Elevated lactoferrin is associated with moderate to severe Clostridium difficile disease, stool toxin, and 027 infection.

We evaluated blood and fecal biomarkers as indicators of severity in symptomatic patients with confirmed Clostridium difficile infection (CDI). Recruitment included patients with CDI based on clinical symptoms and supporting laboratory findings. Disease severity was defined by physician's assessment and blood and fecal biomarkers were measured. Toxigenic culture done using spore enrichment and toxin B detected by tissue culture were done as confirmatory tests. Polymerase chain reaction (PCR) ribotyping was performed on each isolate. There were 98 patients recruited, with 85 (87%) confirmed cases of toxigenic CDI (21 severe, 57 moderate, and seven mild), of which 68 (80%) were also stool toxin-positive. Elevated lactoferrin (p = 0.01), increased white blood cell (WBC) count (p = 0.08), and low serum albumin (p = 0.03) were all associated with the more severe cases of CDI. Ribotype 027 infection accounted for 71% of severe cases (p < 0.01) and patients with stool toxin had significantly higher lactoferrin levels and WBC counts (p < 0.05). Our findings show that elevated fecal lactoferrin, along with increased WBC count and low serum albumin, were associated with more severe CDI. In addition, patients infected with ribotype 027 and those with stool toxin had significantly higher fecal lactoferrin and WBC counts.

Tetracycline delivery from fibrin controls peritoneal infection without measurable systemic antibiotic.

The addition of antibiotics to an adhesive haemostat results in an ideal system for the treatment of a localized infectious disease. Fibrin sealant (FS) is a biocompatible, resorbable, adherent haemostat that can deliver antibiotics. Previous use of fibrin to deliver antibiotics resulted in rapid release and limited bioactivity. We have reported previously that poorly soluble antibiotics significantly retard release from FS, resulting in extended delivery in vitro, and overcome antibiotic-resistant infection. We now report that localized antibiotic delivery from FS controls peritoneal infection without measurable systemic antibiotic. Rats and mice were implanted with preformed FS discs containing tetracycline free-base to evaluate control of peritoneal sepsis and to measure serum tetracycline levels. Infection was initiated with Staphylococcus aureus. Morbidity and mortality were evaluated for 14 days. Serum was isolated from jugular vein blood with subsequent evaluation for antimicrobial activity. Mice prophylactically treated with FS-tetracycline (FS-TET) 500 mg/kg 2 days before infection cleared the S. aureus infection, resulting in 100% survival. Mice treated with FS-TET 500 mg/kg 7 days before infection survived. Mice treated with FS-TET 1750 mg/kg 35 days before infection also survived. Rats treated with FS-TET 500 mg/kg had undetectable serum tetracycline levels, whereas in vitro release of tetracycline from FS-TET pellets in rat serum was readily detected. We conclude that fibrin is an excellent vehicle for extended delivery of low solubility tetracycline. Tetracycline delivered from FS is an appropriate chemotherapy for S. aureus peritonitis. FS-TET controls localized infection without a measurable concentration of systemic tetracycline.

Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance Study in Ohio. The Community-Based Pneumonia Incidence Study Group.

BACKGROUND: Pneumonia is the leading cause of death due to infectious diseases in the United States; however, the incidence of most infections causing community-acquired pneumonia in adults is not well defined. METHODS: We evaluated all adults, residing in 2 counties in Ohio, who were hospitalized in 1991 because of community-acquired pneumonia. Information about risk factors, symptoms, and outcome was collected through interview and medical chart review. Serum samples were collected from consenting individuals during the acute and convalescent phases, and specific etiologic diagnoses were assigned based on results of bacteriologic and immunologic tests. RESULTS: The incidence of community-acquired pneumonia requiring hospitalization in the study counties in 1991 was 266.8 per 100,000 population; the overall case-fatality rate was 8.8%. Pneumonia incidence was higher among blacks than whites (337.7/100,000 vs 253.9/ 100,000; P < .001), was higher among males than females (291.4 vs 244.8; P < .001), and increased with age (91.6/100,000 for persons aged < 45 years, 277.2/ 100,000 for persons aged 45-64 years, and 1012.3/ 100,000 for persons aged > or = 65 years; P < .001). Extrapolation from study incidence data showed the projected annual number of cases of community-acquired pneumonia requiring hospitalization in the United States to be 485,000. These data provide previously unavailable estimates of the annual number of cases that are due to Legionella species (8000-18,000), Mycoplasma pneumoniae (18,700-108,000), and Chlamydia pneumoniae (5890-49,700). CONCLUSIONS: These data provide information about the importance of community-acquired pneumonia and the relative and overall impact of specific causes of pneumonia. The study provides a basis for choosing optimal empiric pneumonia therapy, and allows interventions for prevention of pneumonia to be targeted at groups at greatest risk for serious illness and death.

