Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost.

BACKGROUND: Intravenous administration of a third-generation cephalosporin is optimal antibiotic treatment for spontaneous bacterial peritonitis. AIMS: To compare an intravenous-oral step-down schedule with ciprofloxacin (switch therapy) to intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis, and to evaluate the impact of terlipressin and albumin in the treatment of type 1 hepatorenal syndrome on mortality. METHODS: A total of 116 cirrhotic patients with spontaneous bacterial peritonitis, were randomly given switch therapy with ciprofloxacin (61 patients) or intravenous ceftazidime (55 patients). All patients who developed type 1 hepatorenal syndrome were treated with terlipressin (2-12 mg/day) and albumin (20-40 g/day). RESULTS: Resolution of infection was achieved in 46/55 patients treated with ceftazidime (84%) and in 49/61 patients treated with ciprofloxacin (80%, P = N.S.). An intravenous-oral step-down schedule was possible in 50/61 patients (82%) who received ciprofloxacin; 45/61 patients (74%) were discharged before the end of antibiotic treatment and completed it at home. The mean saving per patient due to the reduction of hospital stay in the ciprofloxacin group was 1150 . Type 1 hepatorenal syndrome was treated successfully in 12/19 patients (63%). As a consequence, the in-hospital mortality rate due to infection was 10%. CONCLUSIONS: Switch therapy with cephalosporin is more cost-effective than intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in cirrhotic patients who are not on prophylaxis with quinolones.

Induction of autoantibodies during alpha interferon treatment in chronic hepatitis B.

Thirty-two patients with chronic hepatitis B treated with alpha interferon were tested for 12 different antibodies. Only a minority (18%) of cases developed antinuclear antibodies and none developed clinical signs of autoimmune disease. These data suggest that, at the dose regimen used, interferon therapy of chronic hepatitis B is not associated with triggering of autoimmunity.

Urinary pharmacokinetics and theoretical pharmacodynamics of intravenous levofloxacin in intensive care unit patients treated with 500 mg b.i.d. for ventilator-associated pneumonia.

This study assessed the urinary pharmacokinetics and theoretical pharmacodynamics of levofloxacin in ICU patients treated with 500 mg b.i.d. i.v. for ventilator associated pneumonia to evaluate if this high dosage regimen might ensure appropriate exposure in the treatment of severe UTIs in ICU patients. Nineteen patients (11M, 8F; age, 52 +/- 21 years; weight, 75 +/- 16 kg) presenting with normal renal function (estimated creatinine clearance, 1.83 +/- 0.61 ml/min/kg; diuresis, 1709 +/- 643ml / 24h) were assessed. In steady-state conditions, urine samples were collected at 0-2h, 2-4h, 4-8h and 8-12h during a dosing interval, and urinary concentrations of levofloxacin were assayed by HPLC. Mean (+/- SD) levofloxacin urinary concentrations were 329.1 +/- 159.9, 388.6 +/- 143.5, 266.0 +/- 102.8 and 168.1 +/- 93.3mg/L at 0-2h, 2-4h, 4-8h and 8-12h, respectively, with urinary AUC0-tau of 3171.4 +/- 1192.1mg/L x h. Mean (+/- SD) levofloxacin excretion rates were 44.1 +/- 20.7, 42.8 +/- 8.2, 31.7 +/- 5.8 and 19.8 +/- 4.2 mg/h during the 0-2h, 2-4, 4-8h and 8-12h interval, respectively. Our findings suggest that, consistently with levofloxacin showing high renal excretion as unmodified drug, 500mg b.i.d. i.v. of levofloxacin ensure and maintain urinary concentrations at least 50-fold higher than the MIC90 of most sensitive uropathogens during the overall dosing interval in ICU patients with normal renal function. Considering the major pharmacodynamic determinants for the concentration-dependent bactericidal activity of levofloxacin as applicable at the urinary level (CU/MIC of >12.2 and/or AUC24h U /MIC of >125h), this high dosage regimen may ensure optimal exposure for the treatment of catheter-related and severe lower UTIs not only against sensitive microorganisms, but probably also whenever microorganisms usually considered as intermediate susceptible or resistant to levofloxacin may be involved.

Levamisole therapy in chronic type B hepatitis. Results of a double-blind randomized trial.

