Antibacterial mechanisms of the urinary bladder.

THE DISAPPEARANCE OF BACTERIA FROM THE NORMAL URINARY BLADDER IS APPARENTLY A FUNCTION OF TWO HOST DEFENSE MECHANISMS: the mechanical clearance of organisms by voiding, and the antibacterial activity of the bladder wall. This study quantified the relative contribution of each of these mechanisms to the resistance of the bladder to bacterial infection.(32)Phosphorus-labeled E. coli. S. aureus, and P. mirabilis were each injected into the urinary bladders of unanesthetized female guinea pigs. At intervals after voiding, the bladders were removed, washed, homogenized, and assayed for residual radioactivity and viable bacteria. Mechanical clearance was measured by the changes in total radioactive count. Antibacterial activity was quantified by comparing the bacterial to radioactive ratios of the original bacterial inoculum with similar ratios in the bladder homogenates. More than 99.9% of the bladder inoculum was rapidly excreted and about 0.1% (10(4)-10(5)) organisms remained attached to the bladder wall. Of those E. coli attached to the bladder, rapid sequential reduction in viability occurred and reached a level of 85% loss at 30 min after inoculation. 4 hr after challenge, less than 10% of those organisms still attached to the bladder mucosa remained viable. P. mirabilis was handled with equal facility, but S. aureus showed a reduction in viability of only 46% at 1 hr and 67% at 4 hr after inoculation. 6 hr after infection with S. aureus, 6 of 12 guinea pig bladders showed multiplication of the organisms still attached to the bladder wall; only 1 of 12 animals challenged with E. coli had comparable multiplication. The mechanism whereby the bladder wall kills bacteria is unclear, but it did not appear to be related to an antibacterial activity of urine, clumping of organisms on bladder mucosa, phagocytosis by leukocytes, or serum levels of bactericidal antibody. Although it is clear that the bladder exhibits intrinsic antibacterial properties, the role of this defense mechanism in the pathogenesis of urinary tract infection requires further clarification.

Heterogeneity, Cell Biology and Tissue Mechanics of Pseudostratified Epithelia: Coordination of Cell Divisions and Growth in Tightly Packed Tissues.

Pseudostratified epithelia (PSE) are tightly packed proliferative tissues that are important precursors of the development of diverse organs in a plethora of species, invertebrate and vertebrate. PSE consist of elongated epithelial cells that are attached to the apical and basal side of the tissue. The nuclei of these cells undergo interkinetic nuclear migration (IKNM) which leads to all mitotic events taking place at the apical surface of the epithelium. In this review, we discuss the intricacies of proliferation in PSE, considering cell biological, as well as the physical aspects. First, we summarize the principles governing the invariability of apical nuclear migration and apical cell division as well as the importance of apical mitoses for tissue proliferation. Then, we focus on the mechanical and structural features of these tissues. Here, we discuss how the overall architecture of pseudostratified tissues changes with increased cell packing. Lastly, we consider possible mechanical cues resulting from these changes and their potential influence on cell proliferation.

Use of quantitative bacteriologic techniques to diagnose catheter-related sepsis.

A case of polymicrobial sepsis occurred in a patient who had a permanent indwelling hyperalimentation catheter. Because it was undesirable to remove the catheter, quantitative bacteriologic techniques were used to determine whether the catheter was the source of sepsis. Blood drawn from a peripheral vein had 25 colonies per milliliter whereas blood drawn through the catheter had more than 10,000 colonies per milliliter. On the basis of these results, the catheter was removed. The catheter tip was found to be infected with the same organisms that were present in the blood. Quantitative bacteriologic techniques may prove useful in diagnosing catheter-related sepsis when it is undesirable to remove the catheter.

Nonsurgical treatment of cerebral nocardiosis.

In previously healthy, 49-year-old man, CNS infection due to Nocardia asteroides was manifested initially as sterile meningitis and then as a single large brain abscess and was treated successfully with medical therapy alone. Resolution of the brain abscess was documented with serial computed tomographic scans. The strain of N asteroides was sensitive to both sulfisoxazole and ampicillin. Although surgical intervention must always be considered in the treatment of brain abscess caused by N asteroides, medical therapy is preferable if the patient responds initially.

Prevention of bone and joint infections.

