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We present clinical and virological data on 9 patients, 7 women and 2 men aged 31-56 years, with recurrent aseptic meningitis (Mollaret's meningitis). Polymerase chain reaction detected Herpes simplex virus type 2 DNA in cerebrospinal fluid samples from all patients collected during their latest attacks of meningitis. Six patients had no history of genital herpes. Only 1 patient was offered prophylactic antiviral treatment during the study period (45 months).

Previous studies have indicated that response to interferon therapy is inversely proportional to the amount of body iron stores. We have studied the relationship between serum ferritin, transferrin saturation, liver iron, presence of HFE-C282Y gene mutation and response to treatment in patients with chronic hepatitis C infection.Two hundred and fifty-six naive, HCV-RNA positive patients (60% males, median age 38 years, range 21-70) were treated with interferon and ribavirin for 6 months. Iron indices and the presence of the C282Y mutation were measured. In 242 (94%) patients iron deposition were determined by Perls staining method. Patients with negative HCV-RNA at 6 months after the end of treatment were defined as sustained viral responders.Non-responders (n = 127) had significantly higher median s-ferritin values compared with sustained viral responders (130 microg/L vs. 75 microg/L P0.001). There was no difference in transferrin saturation among the two response groups. Only 23% (4/7) of patients with Perls grade 1 in liver biopsies responded to treatment vs. 54% (122/225) patients without iron deposition (P = 0.02), however, 10/13-non-responders had HCV genotype one. Two patients (0.8%) were homozygous for the C282Y mutation, 36 patients were heterozygous (14%). Among mutation carriers 26/38 achieved sustained response compared with 102/216 non-carriers (68% vs. 48%, P = 0.02). In a multivariate analysis s-ferritin (P = 0.030) and C282Y carrier status (P = 0.012) remained independent predict of sustained response.Raised s-ferritin values predicate non-response to interferon-ribavirin therapy in hepatitis C patients. Response rate in C282Y mutation carriers seems greater than in non-carriers.

Hepatitis C virus (HCV) has been a major cause of post transfusion hepatitis, and is still an important cause of chronic liver disease throughout the world. How to treat patients with chronic HCV infection has been brought into focus in recent years, and a substantial amount of data has been obtained about the development of hepatitis C with and without treatment. This survey considers the diagnosis of hepatitis C, and present treatment modalities and their potential. The patients most likely to respond to treatment are described, and the authors finally discuss why treatment of hepatitis C still should take place in controlled studies.

Eighty patients with suspected or diagnosed bacterial infections were treated with ceftazidime. Sixty-five patients with 88 sites of infections could be assessed clinically. A cure or improvement was achieved in 61 patients (94%) with a total of 83 infection sites (94%). Failures were seen in four critically ill patients with severe underlying diseases. Eighty-six pathogens, most frequently Enterobacteriaceae, were isolated from appropriate specimens. The infecting organisms were all eradicated during therapy. In two patients reinfection with a new strain occurred. Except for a severe anaphylactic reaction in one patient, ceftazidime was well tolerated.

Successful treatment of respiratory tract infections with erythromycin may depend upon adequate penetration of the drug to the site of infection. The delivery of antibiotics into respiratory tract secretions is a simple passive diffusion process along a concentration gradient according to Fick's principle. A number of other factors including physicochemical characteristics of the drug and host defence mechanisms may further modify the tissue penetration. A common feature of penetration studies in respiratory tract infections is the wide range of results. This is due to the numerous variables involved in this kind of study. However, the studies performed at steady state, and after oral administration of erythromycin, show a rapid increase in drug concentrations in adenoid and tonsillar tissue homogenates and sustained levels equal to or higher than in serum. In secretions of the middle ear, paranasal sinuses and bronchiae the penetration and elimination of erythromycin is much slower. The drug levels were equal to--or in some cases even higher than--steady state serum concentrations. Fluctuations, however, were less pronounced. In lung tissue homogenates erythromycin concentrations higher than the serum levels have generally been found. In respiratory tract secretions and tissues the penetration of erythromycin is good. Sufficient levels are reached to inhibit in vitro the growth of most common pathogens involved in respiratory tract infections with the exception of some strains of Haemophilus influenzae.