A double-blind, randomized, controlled trial has been undertaken to evaluate treatment of chronic hepatitis type B with levamisole. Ten patients received levamisole (150 mg/day, 3 days/wk) and 10 received placebo until seroconversion to antibody to hepatitis B e antigen eventually occurred, or for a maximum of 18 mo. Final evaluation at 24 mo after starting treatment revealed that 60% of the patients in the levamisole group had become hepatitis B e antigen negative, 90% were hepatitis B virus-deoxyribonucleic acid negative in serum, and 8 of 9 (89%) patients had cleared hepatitis B core antigen from the liver. On the other hand, in the placebo group only 4 of the 10 subjects (40%) were hepatitis B e antigen and hepatitis B virus-deoxyribonucleic acid negative in serum and 3 of 8 (37.5%) of them became hepatitis B core antigen free in the liver. Moreover, in 8 patients of the treated group and in 4 of the control cases aminotransferase activities fell into the normal range. A liver biopsy specimen was obtained after treatment in 17 patients and 7 of 9 levamisole recipients showed marked improvement in hepatic histology, compared with 3 of 8 placebo recipients. These data show that patients treated with long-term levamisole therapy have a tendency toward normalization of aminotransferase activities and suppression of hepatitis B virus replication, suggesting that the drug may be of benefit in chronic hepatitis B e antigen-positive hepatitis.

Evolution of upper limb function in children with congenital hemiplegia.

Hand function deficits in hemiplegic children are a major cause of disability, but there is a lack of appropriate instruments for evaluating the evolution of this deficit over time and for verifying the efficacy of its treatment. We evaluated changes in upper limb function in relation to age and the course of individual rehabilitation treatment in 20 children (13 males and 7 females) who were first seen within the first four years of life and subsequently followed until a mean age of 13 years and four months (range, 11-17 years) in accordance with a diagnostic/rehabilitation program initiated in our division in 1989. All of the children were treated by us; those whose paretic upper limb functioned well were not treated in any specific or directed manner. The protocol involved a qualitative evaluation of the spontaneous use of the paretic hand and a quantitative evaluation of grip. Analysis of the results revealed an age-related global improvement over time, occurring within the first five years of life and more pronounced in terms of grip than spontaneous use. This finding makes our protocol more specific than those currently used because it more reliably establishes the real capacity to use the paretic hand in different situations of everyday life. The most important changes concerned the children with more impaired functional capacity, whereas the children who presented with good functional skill retained this capacity over time, thus confirming the initial decision not to treat them.

Chronic persistent hepatitis type B can be a progressive disease when associated with sustained virus replication.

In 44 hepatitis B virus (HBV) carriers with chronic persistent hepatitis (CPH), serial liver biopsies were available. At presentation 38 patients had HBV-DNA in their serum including 31 HBeAg positive and seven anti-HBe positive cases. The remaining six patients were anti-HBe positive and HBV-DNA negative. During a mean histologic follow-up of 4.2 years, 12 (32%) of the 38 HBV-DNA positive patients progressed to chronic active hepatitis (six cases) or to active cirrhosis (six cases), while 26 patients showed either unchanged features of CPH (21 cases), or histologic improvement to normal liver (five cases). Persistence of HBV-DNA in serum, independently of HBeAg/anti-HBe events, was significantly (p less than 0.01) associated with deterioration of liver disease, while termination of HBV replication correlated significantly (p less than 0.05) with spontaneous biochemical remission and with unchanged or improved histology. None of the six anti-HBe positive patients without serologic markers of hepatitis B virus replication showed histologic deterioration. These findings indicate that continuing HBV replication is a marker which predicts unfavourable evolution of chronic persistent hepatitis and frequent transition to chronic active hepatitis or cirrhosis.

Spontaneous reactivation of hepatitis B virus infection in patients with chronic type B hepatitis.

Eighty-eight consecutive hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive, heterosexual patients of Caucasian origin presenting with chronic hepatitis were followed for 1 to 15 years (mean, 5.4 years). During the study period, 45 (51%) patients cleared HBeAg and hepatitis B virus-deoxyribonucleic acid from serum and were followed for 53 +/- 29 months (mean +/- SD) after seroconversion to antibody to hepatitis B e antigen. All patients manifested biochemical improvement. During follow-up, 10 (22%) of the 45 patients experienced spontaneous reactivation of hepatitis B replication with reappearance of serum hepatitis B virus-deoxyribonucleic acid and, in 4 patients, of hepatitis B e antigen. All patients then showed biochemical exacerbation of disease. These serologic events were transient, lasting an average of 12 months, in 8 (80%) patients. All patients were asymptomatic or minimally symptomatic. Histologic findings of liver tissue from 7 patients showed progression from chronic active hepatitis to active cirrhosis in 2 (28%) patients, while in the remaining 6 cases histology remained unchanged or improved from chronic active to chronic persistent hepatitis. These data indicate that spontaneous reactivation of hepatitis B infection occurs in heterosexual patients with chronic hepatitis B and this event is usually transient and asymptomatic, although in some patients it may be the major cause of progressive hepatic damage.