The importance of preventing infections in bone and joint surgery is clear because of the devastating clinical and economic consequences. Prophylactic antibiotics have reduced the incidence of wound infection in surgery of noncompound hip fractures. Five studies of antibiotic prophylaxis in total hip replacement have concluded that prophylaxis has reduced the frequency of deep wound infection after surgery. The use of operating rooms supplied with ultra-clean air was also associated with a reduction in infection after insertion of a prosthetic joint. These studies suggest that ultra-clean air and antibiotic prophylaxis have independent and cumulative effects in preventing joint infection following surgery. Foci of infection elsewhere in the body can seed a prosthetic joint and, therefore, must be treated vigorously. However, there are no convincing data as to the potential risk to the prosthetic joint of procedures such as dental work or gastrointestinal or genitourinary tract manipulation. Currently, antibiotic prophylaxis for all patients with prosthetic joints about to undergo such procedures cannot be recommended.

Pneumococcal bacteremia at a medical/surgical hospital for adults between 1975 and 1980.

All 72 episodes of pneumococcal bacteremia from 1975 through 1980 at Montefiore Hospital, Pittsburgh, a medical/surgical hospital for adults, were reviewed. There were 10 to 14 episodes per year, accounting for 4 to 5 percent of all bacteremias; it was estimated that one episode occurred for every thousand patients discharged. Patients' ages ranged from 16 to 94 years (mean 61 years); 65 percent were male. There was an underlying disease in 87 percent of all patients, and 78 percent of the infections were community-acquired. Treatment with antimicrobial drugs was given to all but six patients. Overall mortality was 43 percent, but it was higher for asplenic patients (five of six died). In 44 percent of patients, one to four complications occurred. Outcome correlated with presence of coexisting disease (p less than 0.03), development of one or more complications (p less than 0.04), presence of asplenia (p = 0.04), and the type of antimicrobial treatment used (p less than 0.001; patients treated with penicillin alone fared better). Typing of isolates in the last two study years revealed that 67 percent of isolates were pneumococcal types present in 14-valent pneumococcal vaccine available at the time of the study. It is concluded that pneumococcal bacteremia occurs primarily in patients with underlying disease, and that pneumococcal vaccine should be offered to such patients.

Antibody responses to meningococcal polysaccharide vaccine in adults without a spleen.

Asplenic persons are at risk for the development of overwhelming sepsis from certain encapsulated bacteria, including meningococci. Since it is not known if asplenic persons can have antibody responses, this study compared such responses following bivalent groups A and C meningococcal polysaccharide vaccine in 22 asplenic subjects and healthy control subjects. There were no adverse reactions to the vaccine. Antibody responses were measured using a solid-phase radioimmune assay; results were compiled for both seroconversions and changes in mean antibody titers of IgG, IgA, and IgM classes. Subjects who underwent splenectomy for trauma and control subjects with spleens showed a polyclonal antibody response to both vaccine antigens. Those persons who underwent splenectomy for nonlymphoid tumors had nearly as good a response as normal subjects. By contrast, asplenic subjects with lymphoid tumors who had received prior chemotherapy and radiotherapy had poor responses to both antigens. It is concluded that meningococcal vaccine is immunogenic in asplenic persons, with the aforementioned exceptions, and that this vaccine should be routinely administered to such persons.

Pharmacokinetics of cephradine administered intravenously and orally to young and elderly subjects.

The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5-minute intravenous (IV) infusion followed the next day by a 1-gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 +/- 0.41 mcg/mL) and 8 hours (0.73 +/- 0.22 mcg/mL) than in the young group at 6 hours (0.43 +/- 0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 +/- 0.34 vs. 4.81 +/- 0.59 ml/min/kg) and the elimination half-life was significantly longer (1.71 +/- 0.20 vs 1.12 +/- 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age-related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients.

Factors associated with acquisition of Pseudomonas aeruginosa resistant to gentamicin.

Concern over the increased occurrence of Pseudomonas aeruginosa resistant to gentamicin colonizing and/or causing disease in patients prompted our review of the years 1974 and 1975 for all P aeruginosa isolates, both gentamicin-resistant and gentamicin-sensitive. In this period, 39 patients had gentamicin-resistant P aeruginosa recovered from clinical specimens while 683 patients had gentamicin-sensitive strains. Compared to both matched and/or randomly selected controls with gentamicin-sensitive infections, patients with gentamicin-resistant infections had a higher incidence of (1) prior antibiotic therapy (p less than 0.01), (2) prior therapy with gentamicin (p less than 0.005), and (3) exposure to multiple antibiotics.

