Pharmacokinetics and tissue penetration of pefloxacin plus metronidazole after administration as surgical prophylaxis in colorectal surgery.

The levels of metronidazole and pefloxacin in plasma and tissue penetration of both drugs were studied after prophylactic administration to 7 patients undergoing colorectal surgery. Metronidazole (1,500 mg) and pefloxacin (800 mg) were administered as an intravenous infusion 1 hour before surgery. Mean plasma levels of pefloxacin decreased from 12.92 +/- 4.10 microg/ml at the end of the infusion to 2.18 +/- 1.03 microg/ml at 36 h. These values were above the MIC90 for E. coli (0.125 microg/ml) and E. faecalis (0.5 microg/ml), microorganisms responsible for abdominal infections. Tissue pefloxacin levels were also measured with a range from 0.72 - 7.78 microg/g in subcutaneous cell tissue, from 1.94 - 17.55 microg/g in peritoneum and from 2.76 - 21.99 microg/g in colon wall. Mean plasma concentrations of metronidazole decreased from 39.89 +/- 17.08 microg/ml at the end of the infusion to 2.63 +/- 1.11 microg/ml at 36 h. During this period, concentrations were higher than 2 microg/ml, the MIC90 value for B. fragilis, the anaerobic pathogen more frequently involved in postoperative infections after rectal and colonic surgery. Tissue metronidazole levels ranged from 3.64 - 13.37 microg/g in subcutaneous cell tissue, from 3.26 - 41.66 microg/g in peritoneum and from 6.72 - 43.12 microg/g in colon wall. The AUC/MIC values (efficacy parameter for concentration-dependent killing antibiotics such as pefloxacin and metronidazole) obtained were the following: metronidazole AUC/MIC value for B. fragilis was 173; pefloxacin AUC/MIC values for E. coli and E. faecalis were 941 and 235, respectively. The values of these parameters are higher than the recommended values to ensure efficacy, which means good exposure of the antimicrobials to the microorganisms. In conclusion, the combination of pefloxacin and metronidazole as prophylactic agents to prevent infections in patients undergoing colorectal surgery produce plasma and tissue levels above the MIC values of the main pathogens responsible for this kind of infections.

Pharmacokinetics and tissue distribution of intravenous pefloxacin for antibiotic prophylaxis in biliary surgery.

The plasma levels and tissue penetration of pefloxacin were studied after prophylactic administration to patients undergoing elective biliary surgery. Pefloxacin was administered as a single dose of 800 mg given intravenously as an infusion 1 h before surgery. Over a period of two years, cultures of bile and stone were performed after cholecystectomy in order to find the main pathogens present in the geographical area of the hospital of Txagorritxu (Vitoria, Spain), as well as to test the antimicrobial susceptibility of these bacteria to pefloxacin. Thirty seven per cent of the bile and stone cultures were positive, and 75 different species were isolated. E. coli was the predominant microorganism (25%). Other frequent microorganisms were E. faecium (9.3%), S. epidermidis (6.6%) and Cl. perfringens (6.6%). Most species isolated were susceptible to pefloxacin, with MIC(90) values of 0.125 microg/ml for E. coli, 0.5 microg/ml for S. epidermidis and 1 microg/ml for Cl. perfringens. E. faecium was resistant, with a MIC(90) value of 8 microg/ml but a MIC(50) of 4 microg/ml (intermediate). After pefloxacin infusion, adequate drug plasma levels (>MIC(90)) for the most frequent pathogens were found throughout the procedure. Elimination half-life was estimated as 22.03+/-6.91 h; the area under the concentration-time curve from zero to infinite had a value of 275.07+/-130.02 mg h/l and the values for volume of distribution at steady-state and plasma clearance were 96.48+/-28.65 L and 3.60+/-1.83 l/h, respectively. Bile pefloxacin concentrations generally exceeded the minimum inhibitory concentrations for most relevant pathogens. Drug levels in gallbladder and subcutaneous tissues were also above the MIC(90) for extended periods. Patients were observed daily throughout their hospital stay. This included examination of the surgical wound and recording of body temperature. No cases of anaerobic infection were noted in the study patients. Other constants such as hospitalization stay and time of recuperation were normal for this type of surgery. According to these results, pefloxacin presents many features that make it suitable for use as a therapeutic prophylactic agent, such as its broad spectrum of antimicrobial activity and favorable pharmacokinetic properties.

