngeneic mice with trinitrophenyl-modified MAIDS EC resulted in delayed ear swelling responses after challenge that were equivalent to those induced by hapten-modified EC from normal mice, suggesting that the contact sensitivity inducing potential of MAIDS LC was preserved. To investigate antigen presenting and processing function, EC and spleen cells were tested with the ovalbumin-specific IAb-restricted T cell hybridoma BO.17.10 and either ovalbumin 323-339 peptide or intact ovalbumin protein. MAIDS spleen cells had a reduced antigen presenting capacity compared with normal spleen cells, whereas EC from these mice showed the same processing and presenting capacity as normal controls. In summary, our results demonstrate that the frequency, morphology, level of MHC class II antigen expression and ability to process and present antigen is normal for LC from mice with MAIDS whereas the function of splenic T cells and APC from infected mice is significantly impaired.

Successful therapy of experimental chronic foreign-body infection due to methicillin-resistant Staphylococcus aureus by antimicrobial combinations.

We compared the efficacy of a long-duration (3-week) therapy of vancomycin, fleroxacin, fleroxacin plus rifampin, and vancomycin plus fleroxacin and rifampin in a recently developed rat model of chronic staphylococcal foreign-body infection. Subcutaneous tissue cages containing polymethylmethacrylate coverslips were infected with 1 x 10(5) to 5 x 10(5) CFU of methicillin-resistant Staphylococcus aureus. Three weeks later, a quantitative culturing of the fluid that had accumulated in the cages was done (mean, 6.72 log10 CFU/ml; n = 110) and treatment was initiated after randomization. The CFUs in the cage fluid were counted on days 11 and 22 and 1 week after the termination of treatment; in addition, a final culture of coverslips (surface-bound microorganisms) was performed. The three-drug therapy was significantly superior to the other treatments on day 11 (a 5.16 log10 decrease of bacterial counts versus a 2.12 log10 to 2.94 log10 decrease for vancomycin, fleroxacin, and fleroxacin plus rifampin; P less than 0.01). On day 22, count decreases were 4.16 log10 for vancomycin, 4.91 log10 for fleroxacin (vancomycin versus fleroxacin, not significant), 6.14 log10 for two-drug therapy, and 6.34 log10 for three-drug therapy (vancomycin-fleroxacin-rifampin versus fleroxacin-rifampin, not significant; fleroxacin-rifampin versus monotherapies, P less than 0.01); the numbers of CFU in most cage fluids were under the detection limit (20 CFU/ml) in combination groups. One week after the end of treatment, 92% of fluids and coverslips (detection limit, 1 CFU) were culture negative with tritherapy, 88% of fluids and 41% of coverslips were negative with bitherapy, and less than 12% of fluids and coverslips were negative with single drugs (for coverslips, P was <0.01 for vancomycin-fleroxacin-rifampin versus fleroxacin-rifampin and P was <0.001 for fleroxacin-rifampin versus the monotherapies). No mutants resistant to rifampin or fleroxacin were detected. In conclusion, antimicrobial combinations were highly effective and superior to single drugs in treating a chronic staphylococcal foreign-body infection for 3 weeks. The three-drug therapy decreased bacterial counts more rapidly than the two-drug therapy under study and appeared to be curative in most cases.

Perioperative antibiotic prophylaxis of wound and foreign body infections: microbial factors affecting efficacy.

Numerous microbial factors are responsible for perioperative infections and influence the efficacy of antibiotic prophylaxis. These factors include the staphylococcal carrier state, bacterial adherence to a number of host proteins, the production of glycocalyx by sessile bacteria, and shifts in antibiotic resistance. A full understanding of the mechanisms involved will lead to further reductions in the number of postoperative infections. Unfortunately, the microbial factors affecting prophylaxis cannot be evaluated separately under clinical conditions; they are easier to study under circumstances whose bacteriologic features are well defined and in which the presence of foreign materials (e.g., sutures) greatly potentiates pathogenic mechanisms. Such circumstances exist, for example, in infections developing after "clean" surgery and in experimental models. Since even clean wounds are found to be contaminated when sampled carefully, the control of infection is more a quantitative than a qualitative problem. The critical period for the development of infection is short: an antibiotic course not exceeding 24 hours seems effective in preventing infection.