Epidemiology of accidental needle-puncture wounds in hospital workers.

All employees, including physicians, of a 450 bed hospital were monitored for puncture wounds from contaminated needles over a four-year period. Five hundred seventy-nine incidents were reported. Nurses were involved in 66% of instances, housekeeping 16%, laboratory workers 10%, physicians 4% and x-ray technicians 4%. Many puncture wounds were avoidable, suggesting the need for ongoing employee education. In 67% of the injuries blood from the patient in whom the needle had been used was tested for HBsAg; 1% of those tested were positive. In such instances, employees were given immune globulin. These data indicate that needle puncture wounds are a frequent problem for hospital workers, and carry a risk for transmitting hepatitis B. Efforts to prevent such injuries are needed.

Individually controlled aspirin in the long-term treatment of patients with chronic arterial diseases.

A simple method of measuring the biological effect of acetylsalicylic acid (ASA), based on the determination of the disaggregation rate (DR) of platelet aggregation induced by adenosine diphosphate (ADP), is described. The DR was found to correlate with the inhibition of the production of malondialdehyde (MDA) by platelets (r = 0.66, P less than 0.001). Therefore, the DR was used for laboratory monitoring of the ASA effect. The study included 63 arteriosclerotic patients--patients with ischemic heart disease (IHD), peripheral arterial disease (PAD), or cerebrovascular insufficiency (CVI) -- who were analyzed before treatment and after receiving ASA in an individually controlled dosage. Before treatment the authors found an increased level of MDA and a longer euglobulin clot lysis time in patients when compared with healthy volunteers (n = 16). Extremely different doses of ASA were required to normalize initially elevated MDA levels in patients. Normalization of the MDA level corresponds to a DR of at least 50% (in comparison with 0-13% without treatment). When judging the ASA dose individually from the 50% DR, the authors demonstrated that there were no differences in the levels of cyclooxygenase- and lipoxygenase-derived eicosanoids between healthy volunteers (n = 16) and arteriosclerotic patients receiving 100-250 mg (n = 18), 500 mg (n = 17), or 750-1500 mg ASA per day (n = 6). Thus, their results support the idea of using individually controlled ASA as the most promising way of resolving the "aspirin dilemma" and provide a simple and reproducible method of measuring the biological effect of ASA.

Diagnosis and treatment of osteomyelitis.

The diagnosis and management of osteomyelitis continues to present problems. Technetium bone scans may identify acute osteomyelitis before the characteristic disease changes are visible on x-ray studies, but they have a number of drawbacks. Microbiological studies are critical in making precise diagnoses of the cause so that proper therapy will be given. In treatment of acute osteomyelitis, several investigators report good results from four-week administration of parenteral antibiotic, or one week of parenteral treatment followed by three weeks of oral therapy. Chronic osteomyelitis requires surgical removal of dead tissue followed by lengthy parenteral and oral antibiotic therapy. Chronic forms of the disease caused by resistant gram-negative organisms may prove responsive to quinoline therapy. These agents may attain inhibitory levels on oral administration, and have proved to be effective in animal models. Clinical trials, however, are required to determine their usefulness in the treatment of clinical disease.

Short-term outcome of painful bone marrow oedema of the knee following oral treatment with iloprost or tramadol: results of an exploratory phase II study of 41 patients.

OBJECTIVES: To compare the therapeutic effects of oral iloprost and tramadol on the outcome of bone marrow oedema (BME) of the knee by MR imaging and clinical assessment. METHODS: Forty-one patients with painful ischemic or mechanical BME of the knee were enrolled in a double-blind, randomized controlled study. Patients were randomized either to iloprost (n = 21, group 1) or tramadol (n = 20, group 2). The treatment duration was 4 weeks. The Larson knee score was used to assess function before treatment and then 3 days, 1, 2, 3, 4 weeks and 3 months after the start of treatment. Short tau inversion recovery and T1-weighted MR images of the affected knees were obtained before and 3 months after the start of treatment. Bone marrow oedema was assessed visually and by computer-assisted quantification for baseline and follow-up MR examinations. RESULTS: Thirty-three patients completed the study as scheduled. The mean Larson score improved from 58.6 points to 81.8 points in group 1, and from 59.6 points to 86.8 points in group 2, after 3 months (no significant difference between the treatment groups). On MR images, complete BME regression in at least one bone was observed in nine patients (52.9%) in group 1, as opposed to three patients (18.7%) in group 2, after 3 months (P = 0.034). Correspondingly, the median BME volume decreased by 58.0% in group 1, and by 47.5% in group 2. CONCLUSIONS: The analgesic effect of iloprost and tramadol was similar. BME regression on MR images was more pronounced under iloprost treatment.