Risk factors for domestic acquisition of legionnaires disease. Ohio legionnaires Disease Group.

BACKGROUND: Legionnaires disease is a common cause of adult pneumonia. Outbreaks of legionnaires disease have been well described, but little is known about sporadically occurring legionnaires disease, which accounts for most infections. Exposure to contaminated residential water sources is I plausible means of disease acquisition. METHODS: Employing a matched case-control study design in 15 hospitals in 2 Ohio counties, we prospectively enrolled 146 adults diagnosed as having nonepidemic, community-acquired legionnaires disease and compared each with 2 hospital-based control patients, matched for age, sex, and underlying illness category. An interview regarding potential exposures was followed by a home survey that included sampling residential sources for Legionella. Interview and home survey data were analyzed to estimate the risk of acquiring legionnaires disease associated with various exposures. RESULTS: Multivariate analysis showed that a nonmunicipal water supply (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.17-4.37), recent residential plumbing repair (OR, 2.39; 95% CI, 1.10-5.18), and smoking (OR, 3.48; 95% CI, 2.09-5.79) were independent risk factors for legionnaires disease. Univariate analysis suggested that electric (vs gas) water heaters (OR, 1.97; 95% CI, 1.10-3.52), working more than 40 hours weekly (OR, 2.13; 95% CI, 1.12-4.07), and spending nights away from home before illness (OR, 1.68; 95% CI, 1.03-2.74) were additional possible risk factors. Lower chlorine concentrations in potable water and lower water heater temperatures were associated with residential Legionella colonization. CONCLUSIONS: A proportion of sporadic cases of legionnaires disease may be residentially acquired and are associated with domestic potable water and disruptions in residential plumbing systems. Potential strategies to reduce legionnaires disease risk include consistent chlorination of potable water, increasing water heater temperatures, and limiting exposure to aerosols after domestic plumbing repairs.

Reevaluation of the definition of Legionnaires' disease: use of the urinary antigen assay. Community Based Pneumonia Incidence Study Group.

Cases of Legionnaires' disease have been categorized as definitive and presumptive. The sensitivity and specificity of antibody titers of > or = 256 and of urinary antigen ratios of > or = 3 were evaluated in 68 patients with "definitive" Legionnaires' disease and in 636 patients with pneumonia who had negative cultures and did not have fourfold rises in titers of antibody to Legionella pneumophila. An acute-phase antibody titer of > or = 256 did not discriminate between cases and noncases (10% vs. 6%; P = .29). The urinary antigen assay gave a positive result in fewer than 1% of noncases but was positive in 55.9% of all cases. This assay was most sensitive (80%) in cases in which L. pneumophila serogroup 1 was isolated. We propose that the case definition for definitive Legionnaires' disease be expanded to include positive urinary antigen assays and that the category of presumptive Legionnaires' disease--based on acute-phase or standing antibody titers of > or = 256 in the nonoutbreak setting--be discarded. The urinary antigen assay will be a valuable tool in the prompt diagnosis of Legionnaires' disease.

Pharmacokinetics of imipenem in serum and skin window fluid in healthy adults after intramuscular or intravenous administration.