The elimination kinetics and penetration of ceftazidime into skin blister and lymphatic fluid were studied in nine healthy volunteers following a 1 g iv bolus injection. From the concentration time curve in plasma the following pharmacokinetic parameters (mean +/- S.D.) were calculated: elimination half-life 1.85 +/- 0.33 h; area under the curves 127 +/- 12 mg . h/l; apparent volume of distribution: 21.1 +/- 2.61; total plasma clearance: 133 +/- 13 ml/min and renal clearance: 109 +/- 7 ml/min. Urine recovery after 8 h was 82% of the administered dose. Nearly the same elimination rate constant, half-life and area under the curve were demonstrated for blister fluid and lymph. The penetration of ceftazidime into cerebrospinal fluid (n = 19), aqueous humour (n = 21) and pleural effusions (n = 5) were studied in patients after a 2 g iv bolus injection. In patients with normal meninges (n = 14) the penetration was poor: the concentrations were less than 1 mg/l. In patients with meningitis (n = 5) levels of 18, 17, 16, 1 and 0.8 mg/l were found. Aqueous humour penetration was satisfactory, and a mean concentration of 11 +/- 4 mg/l corresponding to a penetration ratio of 19% was found. The penetration of ceftazidime into large pleural effusions was also good with concentrations from 17 +/- 3 to 28 +/- 2 mg/l, corresponding to a mean penetration ratio of 38%.

We have studied the pharmacokinetics of ceftazidime in 37 patients suffering from serious bacterial infections. All the patients had impairment of renal function and received moderate to high doses of frusemide concurrently. The doses of ceftazidime were given according to renal function as recommended by the manufacturer. Serum and urine samples were frequently collected, and drug concentrations measured by high performance liquid chromatography. The patients were grouped and evaluated according to renal function, mean (SD) creatinine clearances ranging from 70.1 (12.4) to 11.0 (3.2) ml.min-1. The pharmacokinetics of ceftazidime depended on renal function. A statistically significant increase in ceftazidime elimination half-life and decreases in urinary recovery, total body clearance, and renal clearance in proportion to the decrease in renal function were observed (p less than 0.05). The apparent volume of distribution also increased, but not significantly (p greater than 0.05). A linear correlation was found between the total body and renal clearances of ceftazidime and creatinine clearance. The extrarenal clearance increased from 3.9 to 14.0 ml.min-1 with decreasing renal function. Concurrent treatment with ceftazidime and moderate to high doses of frusemide did not impair renal function and no evidence of nephrotoxicity was found.

Four methods for the identification of Staphylococcus aureus (tube coagulase test, thermostable nuclease test, indirect agglutination of fibrinogen coated erythrocytes and a commercial latex kit: SeroSTAT Staphylococcus Test) have been compared. Clinical isolates (698) and 40 reference strains of Micrococcaceae were included in the study together with control organisms. The coagulase test gave no false positive results but 39/406 clinical isolates of S. aureus were negative at 2h and one half were only weakly positive. At 18 h, all but 2 of 406 isolates gave a positive reaction. The thermostable nuclease test was very specific; no clinical isolates of S. aureus gave negative results and no "coagulase-negative" clinical isolates gave a definite positive reaction. The indirect haemagglutination method was sometimes difficult to interpret and frequently gave negative or doubtful results for S. aureus. The SeroSTAT test was easy to use and interpret and was specific; the method is suitable for routine laboratory use, particularly when a rapid result is desirable.