Therapy for chronic hepatitis B with lymphoblastoid interferon-alpha and levamisole.

About one third of patients with chronic hepatitis B show a sustained response when treated with interferon-alpha. Combining interferon-alpha with immunomodulators might be a way to increase response rate. The aim of this study was to compare the efficacy of lymphoblastoid interferon-alpha given alone with its efficacy when combined with levamisole in chronic hepatitis B. Forty-five patients with HBeAg-positive chronic hepatitis were randomly selected (with stratification for ALT levels) to receive a 6-mo course of combination therapy with lymphoblastoid interferon-alpha (5 million units/m2 three times per week) and levamisole (150 mg three times per week) or lymphoblastoid interferon at the same dose regimen and a matching placebo. Final evaluation 18 mo after randomization revealed a loss of both HBeAg and hepatitis B virus DNA with ALT normalization in 38% of patients treated with interferon-alpha alone and in 10% of patients receiving combination therapy. The higher response rate observed in patients treated with interferon-alpha alone was maintained after stratification for basal ALT levels (i.e., higher [45% vs. 10%] or lower [31% vs. 9%] than three times the upper normal value). The length of time to sustained HBeAg clearance was significantly (p < 0.05) shorter in patients receiving monotherapy than in patients receiving combination therapy. Blinded histological assessment revealed improvement in 44% of patients treated with interferon-alpha alone compared with improvement in 6% of patients receiving combination therapy. These results indicate that levamisole has no additive effects when combined with interferon-alpha in the treatment of HBeAg-positive chronic hepatitis.

Interferon treatment of anti-HBe positive and HBV DNA positive chronic hepatitis B.

The efficacy of human lymphoblastoid interferon (Wellferon) was studied in 25 patients with anti-HBe positive, HBV DNA positive chronic hepatitis B. The patients were randomized to receive 5 MU/m2, three times weekly or no treatment for 6 months. The study is ongoing and to date 19 patients have been followed up for more than 3 months and 14 for more than 6 months. At 9 months, serum HBV DNA had become negative and ALT levels normalized in 57% of interferon-treated patients. This compared with 33% becoming serum HBV DNA negative and 16% with ALT normalization in the untreated group. Clearance of HBV DNA in interferon treated patients was not consistently associated with the appearance of transaminase peaks during therapy, in contrast with those seen in HBeAg positive patients. The preliminary results of this trial suggest that interferon reduces HBV replication in anti HBe/HBV DNA positive patients with chronic hepatitis B.

Long-term follow-up of anti-HBe-positive chronic active hepatitis B.

Twenty-eight patients with chronic active hepatitis without cirrhosis who were positive for hepatitis B surface antigen and antibody to hepatitis B e antigen were followed for 1 to 15 years (mean 6.6 years) and underwent follow-up biopsy. At presentation, 12 of the 28 patients (43%) had hepatitis B virus DNA in serum, 10 (36%) had serologic evidence of hepatitis delta virus infection and 6 (21%) had no serologic markers of either hepatitis B virus replication or hepatitis delta virus infection. During follow-up, 15 (54%) patients developed active cirrhosis, including eight patients with hepatitis delta virus infection and five with hepatitis B virus DNA in serum. In seven (47%) of the 15 patients, cirrhosis developed within the first 2 years; all seven patients had bridging necrosis in the first liver biopsy, and five of these were infected with hepatitis delta virus. The remaining 13 (46%) patients did not develop cirrhosis during follow-up and showed either unchanged features of chronic active hepatitis (seven cases) or histologic improvement to chronic persistent hepatitis (five cases) or to normal liver (one case). In conclusion, the prognosis of anti-HBe-positive patients with chronic hepatitis B is poor, as 54% of the cases developed cirrhosis during a mean histologic follow-up period of 4.5 years, mainly in association with hepatitis delta virus infection or continuing hepatitis B virus replication.