The pharmacokinetic profiles of imipenem after intramuscular (i.m.) and intravenous injections were examined in adult volunteers. Levels of imipenem in serum after i.m. injection of a microcrystalline suspension of imipenem-cilastatin (500 mg each) reached a peak (8.0 micrograms/ml) at 1.5 h after administration, and concentrations were maintained in excess of 1.5 micrograms/ml for 6 h. Serum elimination half-life (1.3 h), volume of distribution (14.5 liters), and area under the curve (AUC; 27.8 micrograms.h/ml) after i.m. injection did not significantly differ from those of a comparable dose given by intravenous infusion. Bioavailability after i.m. injection was 89%. Imipenem levels in skin window fluid after i.m. administration were maximal (4.3 micrograms/ml) at 4 h after injection, at which time imipenem concentrations exceeded those produced by intravenous infusion. The AUCskin window/AUCserum ratio for skin window fluid after i.m. injection was 68%, indicating good penetration of the drug into skin fluid. This study shows that i.m. injection of 500 mg of imipenem-cilastatin results in concentrations of imipenem in serum and skin fluid that are, for at least 6 h, consistent with antimicrobial activity against susceptible organisms.

Effect of vacuum mixing on the mechanical properties of antibiotic-impregnated polymethylmethacrylate bone cement.

Polymethylmethacrylate bone cement, containing either no added antibiotic, 0.5 g of Vancomycin, 1.0 g of Vancomycin, or 1.0 g of Tobramycin, was mixed either in air or a vacuum chamber. Following storage in a water bath at 37 degrees C for 48 h, the specimens were tested in four-point bending. The porosity of the specimens was assessed radiographically, and their antibacterial activity was monitored for 21 days. The bending strength of the vacuum mixed specimens containing no antibiotic was 40% greater than that of similar air-mixed specimens. However, there were no significant differences in the bending strength of either the air- or vacuum-mixed specimens when any of the antibiotic dosages were added. The bending modulus of the vacuum-mixed specimens, containing no antibiotic, was significantly greater than the moduli of all the other specimen groups which did not differ from each other. Vacuum mixing reduced the apparent porosity of the specimens fivefold, and while the addition of antibiotic did not effect porosity of the air-mixed specimens, that of the vacuum-mixed specimens was doubled. Although initial rapid decreases were seen, leaching of antibiotic from the cement and antibacterial activity continued through the 21-day monitoring period.

Pharmacokinetics of intravenous cefmetazole with emphasis on comparison between predicted theoretical levels in tissue and actual skin window fluid levels.

Cefmetazole is a cephamycin antibiotic which is resistant to hydrolysis by various beta-lactamases. This study evaluated the pharmacokinetics of cefmetazole, including its intravascular and interstitial fluid distribution, by using the skin window (SW) technique. A 2-g dose of cefmetazole was given intravenously over 30 min to each of 12 healthy adult male volunteers every 6 h for nine doses. Plasma levels were assayed at predetermined intervals after doses 1, 5, and 9. Interstitial fluid levels were determined by the SW technique. Antibiotic levels were assayed by the agar well bioassay technique. A concentration-versus-time plot indicates that cefmetazole is rapidly distributed, with mean peak levels in plasma equal to 126 micrograms/ml at the end of the half-hour infusion. The mean plasma half-life was 1.1 h. Plasma and tissue distribution constants permitted calculation of theoretical levels in tissue. Parallel elimination slopes for SW and theoretical tissue level showed that the SW model distribution kinetics are closely related. The area under the curve for the SW was 73.9 mg.h/liter. This was comparable to the theoretical level in tissue, which was 96 mg.h/liter. Furthermore, the area under the curve of theoretical tissue level/plasma was 0.6 and that of SW/plasma was 0.47. These results demonstrate that the SW technique yielded a result quite close to the theoretical tissue level. Ultrafiltration analysis indicated that as cefmetazole levels in plasma increased from 10 to 250 micrograms/ml, plasma protein binding of the antibiotic dropped from 85 to 65%. Finally, 60 to 70% of the drug was recovered from the urine as biologically active drug over 6 h postinfusion.

In vitro susceptibility of the Bacteroides fragilis group in community hospitals.

The antimicrobial susceptibility of clinical isolates of the Bacteroides fragilis group was determined at six community hospitals (one large, greater than 600 beds; and five smaller, 96-325 beds). Imipenem was the most active beta-lactam with 100% of isolates being sensitive at 4 micrograms/ml. The percentage of isolates inhibited at 16 micrograms/ml (and 32 micrograms/ml) for the 7-alpha-methoxy antibiotics was: cefoxitin 66 (90); moxalactam 73 (85); cefotetan 68 (72); cefmetazole 40 (61). Metronidazole, chloramphenicol, and clindamycin were active against 100%, 100%, and 89% at breakpoints of 8 micrograms/ml, 8 micrograms/ml, and 4 micrograms/ml, respectively. The activity of several beta-lactams in our report differed slightly from that reported from university teaching hospitals. There were differences at many of the breakpoints for activity of some of the beta-lactam antibiotics for isolates from the large community hospital as compared with the combined isolates from the smaller community hospitals. Interestingly, the pattern was one of more resistance at the smaller community hospitals.