In the secondary defence line against bacterial invasion, the phagocytic cell systems serve as effector mechanisms of specific and unspecific immunity. In bacterial infections including septicaemia the outcome of the host-parasite interaction is determined by the ability of the mono- and polymorphonuclear phagocytes to recognize and kill the invading organisms in the presence of humoral and lymphocytic factors. The quantitative aspects of phagocytic deficiency is well recognized, in general and the risk of bacterial infection in a given patient is related directly to the duration of granulocytopenia and inversely to the number of circulating granulocytes. Reduced numbers of monocytes or, as in the splenectomized patient, lack of tissue macrophages may also add to increase suseptibility to infection with certain bacteria. Functional defects in phagocytosis in the presence of normal peripheral neutrophil and monocyte counts become increasingly important with the sophisticated procedures of modern medicine. In reviewing the functional capacity of the phagocytes it is convenient to consider four interrelated phases: 1) the vascular phase characterized by amrgination, adherence and diapedesis of the cells, 2) the chemotaxis of the directed movement of the cells to site of microbial invasion, 3) the phagocytosis or ingestion of microorganisms, and 4) the cellular factors involved in the killing and decomposition of the microorganisms. Enhanced susceptibility to infection has been related to defects in any of these functions, and the basic types of inborn or acquired abnormalities are reviewed. The problems of iatrogenic defects in antimicrobial host resistance may, hopefully, be reduced by an increasing knowledge in pathophysiology and the various steps involved in the cellular defence mechanisms.

Antibiotic sensitive Staphylococcus aureus phagocytosed by human neutrophil granulocytes were exposed to penicillin G (benzyl penicillin), gentamicin or rifampicin in concentrations from 2.5 U/ml, 2.5 microgram/ml and 0.2 microgram/ml to 250 U/ml, 250 microgram/ml and 20 microgram/ml, respectively. The bacteria were protected from the antibacterial effects of penicillin G and gentamicin. Considerable numbers of phagocytosed bacteria remained viable after 24 hours exposure to antibiotic concentrations that killed more than 99% of extracellular bacteria in less than one hour. Killing of intracellular bacteria was more pronounced with rifampicin, indicating that the penetration of this drug into the phagocytic vacuole is superior to penicillin G and gentamicin.

Polymorphonuclear leukocytes (PMNLs) are a cornerstone of host defense against infection, and the interaction of PMNLs with antimicrobial agents has been extensively studied [10, 14, 15]. Reports on the effect of tetracyclines on PMNL functions are contradictory. Chlortetracycline and doxycycline seem to markedly inhibit the phagocytic activity of the cells [5, 18] while no such effect has been demonstrated with tetracycline hydrochloride [9]. More recent reports [16, 17] have demonstrated only a slight decrease in phagocytosis of 32P-labeled Escherichia coli by human and rat PMNLs. Doxycycline administrated to healthy individuals has also been shown to slightly inhibit the migration to skin chambers [4].

The antibiotic concentrations in untreated and endotoxin-treated suction blisters was studied in 15 healthy adults. In a pilot study, 2 mega units of penicillin G were given as an intravenous bolus injection to two subjects. For further studies, a single dose of 800 mg bacampicillin was given orally to 13 individuals. The penicillin G concentrations in the blister fluid were highest approximately 15 minutes after the dose, and exceeded that of serum after 1.5 hours. With ampicillin the blister fluid concentration reached maximum levels after approximately 2 hours, were equal to serum levels after 3 hours, and were later persistently in excess of serum levels. The ampicillin half-life was 136 and 100 minutes in the two types of blister fluid, as compared to 65 minutes for serum. A marked differences between the antibiotic concentrations in inflammatory and non-inflammatory blisters was seen in the pilot study with penicillin G. However, in the experiments with bacampicillin, no significant difference was demonstrated. This suction blister technique appears to be a useful method for studies on extravascular antimicrobial activity in man.

