Sequential changes in hematologic and biochemical parameters in African tick bite fever.

OBJECTIVE: To evaluate the sequential changes and to estimate the frequencies of abnormalities in some commonly measured biological variables in patients with African tick bite fever (ATBF), an emerging spotted fever group (SFG) rickettsiosis in international travelers to rural sub-Saharan Africa. METHODS: A study was done of hemoglobin, total leukocyte count, absolute lymphocyte count, blood platelet count and serum levels of C-reactive protein (S-CRP), alanine aminotransferase (S-ALAT), aspartate aminotransferase, lactic dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, sodium and creatinine during the first two weeks of illness and prior to the institution of antirickettsial therapy in 108 patients with travel-associated ATBF. RESULTS: There were significant falls in mean total leukocyte count, mean absolute lymphocyte count, and mean platelet count, and significant increases in mean S-CRP and S-ALAT. During the first ten days of illness, elevated S-CRP, lymphopenia and elevated S-ALAT were detected in 91.7%, 73.3% and 40.7% of patients, respectively. Most abnormalities were mild. For 55 patients who underwent both S-CRP and absolute lymphocyte count determination, at least one parameter was abnormal in 52 (94.5%) patients. CONCLUSIONS: The sequential changes in many biological parameters during the acute phase of ATBF mimic those reported in other SFG rickettsioses. Mild abnormalities are frequent, with increased S-CRP and lymphopenia being the two most consistent findings.

Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.

BACKGROUND/AIM: 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. METHODS: 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. RESULTS: Non-responders (n = 127) had significantly higher median s-ferritin values compared with sustained viral responders (130 microg/L vs. 75 microg/L P < 0.001). 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. CONCLUSIONS: 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.

Effect of interferon-alpha induction therapy on genotype 2b/3a and low viral load hepatitis C virus infection. A randomized multicentre study.

BACKGROUND: Interferon monotherapy for chronic hepatitis C virus (HCV) infection leads to sustained viral eradication in a minority of patients. However, in selected groups of patients, sustained virological response is observed in as many as 50% of patients. High initial interferon dose (induction therapy) has been reported to increase the initial response rate. We have studied the effect of interferon induction therapy in patients infected with HCV genotype 2b/3a, low viral load and no cirrhosis. METHODS: A total of 71 treatment-naive HCV RNA-positive patients with biopsy-confirmed chronic hepatitis, with genotype 2b or 3a, viral load < or = 3 million copies per ml and no cirrhosis were randomized to receive either standard interferon therapy (3 MIU interferon-alpha-2a thrice weekly) for 26 weeks or 6 MIU interferon-alpha-2a daily for 4 weeks (induction group) followed by the standard dose (3 MIU thrice weekly) for 22 weeks. Those with persistent HCV RNA at 4 weeks stopped treatment. Patients were monitored for HCV RNA during and following treatment, and data were interpreted according to intention-to-treat analysis. RESULTS: Viral clearance occurred more rapidly (after 4 weeks) in the induction group (33/36 = 92%) compared to the standard interferon group (21/35 = 60%) (P = 0.01). Among the initial responders, 23/33 (induction group) compared to 16/21 (standard group) were persistently HCV RNA-negative at the end of treatment. At 52 weeks (6 months' follow-up), 22/36 (61%) (induction group) compared to 10/35 (29%) (standard group) were HCV RNA-negative. Among initial responders, 22/33 (induction group) and 10/21 (standard group) achieved a sustained virological response. Among end-of-treatment responders, 22/24 (induction group) and 10/16 (standard group) were HCV RNA-negative at 6 months' follow-up (P = 0.013). CONCLUSIONS: In patients infected with HCV genotype 2b/3a, low viral load and without cirrhosis, IFN induction therapy increases the initial viral clearance and reduces the risk of relapse in end-of-treatment responders. A sustained virological response was achieved in 61% of the patients receiving IFN induction therapy.

Effect of combined interferon-alpha induction therapy and ribavirin on chronic hepatitis C virus infection: a randomized multicentre study.