Pharmacokinetics of ofloxacin enantiomers after intravenous administration for antibiotic prophylaxis in biliary surgery.

The pharmacokinetics of S-(-)- and R-(+)-ofloxacin, enantiomers of the fluoroquinolone ofloxacin, were characterized after prophylactic administration in 15 patients undergoing elective biliary surgery. A single dose of ofloxacin 400 mg given intravenously as an infusion was administered 1 hour before surgery. Plasma levels of S-(-)- and R-(+)-ofloxacin showed very small differences between both enantiomers, although the ratio of S-(-)- to R-(+)-enantiomer concentration in plasma showed significant differences (p < 0.05) at 4 and 12 hours. Adequate S-(-)-ofloxacin (levofloxacin, the active enantiomer) plasma levels (> or = minimum inhibitory concentration [MIC90] for Escherichia coli) were found throughout the procedure. For pharmacokinetic parameters, the authors found small but statistically significant differences (p < 0.05) in the area under the concentration-time curve, AUC0-infinity (22.30 +/- 2.72 mg h/L for S-(-)-ofloxacin vs. 20.50 +/- 2.06 mg h/L for R-(+)-ofloxacin), and in the clearance (0.15 +/- 0.04 L/h/Kg for S-(-)-ofloxacin vs. 0.16 +/- 0.04 L/h/Kg for R-(+)-ofloxacin). To test the penetration of ofloxacin enantiomers into tissues, the authors measured levels in subcutaneous cell tissue and gall-bladder cell tissue. They did not observe statistical differences between the two isomers, which means that distribution is not an estereoselective process. Enantiomer levels in these two tissues decreased rapidly, but the highest concentrations were reached during the 4 first hours (i.e., when the surgical procedure was being performed). In conclusion, with the prophylactic treatment used, levofloxacin plasma and tissue levels are high enough to prevent surgical infections.

[Characteristics of chronic hepatitis C in patients infected by human immunodeficiency virus]. / Características de la hepatitis crónica C en pacientes infectados por el virus de la inmunodeficiencia humana.

OBJECTIVES: To know the characteristics of chronic hepatitis C in HIV-infected patients and whether there are differences compared with HIV-negative patients, in order to obtain orientative helpful data for the diagnostic-therapeutic decision making, a usually difficult issue in these patients. PATIENTS AND METHODS: Sixty patients with criteria of chronic hepatitis C virus (HCV) criteria were studied. Thirty-three of these patients were coinfected with HIV. The possible associations between the degree of histologic damage and several variables wee studied: age, estimated time of evolution of HCV infection, transaminases, gammaglobulins, GGT, and alcohol consumption. On the other hand, the possible differences regarding the histologic hepatic aggression were assessed. An attempt was made to know whether HIV could negatively influence the evolution of chronic hepatitis C. RESULTS: A direct relationship was observed between hepatic damage, HAI and levels of GOT, GPT, GGT (p < 0.005), and gammaglobulins (p < 0.01). The degree of hepatic fibrosis was directly correlated with the GGT level (mild fibrosis: 47 +/- 34 U/l; severe fibrosis: 86 +/- 60 U/l) (p < 0.05) and the estimated evolution time of infection (p < 0.05). Alcohol consumption was associated with the fibrosis degree (p < 0.01). The degree of histologic damage was similar in the HIV-positive group (HAI: 8.3 +/- 3.6) and HIV-negative patients (HAI: 7.2 +/- 2.8), although the degree of lobular involvement was higher in HIV-positive patients (p < 0.05). CONCLUSIONS: Patients with chronic hepatitis C and infected with HIV did not have a higher degree of hepatic damage than HIV-negative patients. GOT, GPT, and gamma globulin levels, as well as a longer evolution time of HCV infection were associated with a higher degree of hepatic histologic activity. Alcohol consumption seemed to be associated with a poorer course of the liver disease in these patients.

