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The embedding of bacteria in the vegetation of infective endocarditis impedes the penetration of phagocytic cells. IL-8 has a stimulating effect on the immune system, particularly with respect to chemotaxis and activation of granulocytes. Tumor necrosis factor alpha (TNF-alpha) is 1 of the major proinflammatory cytokines. IL-8 and TNF-alpha were visualized by means of immunohistochemistry in paraffin-embedded heart valve biopsies from 6 patients with infective endocarditis who required cardiac surgery during the active phase of the infection. In 5/6 patients there were signs of inflammation, and in these patients IL-8- and TNF-alpha-containing cells were visualized in the heart valve stromas or vegetations. The largest numbers of IL-8-containing cells, and the greatest amount of inflammation, were seen in patients with short preoperative treatment courses. No such relationships were seen with respect to TNF-alpha-containing cells. These observations may suggest that the occurrence of IL-8-containing cells in infected heart valves could be used as a marker of disease activity.

When lymphocytes from humans with serological immunity against rubella were incubated with live rubella virus, supernatants were obtained which when added to non-infected lymphocytes gave a significant inhibition of phytohaemagglutinin (PHA)-induced proliferation. In contrast, supernatants from virus-infected lymphocytes from donors lacking immunity against rubella gave no inhibition of the PHA response.

Two different isoxazolylpenicillins (cloxacillin and dicloxacillin) were compared regarding impairment of renal function after total hip arthroplasty. 85 patients received dicloxacillin and 93 patients received cloxacillin as antibiotic prophylaxis. A total dose of 6 grams was given during a 36-hour period in doses of 1 gram pre-, per- and postoperatively. Creatinine in serum and beta 2-microglobulin in serum and urine were determined preoperatively and 2, 4, and 10 days after the operation. The dicloxacillin-treated patients had an increase in creatinine and beta 2-microglobulin in serum that was not seen in the cloxacillin group. The increase indicates a transient injury in the process of glomerular filtration. Although the increase was temporary and subclinical, a dose reduction is nevertheless recommended for older patients.

In a prospective pilot study 70 patients (age greater than 65 years) who underwent hip arthroplasty were treated with dicloxacillin, a total of 6 g given pre-, per- and postoperatively as antibiotic prophylaxis. Creatinine in serum and beta 2-microglobulin in serum and urine were determined as estimates of renal function. Values were obtained preoperatively and on days 2, 4 and 10 after operation. A slight but significant increase of serum creatinine was seen on day 2 with a gradual decrease almost down to the preoperative baseline value on day 10. Serum beta 2-microglobulin increased more gradually; the increase was significant on day 10. Raised levels of beta 2-microglobulin in urine were most pronounced: a 20-fold increase on day 2, then a slow decrease, still significant increase on day 10. This may indicate a reversible damage of proximal tubules with blocked tubular reabsorption of beta 2-microglobulin. The slightly increased levels of serum creatinine and beta 2-microglobulin would also indicate a minor reversible decrease in glomerular filtration rate. Whether these effects are caused by the operation trauma per se or by the dicloxacillin prophylaxis cannot be determined from this pilot study. It seems quite clear that hip arthroplasty with short term prophylaxis with dicloxacillin does not result in clinically important changes in renal function.

The in vitro post-antibiotic effect (PAE) of cefepime, cefotaxime, ceftazidime and imipenem on reference strains of Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia marcescens were evaluated by bioluminescence assay of bacterial ATP. In parallel with the PAE determination, initial killing and morphology studies were performed. Imipenem produced greater than 1 h PAE on all strains tested, cefepime and cefotaxime on four strains and ceftazidime only on one of the strains tested. The length of the PAE on different strains did not correlate in the same way to MIC. Imipenem induced greater than 1 h PAE at 1/4-2 MIC while the cephalosporins caused greater than 1 h PAE at 4-256 x MIC. A PAE exceeding 1.2h was seen concomitantly with spheroplasts but there was not necessarily strong (greater than or equal to 99%) initial killing at the same time. The PAE duration at greater than or equal to 99% initial killing varied between 2.0 h and 5.0 h. When the cephalosporins produced less than 1 h PAEs, this was seen concomitantly with production on filaments and weak initial killing. The bioluminescence method was not jeopardized by filament formation and no negative PAE was found in contrast to the viable count method. The study showed that neither a certain multiple of MIC, the presence of spheroplasts nor strong initial killing can predict the length of PAE for beta-lactam antibiotics on gram-negative bacteria.