Following iv bolus injection of 3.2 g Timentin (ticarcillin 3.0 g plus clavulanic acid 0.2 g) to 12 volunteers, the antibiotic concentrations were analysed by HPLC methods in serum, urine and fluids from subcutaneous threads, suction blisters and lymph during 8 h. Pharmacokinetic parameters, urine recovery, penetration and ticarcillin/clavulanic acid ratios were calculated. The antibiotic concentration in thread fluid closely followed the serum concentration. For ticarcillin the mean (+/- S.D.) elimination half-lives in serum and thread fluid were 1.0 +/- 0.1 and 1.2 +/- 0.1 h, respectively. For clavulanic acid the half-lives in these fluids were 0.9 +/- 0.1 and 1.0 +/- 0.1 h. The lymph and blister fluid concentration followed a similar pattern, but differed from those in serum, the mean (+/- S.D.) elimination half-lives for both compounds ranging from 1.1 +/- 0.2 to 3.2 +/- 0.3 h. The urine recovery of ticarcillin was 86% and of clavulanic acid 51% of the administered dose. The penetration of clavulanic acid into the different tissue fluids was superior to ticarcillin, ranging from 78 to 88% for clavulanic acid and 52-70% for ticarcillin. The concentration ratios of the two compounds, being 15:1 at the time of injection, varied widely in the different tissue fluids with time. This was also the case with AUC(0-infinity) ratios. A relative decrease of clavulanic acid was observed, most pronounced in serum and thread fluid. However, the antibiotic concentrations achieved in serum, urine and extravascular fluid should be adequate in most infections caused by a wide range of clinically important pathogens.

After oral administration of 0.8 g of bacampicillin, the median concentration of ampicillin in serum peaked at 1-2 hr and reached 8.4 and 12.3 micrograms/ml in two groups of 13 and four healthy volunteers, respectively. In the fluid of dermal blisters produced by suction, the peak values were 2.6 and 2.7 micrograms/ml, respectively. After oral administration of 1.6 g of bacampicillin to four healthy individuals, the median peak concentrations were 15.5 micrograms/ml in serum and 3.8 micrograms/ml in blister fluid. The rate of penetration of ampicillin into the blister fluid was lower than the rate of gastrointestinal absorption of bacampicillin, and the elimination of ampicillin from the blister fluid was slower than from serum; the half-life in blister fluid was approximately twice that in serum. Concentrations of ampicillin in the blister fluid exceeded those in serum at greater than or equal to 3 hr. Concentrations of less than 0.7 micrograms/ml were observed in blister fluid 11 hr after administration of the dose. The bioavailability of ampicillin was relatively greater after a 1.6-g dose of bacampicillin than after a 0.8-g dose. Inflammation in the blister fluid that was induced by endotoxin, which provoked a strong cellular response but cased no increase in the concentration of protein in the fluid, did not significantly influence the pharmacokinetics of ampicillin. The results suggest that the pharmacokinetics of antimicrobial agents in serum and in extravascular foci may be relevant to the setting of breakpoints between sensitivity and resistance of pathogens of antimicrobial agents.

Sixteen patients with chronic or recurrent urinary tract infections, 14 with septicaemia, 2 with salmonellosis, 2 with pneumonia and 1 with acute mastitis were treated with 200 mg (2.2-3.6 mg/kg) netilmicin intramuscularly every 8 hours for 7-10 days (mean 8.8 days). 28 patients were cured, 5 showed marked improvement and 2 patients with septicaemia and severe underlying diseases failed to respond to treatment. The bacterial isolates were inhibited by 4.0 mg netilmicin/l or less. Antibiotic serum level determinations were performed in 32 patients. Mean serum concentrations of netilmicin 1 and 8 hours after injection were 12.6 and 2.0 mg/l respectively in 27 patients with normal serum creatinine levels. In 5 patients with elevated serum creatinine, mean peak and trough values were 21.5 and 5.8 mg/l, respectively. Mean netilmicin concentrations in serum and skin blister fluid obtained from 4 patients were equal 2-3 hours after injection, indicating appropriate tissue penetration. Nephrotoxicity occurred in 2 patients. Ototoxicity was not demonstrated. Netilmicin appears to be an effective and safe drug in the treatment of a variety of bacterial infections.