Canine model for the simultaneous measurement of antibiotic levels in tissues and bacterial killing rate.

Antibiotic levels in serum are commonly used to guide antibiotic therapy. The antibiotic levels in interstitial fluid are a more accurate reflection of the efficacy of antibiotic penetration into the tissues. Although there are experimental models for determining interstitial fluid levels, there is no model for measuring the in vivo killing of bacteria, which is the endpoint of antibiotic therapy. We developed an accurate, reliable animal model which allows measurement of the in vivo killing of bacteria along with a determination of antibiotic levels in tissues. Modified Sykes-Moore chambers were applied to the dissected external oblique muscle of 14 dogs. The chambers were inoculated with clinical isolates of Staphylococcus aureus or Escherichia coli. The dogs were treated with cefoxitin or gentamicin. Quantitative cultures were performed, and the antibiotic levels in interstitial fluid were determined.

Timentin versus piperacillin in the therapy of serious urinary tract infections.

In a comparative study, 47 patients received Timentin, a combination of ticarcillin plus clavulanic acid, or piperacillin to treat serious urinary tract infections. Thirty-nine infections in 38 patients were clinically evaluable (21 in the Timentin-treated group and 18 in the piperacillin-treated group). These included pyelonephritis (10 in the Timentin-treated group and five in the piperacillin-treated group), bladder infections with sepsis (11 in the Timentin-treated group and 11 in the piperacillin-treated group) and bladder infections without fever (two in the piperacillin-treated group). The addition of clavulanic acid to ticarcillin greatly enhanced the susceptibility of five of the 28 evaluable pathogens in the Timentin-treated group (two Escherichia coli isolates, two Staphylococcus aureus isolates, and one Klebsiella pneumoniae isolate). The minimal inhibitory concentrations at which 50 and 90 percent of the bacterial growth was inhibited were 4 and 64 micrograms/ml, respectively, for Timentin, and 4 and 32 micrograms/ml, respectively, for piperacillin. All evaluable patients had a satisfactory symptomatic response at the end of the trial. Of 28 evaluable pathogens treated with Timentin, 18 were eradicated up through the one-week post-therapy evaluation period; of 27 evaluable pathogens treated with piperacillin, 18 were eradicated up through the same time period. Eradicated pathogens included E. coli (six of 13 in the Timentin-treated group and six of 11 in the piperacillin-treated group), other Enterobacteriaceae (three of three in the Timentin-treated group and eight of 10 in the piperacillin-treated group), Pseudomonas aeruginosa (two of four in the piperacillin-treated group), enterococcus (two of three in the Timentin-treated group and two of two in the piperacillin-treated group), staphylococcal species (four of five in the Timentin-treated group), and other organisms (three of four in the Timentin-treated group). Resistance did not develop in any of the persisting pathogens. Adverse effects thought possibly to be related to the study drugs were minimal and included rash in one Timentin-treated patient and diarrhea in another.

Diffusibility of the newer cephalosporins into human interstitial fluids.

A skin window technique was used to investigate the ability of three of the newer cephalosporins, moxalactam, cefoperazone, and ceftriaxone, to enter the interstitial fluid of normal, healthy volunteers. Intravenous and intramuscular routes of delivery were compared. The method of delivery did not greatly affect diffusibility with moxalactam and ceftriaxone. Intravenous infusion resulted in greater diffusibility with cefoperazone than did intramuscular injection. Cefoperazone demonstrated the lowest diffusibility of the three test drugs. Ceftriaxone, administered at one-half the dose of cefoperazone and moxalactam, demonstrated the greatest ability to diffuse into interstitial fluid despite its high level of binding to plasma protein. The better diffusibility of ceftriaxone may be explained by a persistently high concentration gradient provided by its long serum half-life. Overall, the results support the concept of the concentration gradient as an important determinant of antibiotic activity.