The in-vitro post-antibiotic effect (PAE) of amikacin alone and in combination with ceftazidime, ceftriaxone and piperacillin was studied for two strains of Enterococcus faecalis using a bioluminescent assay of bacterial ATP. The two strains of E. faecalis were resistant to amikacin, ceftazidime and ceftriaxone but sensitive to piperacillin. The bacterial cultures were incubated with the beta-lactam antibiotics for 1 h and concentrations of amikacin between 2-64 mg/l were then added. Thereafter, incubation continued with the combinations for one more hour. After dilution, regrowth was monitored by measuring bacterial ATP every hour. Increasing concentrations of amikacin (2-64 mg/l), ceftazidime (8-32 mg/l) and ceftriaxone (32-128 mg/l) resulted in little or no PAE (0-0.3 h) on these strains. PAEs of 0.5 to 1.6 h resulted from exposure to piperacillin (4-32 mg/l). In combination amikacin and piperacillin increased the PAE to 5.5 h. A synergistic PAE was also seen when the enterococci were exposed to amikacin combined with ceftazidime or ceftriaxone in concentrations close to the MICs of the latter antibiotics.

Two hundred and twenty patients with serious infections verified or suspected to be of Gram-negative aetiology were treated in an open randomized comparative multicentre trial with amikacin 15 mg/kg/day given either as a single dose or in two divided doses at 12-h intervals. Amikacin was administered as a short-term iv infusion. When additional therapy was considered necessary piperacillin or ampicillin was recommended. The trial continues and an interim report on data from the 12 participating Scandinavian hospitals is presented. One hundred and forty-four patients have been evaluated for efficacy and 213 patients for safety. There were no significant differences between the two dosage regimens regarding efficacy and safety. A satisfactory clinical response was recorded in 129 (90%) of the evaluable patients. One serious adverse reaction was seen in a patient in the once-daily group. This was ototoxicity which was superimposed on a long standing hearing defect possibly caused by previous streptomycin therapy.

Once-daily dosing of amikacin is a novel therapy regimen which seems pharmacokinetically appropriate for the primary group of patients considered for aminoglycoside therapy. In this study of 29 elderly patients with serious infections, amikacin 11 mg/kg or 15 mg/kg bw was administered as a short-term (30 min) intravenous infusion. The amikacin serum concentration-time profile was best described by a bi-exponential equation with a half-life of about 4.8 h. A triexponential equation was not applicable because the slow terminal elimination phase was not detected during the 24 h dosing interval. In practice, a uni-exponential equation is often used, and this may lead to incorrect conclusions about the elimination rate of amikacin. Amikacin clearance provides more direct information about elimination of amikacin than does serum half-life. Thus, there was a better correlation between the individual amikacin clearances and creatinine clearances (r = 0.89), than between the serum half-lives of amikacin and the creatinine clearances (r = 0.71). For elderly patients a smaller dose of amikacin than the regular daily dose of 15 mg/kg bw, i.e. about 11 mg/kg bw, seems recommendable, when it is given once daily. From the data obtained it is also obvious that once-daily dosing of amikacin does not eliminate the need for checking serum concentrations of the drug.

36 patients with severe community-acquired pneumonia, treated in an intensive care unit (ICU), were examined in a prospective study using a comprehensive diagnostic program to establish an early etiological diagnosis. The resulting prompt and adequate antimicrobial therapy may have decreased the number of fatal cases. Special emphasis was placed on the use of a method incorporating fiberoptic bronchoscopy, together with protected brush sampling and bronchial lavage. An etiological diagnosis was established in 81% (29/36) of the cases. This etiological diagnosis was established within 48-72 h in 53% (19/36) of the patients, S. pneumoniae being the most frequent agent found (12 patients). This information, however, was poorly utilized since in only 11/19 of these patients was the antimicrobial therapy changed from a broad-spectrum antibiotic to a more specific narrow spectrum agent. The overall mortality rate was 22% (8/36). 7/8 patients who died had compromising factors. Most deaths in community-acquired pneumonia are still associated with pneumococcal infection. We conclude that fiberoptic bronchoscopy with brush samples via a plugged double lumen catheter provides the least misleading information concerning the etiological agent in pneumonia; sampling should be done as soon as possible after admission to the hospital, ideally before the need for ICU treatment; factors other than prompt antimicrobial therapy may influence the outcome of severe community-acquired pneumonia.