[Clinical implications of hepatitis C virus genotype in human immunodeficiency virus infected patients with chronic liver disease]. / Implicaciones clínicas del genotipo del virus de la hepatitis C en infectados por el virus de la inmunodeficiencia humana con hepatopatía crónica.

OBJECTIVE: To know the prevalence of viral genotype in patients infected with hepatitis C virus (HCV) and coinfected with HIV and evaluate its clinical implications. PATIENTS AND METHODS: The genotype of the HVC was studied (INNO-LiPA HCV II, Imnogenetics, Belgium) in 40 patients coinfected with HIV; from 28 of these patients histologic data of chronic hepatitis were available. The most prevalent genotype was analyzed in this type of patients and its associations with different issues: risk behavior, histologic activity of liver disease and viremia level (quantitative PCR, Amplicor HCV, Roche Diagnostics). RESULTS: Genotype 1 was the most prevalent (55%), and subtype 1a predominated (36.3%). In most cases genotypes 1a and 3 were found (65%) and in four cases (10%) there was coinfection with two genotypes. The most common risk behavior was parenteral drug use (PDU) (34 cases), which might account for the higher prevalence of genotypes 1 and 3. A mild hepatic histologic activity was most frequently associated with genotype 3 compared with genotype 1 (63.6% versus 46.6%). The Knodell histologic activity index (HAI) was higher in the four patients with coinfection 1 + 3 versus the remaining patients (11.2 +/- 2.8 versus 7.8 +/- 3.6). The percentage of patients with genotype 1 with a viral load > 10(5) was higher than that of patients with genotype 3 (80% versus 7.6% [4]) (p < 0.05); in the two cases with subtype 1b viremia levels exceeded this limit. CONCLUSIONS: The prevalent HCV genotypes in patients coinfected with HIV in our environment seem to be 1a and 3, which is probably associated with the more common high risk behavior of PDU among these patients. Genotype 3 seems to be associated with a milder histologic liver damage and a lower viral load, and these two characteristics might be related. The HCV genotype should be considered in subjects coinfected with HIV to obtain a better clinical and prognostic evaluation of the chronic liver disease it causes.

[Interferon treatment of chronic hepatitis C in human immunodeficiency virus infected patients]. / Tratamiento con interferón de la hepatitis crónica C en infectados por el virus de la inmunodeficiencia humana.

OBJECTIVE: To know the efficiency and tolerance of INF therapy for chronic virus C hepatitis (HCV) in HIV infected patients compared with non infected patients. PATIENTS AND METHODS: INF-alpha was administered to 39 patients with chronic hepatitis C virus infection criteria. In 17 cases (43.5%) there was coinfection with HIV. Histologic data were available from 30 patients (75%) and also of viral load during therapy (Amplicor HCV, Roche Diagnostics) from 8 patients. We determined the response at the end of the first two months of therapy (ER), at the end of therapy (FR) and after discontinuation (DR) when the transaminase level was normalized and viral RNA was not detected in cases when it was measured. The response rates to INF were compared between HIV-positive and HIV-negative patients and the secondary effects observed evaluated, as well as tolerance and severity, with a particular emphasis on the CD4 lymphocyte level among HIV-positive patients. RESULTS: An ER was obtained in nine HIV-positive patients (52.9%) and thirteen HIV-negative patients (59%); an FR in eight HIV-positive patients (47%) and eleven HIV-negative patients (50%), and DR in two HIV-positive patients (13.3%) and four HIV-negative patients (28%); although a lower rate of DR was observed among HIV-positive patients, these differences were not significant. The disappearance of HCV ARN at the end of therapy was similar for both groups of patients in whom it was measured: five HIV-positive patients (62.5%) and twelve HIV-negative patients (63.1%). We must consider that HIV-positive patients had a higher number of poor response predictors to INF. Secondary reactions were observed in a higher number of HIV-negative patients (81.8% versus 40.9%) and the level of CD4 lymphocytes was markedly reduced during and after therapy in three patients. CONCLUSION: INF therapy in chronic hepatitis C virus infection in HIV-positive patients initially has a similar efficiency to that observed in HIV-negative patients, although perhaps the maintained response rate is lower. A higher number of secondary reactions among HIV-positive patients was not observed, although possible reductions in CD4 levels must be considered among these patients. The use of INF in these patients --if properly selected--is therefore not contraindicated.

