Rolf Maller

Pharmacodynamics of daptomycin and vancomycin on Enterococcus faecalis and Staphylococcus aureus demonstrated by studies of initial killing and postantibiotic effect and influence of Ca2+ and albumin on these drugs.

The pharmacodynamics of daptomycin and vancomycin on Enterococcus faecalis ATCC 29212 and Staphylococcus aureus ATCC 25923 were investigated by studying the postantibiotic effect (PAE) and initial killing. The influence of Ca2+ and albumin on these drugs was also evaluated. The PAE was studied by use of bioluminescence assay of bacterial ATP. Daptomycin at clinically achievable concentrations produced a dose-dependent PAE on E. faecalis (0.6 to 6.7 h) and S. aureus (1.0 to 6.3 h). The long PAE of daptomycin was seen simultaneously with a potent dose-dependent initial killing assayed by viable count determination. The initial change in bacterial ATP was not as extensive as the decrease in viability. Vancomycin at corresponding concentrations produced shorter PAEs on E. faecalis (0.5 to 1.0 h) and S. aureus (1.3 to 1.8 h). This coincides with a weak non-dose-dependent initial change in viability and intracellular ATP. The MICs of vancomycin were not influenced by different Ca2+ concentrations or by the addition of albumin to the broth. The MICs of daptomycin for both strains were lowered, and the PAEs were prolonged with increasing concentrations of Ca2+ in the broth. The PAE of daptomycin was Ca2+ dependent to the same extent as the MIC was. In the presence of physiological concentrations of albumin and free Ca2+, the PAEs of daptomycin on both strains were reduced and the MICs were increased in comparison with the results obtained in pure Mueller-Hinton broth with approximately the same free Ca2+ concentration. This decrease in daptomycin activity was considered to be due to the albumin binding of daptomycin. Despite the albumin binding of daptomycin, the PAE produced on E. faecalis and S. aureus in the presence of a physiological free Ca2+ concentration was still over 6 h at clinically achievable concentrations.

A New Diagnostic Approach to the Patient with Severe Pneumonia

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.

A clinical and epidemiological study of "ornithosis" caused by Chlamydia psittaci and Chlamydia pneumoniae (strain TWAR).

Ornithosis is a notifiable disease in Sweden since 1954. In 1981 and 1982 a sharp increase in the number of notifications occurred. Since then the number has declined but is still high. A changed epidemiology characterized by no history of bird contact and no common source, raised the suspicion of a new agent. Serological data now suggest that the epidemic was to a substantial part due to Chlamydia pneumoniae (strain TWAR) (48% of the patients during 1981-1982 compared to 9% during 1984-1987). During recent years TWAR infections have thus become uncommon but reappearance can be expected in the near future. The clinical picture as well as the complications appear to be very similar in infections caused by C. pneumoniae and C. psittaci.

Postantibiotic effect of beta-lactam antibiotics on Escherichia coli evaluated by bioluminescence assay of bacterial ATP.

The in vitro postantibiotic effects (PAE) of aztreonam, ceftazidime, cefuroxime, imipenem, and piperacillin on Escherichia coli ATCC 25922 were studied by a bioluminescence assay of bacterial ATP. In parallel with the PAE investigation, viability and morphology studies were performed. The strain was exposed for 2 h to different concentrations of beta-lactam antibiotics. The antibiotic activity was eliminated by 10(-4) dilutions, and regrowth of bacteria was monitored hourly by the bioluminescence assay of bacterial ATP. The length of PAE was dose dependent for ceftazidime (0.5 to 2.6 h), cefuroxime (0.4 to 2.6 h), and imipenem (0.3 to 4.5 h). The long PAE for these antibiotics at higher concentrations was associated with a potent initial killing and the presence of spheroplasts. Aztreonam and piperacillin produced a short, non-dose-dependent PAE (0.4 to 0.95 h). Short PAEs (below 1 h) were seen concomitantly with production of filaments, except in the case of imipenem, which only produced spheroplasts. The bioluminescence method was not jeopardized by filament formation, in contrast to the viable count assay which is normally used for PAE investigations. This makes it possible to study PAE for beta-lactam antibiotics on gram-negative bacteria with bioluminescence.

Active and total T cells in blood and cerebrospinal fluid during the course of aseptic meningitis

Patients with aseptic meningitis (AM) were examined with the active T cell rosette test, which has been claimed to reflect cell‐mediated immunocompetence more accurately than determination of total T cells. Higher percentages of active T cells were demonstrated in CSF compared to blood regardless if specimens were obtained on days 1–4, days 5–10, or later than 20 days after onset of symptoms. Active T cell percentages in CSF decreased when values for specimens obtained on days 5–10 were compared with those taken later than 20 days after onset, while no significant variations of active T cell percentages in blood were observed. The percentages of total T cells were higher in CSF than blood in specimens from days 5–10, and later than 20 days after onset, but no significant fluctuations of total T cells occurred in either CSF or blood over the course of AM.

Inhibition of aminoglycoside activity in heparin.

Measurements of aminoglycosides by an agar disk diffusion assay are inhibited by heparin in a dose-dependent way. When assayed by a homogeneous immunoassay, this was only evident for tobramycin. This indicates that specimens for aminoglycoside measurement should not be obtained in heparinized tubes. When heparin is used clinically as an anticoagulant, the amount in blood does not reach levels that affect the aminoglycoside activity.

IL-8 and tumor necrosis factor alpha in heart valves from patients with infective endocarditis.

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-α) is 1 of the major proinflammatory cytokines. IL-8 and TNF-α 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-α -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-α -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.

Amikacin once daily : a new dosing regimen based on drug pharmacokinetics.

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.

Effects of hip arthroplasty and peroperative dicloxacillin prophylaxis on renal function.

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.

Renal function after hip arthroplasty and isoxazolylpenicillin prophylaxis

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.