BACKGROUND: The efficacy of interferon-alpha (IFN) induction in combination with ribavirin for chronic hepatitis C virus (HCV) infection is not known. METHODS: A total of 256 treatment-naive HCV RNA-positive patients with biopsy-confirmed chronic hepatitis were enrolled in a randomized multicentre study. The patients received either standard combination therapy with 3 MIU interferon-alpha2b thrice weekly for 26 weeks or 6 MIU interferon-alpha2b daily for 4 weeks and 3 MIU 3/7 days for 22 weeks. All patients received ribavirin 1000 mg or 1200 mg (weight dependent) daily during the 26-week treatment period. Patients were monitored for HCV RNA during and following treatment. RESULTS: The sustained virological response rates (26 weeks after end of treatment) were 54% and 47% for patients receiving IFN induction/ribavirin and standard IFN/ribavirin, respectively (P = 0.35). Among patients infected with genotype 1a/1b, the sustained response rates were 32% and 35%. In patients infected with genotype 2b/3a IFN induction/ribavirin led to a sustained response rate of 80% as compared to 65% in the standard combination therapy group (P = 0.073). Steatosis was more frequently seen in liver biopsies from patients infected with genotype 3a as compared to genotypes la/lb. Among genotype 1a/1b infected patients. steatosis was a highly significant predictor of failure to achieve sustained virological response. Logistic regression analysis (multivariate analysis) showed that independent predictors of sustained virological response were low age, female gender, genotype 2b/3a and HCV RNA negativity at 2 weeks. CONCLUSIONS: IFN induction in combination with ribavirin does not increase the sustained virological response rate among patients infected with HCV. Absence of steatosis is an independent predictor of sustained virological response in patients infected with genotypes 1a/1b.

Anisakiasis presenting as an obstructive duodenal tumor. A Scandinavian case.

A case of chronic anisakiasis presenting as an occluding duodenal tumor is described. Significant falls in Anisakis simplex-specific serum IgE and total IgE occurred after resection of the lesion. Histopathologic examination showed a chronic eosinophilic granulomatous infiltrate and a tubular sclerotic structure in the antral submucosa consistent with, but not diagnostic for, an A. simplex larva.

Low frequency of complications in imported falciparum malaria: a review of 222 cases in south-eastern Norway.

We performed a retrospective study of 222 cases of falciparum malaria diagnosed in Oslo and Akerhus counties, Norway, from January 1988 to December 1997. Except for 12 cases, all had acquired the disease in sub-Saharan Africa. Sixty-four (28.8%) cases occurred in assumed non-immune individuals; of these, 41 (64.1%) were compliant to recommended antimalarial chemoprophylaxis. The mean time lag from first symptom to diagnosis (total diagnosis delay) was 4.6 d (median 3 d, range 0-30 d) and the mean time from presentation to diagnosis (doctor's delay) was 1.3 d (median 0 d, range 0-25 d). There were no fatal cases, and only 8 (3.6%) had a complicated course. The following factors were significantly associated with development of complicated disease: higher age, non-immunity combined with chemoprophylaxis non-compliance, prolonged doctor's delay and prolonged total diagnosis delay (p < or = 0.05). Our data suggest that complicated disease in imported falciparum malaria may largely be prevented by high chemoprophylaxis compliance rates in non-immune travellers and a high index of suspicion in physicians evaluating febrile travellers.

Herpes simplex virus type 2 DNA detected in cerebrospinal fluid of 9 patients with Mollaret's meningitis.

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).

[Treatment of hepatitis C]. / Behandling av hepatitt C.

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.

Spectrum of disease in bacteraemic patients during a Streptococcus pyogenes serotype M-1 epidemic in Norway in 1988.