Hepatitis C virus infection in chronic hepatitis B virus carriers.

One hundred eighty-four patients with hepatitis B surface antigen-positive chronic hepatitis were evaluated for antibodies to hepatitis C virus (anti-HCV). Only 11 (8%) of 136 patients with hepatitis B virus (HBV) replication (HBV-DNA-positive in serum) while 7 (35%) of 20 positive for antibody to hepatitis B e antigen (anti-HBe) but HBV-DNA-negative were positive for anti-HCV. By contrast, anti-HCV was never found in 30 anti-HBe-positive "healthy" carriers. Anti-HCV was more frequent in hepatitis D virus (HDV)-positive than in HDV-negative cases (32% vs. 12%). During 1-11 years of follow-up, anti-HCV persisted in 90% of cases, who showed continuing alanine aminotransferase elevation. Liver histology deteriorated in 2 of 4 anti-HCV-positive, anti-HBe-positive, HBV-DNA-negative patients. These results demonstrate the existence of a subgroup of patients with anti-HBe-positive, HBV-DNA-negative, HDV-negative chronic hepatitis B, where HCV may play a leading role in causing liver disease.

Natural history and prognostic factors for chronic hepatitis type B.

One hundred and five hepatitis B surface antigen (HBsAg) positive patients presenting with chronic persistent hepatitis (n = 46) or chronic active hepatitis without cirrhosis (n = 59) were followed longitudinally for one to 16 years (mean 5.5 years) and underwent follow up biopsy. During a mean histological follow up of 3.7 years, active cirrhosis developed in 21 (20%) patients one to 13 years after entry to the study with a calculated annual incidence of 5.9%. The probability of evolution to cirrhosis was significantly higher in patients with chronic active hepatitis and bridging hepatic necrosis than in those with moderate chronic active hepatitis or chronic persistent hepatitis (p less than 0.0001). Cox multiple regression analysis showed that the following three variables independently implied poor prognosis: older age, presence of bridging hepatic necrosis, and persistence of hepatitis B virus DNA in serum (p less than 0.0001). These findings indicate that patients with severe chronic active hepatitis and persistent hepatitis B virus replication are at very high risk of rapid progression to cirrhosis.

Autoantibodies during alpha-interferon therapy for chronic hepatitis B.

The development of autoantibodies and autoimmune reactions has been reported during and after interferon (IFN) therapy. Thirteen different antibodies from the sera of 32 patients with chronic hepatitis B treated with alpha-interferon (alpha-IFN) were tested. Seventeen HBeAg-positive patients received 4.5 megaunits (MU) of recombinant IFN thrice weekly for 4 months, and 15 anti-HBe and HBV-DNA positive patients were treated with 5 MU/m2 of lymphoblastoid IFN thrice weekly for 6 months. Five patients (15%) had antinuclear antibodies (ANA) and one patient (3%) had smooth muscle antibodies before treatment. ANA appeared during IFN treatment in five (18%) of 28 previously negative patients. With discontinuation of treatment, the titer of ANA fell to undetectable levels in all patients. In contrast, none of the patients developed antibodies to endocrine organs, such as thyroid microsomal, thyroglobulin, parietal cells, pancreatic islet cell, and adrenal cortex antibodies or autoantibodies specifically associated with autoimmune liver disease such as liver kidney microsomal antibodies and antimitochondrial antibodies. There was no correlation between autoantibody positivity before therapy or autoantibody occurrence during treatment and response to IFN therapy. None of the patients developed clinical signs of autoimmune disease. These results indicate that these regimens of recombinant and lymphoblastoid IFN therapy of chronic hepatitis B are associated with a low risk of clinically significant autoimmunity.

Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B.