Timentin versus piperacillin or moxalactam in the therapy of acute bacterial infections.

In a randomized comparative study, 116 patients with acute bacterial infections were treated with timentin (ticarcillin plus clavulanic acid) or a comparative agent (piperacillin for respiratory or urinary tract infections, and moxalactam for soft tissue infections). There were 91 clinically evaluated infections (timentin, 46; piperacillin, 29; moxalactam, 16). Twelve patients were bacteremic. A satisfactory clinical response occurred in all 46 patients treated with timentin and in 42 of the 45 treated with a comparative agent. Two clinical failures were due to superinfection (a Staphylococcus aureus pneumonia in the piperacillin group and an enterococcal skin infection in the moxalactam group), and one clinical failure was due to a primary S. aureus skin infection (moxalactam group). One wound isolate of Pseudomonas aeruginosa developed resistance to timentin during therapy (despite clinical improvement). Adverse reactions were uncommon but did include one patient treated with timentin who developed unexplained hallucinations.

Clinical evaluation of ceftriaxone.

Seventy-seven patients with acute bacterial infections were treated with ceftriaxone (1 gm administered intravenously every 12 hours). The 58 patients evaluable for efficacy had 60 infections, including 39 of the respiratory tract, 14 of the urinary tract, and seven of soft tissue. Five patients were bacteremic. The mean duration of ceftriaxone treatment was eight days for patients with respiratory and urinary tract infections and 13 days for patients with other types of infections. A satisfactory clinical response occurred in 56 (93%) of the infections. Eighty-four (94%) of the 89 pretherapy pathogens were bacteriologically eradicated. Included were all 19 isolates of Haemophilus influenzae, all 15 of Streptococcus pneumoniae, all 12 of Escherichia coli, 22 of the 23 isolates of other Enterobacteriaceae species, three of five isolates of Pseudomonas aeruginosa, and three of four isolates of Staphylococcus aureus. Two cases of superinfection (one with bacteremia) occurred with P aeruginosa. There were two cases each of reinfection and colonization with Streptococcus faecalis. One patient developed manifestations of culture-documented S pneumoniae meningitis eight hours after the first dose was administered. Peak and trough plasma levels of ceftriaxone were 142 and 64 micrograms/ml. Ceftriaxone achieved therapeutic levels in infected cerebrospinal fluid and in the abscess fluid of selected patients. Adverse effects, which were mild, included diarrhea in 4% of the patients and elevated transaminase levels in 10%.

Levels of amdinocillin in human plasma and interstitial fluid following intravenous administration.

Amdinocillin levels in human plasma and interstitial fluid were studied in 12 human volunteers. The results showed that relatively high levels of amdinocillin were detected in the interstitial fluid. The fluid to plasma ratio of the area under the curve was 0.25. This is consistent with high diffusibility as seen in drugs with a low percentage of protein binding.

Levels of antibiotic in human blood and interstitial fluid after oral administration of bacampicillin or phenoxymethyl penicillin and intravenous administration of amoxicillin or ampicillin.

Levels of antibiotic in the serum and interstitial fluid were determined for 11 volunteers who received conventional doses of either phenoxymethyl penicillin (penicillin V) or bacampicillin orally and for 11 volunteers who received either amoxicillin or ampicillin intravenously. The levels of antibiotic achieved in both blood and interstitial fluid were higher in the volunteers who received bacampicillin than in those who received penicillin V. The levels of antibiotic in serum and interstitial fluid of participants in the study who received amoxicillin or ampicillin intravenously were comparable with those achieved with equivalent doses of oral bacampicillin. The lowest levels of antibiotic in serum and interstitial fluid were obtained in volunteers who received oral penicillin V, whereas the highest levels were obtained in those given ampicillin and amoxicillin intravenously.

Bacampicillin, Ampicillin, Cephalothin, and Cephapirin levels in human blood and interstitial fluid.

The diffusibility of bacampicillin, ampicillin, cephalothin, and cephapirin into human interstitial fluid was investigated by using crossover studies. We compared bacampicillin with ampicillin and found that bacampicillin was better absorbed after oral administration. Blood, interstitial fluid, and urine levels were consistently higher in volunteers who received bacampicillin. We compared cephalothin with cephapirin and found that blood and interstitial fluid levels were comparable throughout the study.