Antibiotic prophylaxis in orthopedic surgery.

This review covers four areas: the use of prophylactic antibiotics in orthopedic surgery not involving prosthetic devices; the use of prophylactic antibiotics in prosthetic joint implantation; the use of antibiotic-containing cement in prosthetic joint surgery; and the use of prophylactic antibiotics for dental procedures in individuals with implanted prosthetic joints. The major conclusions are as follows: (1) Prophylactic antimicrobial agents lower the rate of wound infection following surgery for closed hip fractures. (2) Antimicrobial prophylaxis reduces the frequency of deep wound infection following total joint replacement; operating rooms with ultraclean air have a similar effect. (3) Antibiotic-impregnated cement is as effective as systemic antibiotics in preventing early infection following total joint replacement. (4) For routine dental work in most patients with total joint replacement, there is insufficient evidence to support antibiotic prophylaxis; for such individuals with periodontal disease or potential dental infection, antimicrobial prophylaxis seems indicated.

Experimental osteomyelitis. IV. Therapeutic trials with rifampin alone and in combination with gentamicin, sisomicin, and cephalothin.

Levels of rifampin, gentamicin, sisomicin, and cephalothin in normal and osteomyelitic rabbit bones were measured, and the efficacy of these drugs in the treatment of osteomyelitis was evaluated. Single drug regimens, including rifampin for 14 days and gentamicin, sisomicin, and cephalothin each for 28 days, were relatively ineffective (5%-33% sterile bone cultures). Rifampin, administered for 28 days, sterilized the bones of 55% of treated animals. The combination of gentamicin and rifampin, given for either 14 or 28 days, sterilized the bones of 67% of treated animals. The combinations of rifampin plus sisomicin and of rifampin plus cephalothin, given for 28 days, were significantly more effective than these agents alone, sterilizing 90%-95% of bones. The combination of rifampin, sisomicin, and cephalothin, given for only 14 days, sterilized the bones of all treated rabbits. Staphylococci isolated from the bones of therapeutic failures that had received rifampin alone or in combination with other antibiotics were highly resistant to rifampin (minimal inhibitory concentration, greater than 250 mug/ml), whereas the organisms recovered from animals not receiving rifampin remained sensitive. Results of in vitro studies of synergy and/or bactericidal activity of antibiotic combinations correlated with in vivo results in some, but not all, instances.

Experimental osteomyelitis. V. Therapeutic trials with oxacillin and sisomicin alone and in combination.

Oxacillin was used alone and in combination with sisomicin in the treatment of experimental osteomyelitis due to Staphylococcus aureus in rabbits. Within diseased bone, levels of oxacillin and sisomicin remained higher than the minimal inhibitory concentration for 2 and 6 hr, respectively, after injection of 50 mg of oxacillin/kg and 10 mg of sisomicin/kg. Treatment with 50 mg of oxacillin/kg four times daily or 50 mg/kg every 4 hr around the clock for 28 days sterilized 30% of the rabbit bones. Sisomicin (10 mg/kg) injected twice daily for 28 days sterilized only 5% of the rabbit bones. In contrast, treatment with the combination of oxacillin and sisomicin for either 14 or 28 days was significantly more effective, sterilizing 78% and 85%, respectively, of the bones of treated animals. S. Aureus isolated from bones of animals treated with sisomicin alone contained aminoglycoside-resistant microcolonies. Resistant microcolonies were not recovered from animals treated with oxacillin or with the combination of oxacillin plus sisomicin. In vitro studies of bacterial killing by each antibiotic alone and in combination showed more bacterial killing with the combination than with either agent alone; in vitro the combination prevented emergence of resistant microcolonies. Combination antibiotic therapy appears to be more effective in treatment of experimental osteomyelitis due to S. aureus than therapy with a single agent.