All 87 known cases of bacteraemia due to Streptococcus pyogenes (beta-haemolytic group A streptococci) occurring during the peak of a nationwide outbreak in Norway (population 4.2 million) between January and June 1988 were reviewed. Clinical features varied widely and appeared largely to be dependent on the patients' age. The case fatality rate ranged from 11% in the age group under 30 years to 44% in patients over 60 years. Clinical complications such as shock, severe renal or respiratory failure or serious local infection occurred particularly in 30-to 59-year old individuals. Shock was manifest in 32% of the patients and carried a 68% case fatality rate. Chronic heart disease in the elderly and pneumonia seemed to be associated with a fatal outcome. In the 25 patients (29%) who died the disease showed a fulminant course, 80% dying within 48 hours after admission. However, 56% of the patients had experienced symptoms for more than two days before admission, suggesting that early diagnosis and treatment might possibly have prevented the development of a serious disease. This study revealed a wide spectrum of clinical manifestations in bacteraemia cases in a unique epidemiological situation caused largely by a single serotype of Streptococcus pyogenes; 89% of the 27 preserved bacteraemia strains carried the M-1 antigen. The observations call attention to the ability of these organisms to cause fulminant clinical illness, indicating a probable increase in both invasiveness and toxicity of group A streptococci responsible for the epidemic.

Ciprofloxacin versus a tobramycin/cefuroxime combination in the treatment of serious systemic infections: a prospective, randomized and controlled study of efficacy and safety.

Sequential intravenous and oral ciprofloxacin (CF) was compared with a combination of tobramycin and cefuroxime (T/C) in the treatment of serious systemic infections. Altogether 310 patients were randomized, 160 receiving CF and 150 T/C, the 2 groups being reasonably well balanced. 29 patients without infection were excluded from the analysis. Complete clinical resolution was obtained in 75% (107/143) patients receiving CF and in 78% (107/138) receiving T/C; the difference was not statistically significant. The rate of bacterial eradication in septicaemia was 72% (95% confidence interval (95% c.i.): 58-86%) for patients treated with CF and 87% (95% c.i.: 77-96%) when T/C was given, while the eradication rates in urinary tract infection were 72% (95% c.i.: 54-90%) and 45% (95% c.i.: 23-67%) for CF and T/C, respectively. Significant differences in bacteriological response for other diagnoses were not detected. Also for lower respiratory tract infections (LTRI) the clinical and bacteriological responses were quite similar, although relatively more failures occurred in CF treated patients with LRTI caused by pneumococci. The frequencies of adverse reactions were comparable, but the reactions were less serious following CF treatment. Our results indicate that CF may be used for empirical treatment of serious infections. However, if pneumococcal etiology is likely, alternative antibiotics should be used, and if necessary, coverage against anaerobic bacteria should be added.

The pharmacokinetics of ceftazidime in patients with impaired renal function and concurrent frusemide therapy.

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.

Pharmacokinetics and tissue penetration of Timentin: a simultaneous study of serum, urine, lymph, suction blister and subcutaneous thread fluid.

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.

Penetration of erythromycin in respiratory tract infections.

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.

Comparison of four methods for differentiation of Staphylococcus aureus from other Micrococcaceae in the routine laboratory.

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.

The evaluation of ceftazidime in the treatment of bacterial infections in eighty seriously ill patients.

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.

Pharmacokinetics and tissue penetration of ceftazidime: studies on lymph, aqueous humour, skin blister, cerebrospinal and pleural fluid.

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%.

Penetration of antibiotics into human leukocytes and dermal suction blisters.

Staphylococcus aureus phagocytized by leukocytes from healthy donors and from patients with chronic granulomatous disease were protected from the antibacterial effect of gentamicin. Considerable numbers of phagocytized bacteria remained viable after exposure for 20 hr to antibiotic concentrations that killed greater than 99% of extracellular bacteria in less than 4 hr. A higher proportion of intracellular bacteria were killed by rifampin; this finding indicated that rifampin penetrates better into the phagocytic vacuole than does gentamicin and/or is more active against phagocytized bacteria than is gentamicin. After oral administration of 450 mg of rifampin to three healthy volunteers, concentrations of the antibiotic in serum and skin blister fluid were measured. Concentrations in serum peaked within 3 hr of oral administration (mean peak level, 13.2 micrograms/ml). Concentrations in blister fluid peaked between 6 hr and 9 hr (mean peak concentration, 2.7 micrograms/ml). Between 9 hr and 12 hr, the concentrations of rifampin in serum and blister fluid were similar; later, levels in blister fluid were higher than those in serum. The mean elimination half-life of rifampin was 2.5 hr in serum and 6.0 hr in blister fluid.