Seventy consecutive HBsAg- and HBeAg-positive patients with biopsy-proven chronic hepatitis were followed prospectively with serial determinations of SGPT levels and hepatitis B virus serum markers including HBsAg, HBeAg, anti-HBe and hepatitis B virus DNA. During a period of 1 to 11 years (mean +/- S.D.: 5.0 +/- 2.3 years), 28 patients remained persistently HBeAg positive, most with continuing biochemical and histologic activity, while 41 cases seroconverted to anti-HBe. One patient became HBeAg and anti-HBe negative. After seroconversion, 87.8% of the cases showed sustained normalization of SGPT, and clearance of hepatitis B virus DNA from serum and histologic improvement was documented in 79% of the cases who had a control liver biopsy, while 15.8% developed cirrhosis. In two patients (4.9%), the disease remained active despite seroconversion, and both cases had evidence of continuing hepatitis B virus replication. Finally, reactivation of liver damage and of hepatitis B virus replication was observed in three additional patients (7.3%) who had transiently normalized SGPT after seroconversion. All 70 patients were analyzed for hepatitis delta virus markers, and only two persistently HBeAg-positive cases were found positive for antibody to hepatitis delta virus in serum, one also having hepatitis delta antigen in the liver. These findings indicate that, in chronic hepatitis type B, termination of virus replication is associated in most patients with biochemical and histologic regression of inflammatory activity. After anti-HBe seroconversion has occurred, virus replication and liver disease may persist or reactivate in a small proportion of patients thus giving origin to the well-recognized group of anti-HBe positive, hepatitis B virus DNA-positive chronic hepatitis type B.

Serum HBV-DNA in anti-HBe positive patients detected by filter and liquid phase hybridization assays.

Serum HBV-DNA is considered the best parameter for monitoring HBV replication in the liver. The filter hybridization assay (spot test) with 32P-labelled HBV-DNA has been the technique more frequently used to date. A simple solution hybridization assay, in which 125I HBV-DNA is used as labelled probe, has been recently standardized. We have compared the performances of these two assays for the detection of HBV-DNA. The results were similar with the two methods: an agreement was found in 39/44 (89%) samples. Three sera were positive only by the spot assay-and two only by the liquid phase assay. However, in these cases, HBV-DNA levels were near the sensitivity limits of the assay. Therefore, the filter and the liquid phase assays can be considered to be suitable methods to monitor HBV replication, a fundamental index for the clinical assessment and prognosis of patients with HBsAg positive chronic hepatitis.

Long-term effect of low dose recombinant interferon therapy in patients with chronic hepatitis B.

Thirty three heterosexual chronic hepatitis B virus (HBV) carriers were randomized, with stratification for disease activity, to receive intramuscular recombinant interferon alpha-2a (r-IFN) at doses of 4.5 megaunits thrice weekly for 4 months, or no treatment. During r-IFN treatment, serum HBV-DNA levels fell in all, but 2 patients. Final evaluation at 16 months after randomization revealed that the rate of complete response, i.e., loss of both HBV-DNA and HBeAg with ALT normalization was 22.2% (2 of 9 cases) in patients on interferon and 12.5% (1 of 8 cases) in untreated patients for the group with high serum alanine aminotransferase (ALT) and with piecemeal necrosis on liver biopsy on entry. The corresponding value was 25% (2 of 8 cases) in treated and 12.5% (1 of 8 cases) in untreated patients with low liver disease activity. Overall, a complete response was thus observed in 23.5% of treated patients and in 12.5% of controls. None of the patients on therapy became HBsAg negative. It is concluded that treatment of heterosexual patients with chronic hepatitis B with r-IFN in the dose regimen used here was not associated with a significant higher rate of serologic and clinical response compared to controls, independently of pretreatment biochemical and histologic activity of liver disease.

A randomized controlled trial of lymphoblastoid interferon-alpha in patients with chronic hepatitis B lacking HBeAg.

Ongoing hepatitis B virus replication in the presence of antibody to HBeAg can be observed in patients with active liver disease. These forms of chronic hepatitis B have been described as having a poor prognosis. We have conducted a randomized controlled trial to assess the efficacy of lymphoblastoid interferon-alpha in 60 patients with antibody to HBeAg and hepatitis B virus DNA-positive chronic hepatitis. Patients received 5 million U/m2 interferon three times a week for 6 mo, or no treatment. Final evaluation 18 mo after randomization showed hepatitis B virus DNA negativity and ALT normalization in 53% of treated patients and in 17% of controls (p less than 0.01). The probability of sustained hepatitis B virus DNA loss was significantly higher in treated patients than in controls (p less than 0.005). Blinded histological assessment revealed improvement in 50% of treated patients compared with 33% of controls. Pretreatment hepatitis B virus DNA and aminotransferase levels and histological appearance were not predictive of response. The results of this trial indicated that marked reduction of viral replication in serum and remission of liver damage can be obtained with lymphoblastoid interferon in about 50% of patients with HBeAg antibody- and HBV DNA-positive chronic hepatitis. This rate of response is higher than that reported previously.