[Characteristics of the carriers of antibodies to hepatitis C virus with normal transaminases levels in HIV infected patients]. / Características de los portadores de anticuerpos frente al virus de la hepatitis C con transaminasas normales en infectados por el VIH.

BACKGROUND: To know the characteristics of the carriers of antibodies to hepatitis C virus (HCV) with persistently normal transaminases levels ("carriers") in coinfected with HIV, the incidence of the real viral activity and the factors that could determine it. PATIENTS AND METHODS: We analyzed 114 patients with criteria for chronic hepatitis C, 41 with detectable antibodies (anti-HCV), but without chemical evidence of a deteriorations of the liver function, all of them infected with HIV. In 6 patients was possible to determine the genotype of the HCV (INNO-LiPA HCV Innogenetics. Belgica) and in 32 the HCV-RNA (Amplicor HCV Roche Diagnostics). We compared the characteristics that could be differential between both groups, investigating the possible factors that could define the group of "carriers" with detectable viral activity. RESULTS: From the 32 "carriers" in which we could determine the HCV-RNA, 15 (46.8%) had a positive result. The incidence of women in the "carriers" group was higher (41.4% vs 22.8%) (p < 0.05). The serum levels of gammaglobulin (gr/dl) was higher in the chronic hepatitis group (2.23 +/- 0.6 vs 1.9 +/- 0.5) (p < 0.01); however, these levels were higher for the 15 patients RNA (-) patients (2.19 +/- 0.7 vs 1.66 +/- 0.41) (p < 0.01). The genotype distribution of HCV found in the "carriers" group with detectable viremia was: genotype 1(5 patients), subtype la (3 patients), subtype lb (2 patients) an genotype 3 (3 patients). There was no significant difference with respect to age, sex, degree of immunosuppression or the length of the infection with HCV. CONCLUSIONS: Approximately half of our "carriers" of anti-HCV without evidence of changes in the liver function, infected with HIV, show detectable viremia and so probably liver biopsy would be indicated. Women are more often "carriers" and the high levels of gammaglobulin could define the existence of a real viral activity.

[Viremia levels of the chronic hepatitis c virus in HIV infected patients, clinical implications]. / Niveles de viremia del virus de la hepatitis crónica C en infectados por el virus de inmunodeficiencia humana. Implicaciones clínicas.

BACKGROUND: To know the clinical implications of the viremia level and its evolution in time of the hepatitis C virus (HCV) in patients with chronic hepatitis and infected with the Human Immunodeficiency Virus (HIV). PATIENTS AND METHODS: We have studied the viremia level of the HCV in a a 38 patients group with active chronic hepatitis and infected with the HIV, using a quantitative PCR technic (Amplicor HCV, Roche Diagnostics); we had histological data in 33 of these patients. In 20 patients was analyzed the evolution in time of the viremia level with two or three serialized measurements (20 and 10 patients respectively), throughout 7.5 and 14.8 months on the average. We have analyzed some aspects like the risky behaviors associated with transmission, the estimated time from the contagious, the degree of histological damage and the immunitary impairment. RESULTS: We have observed a tendency to present a higher viremia level (logarithmic expression) with longer evolution time from the infection (p = 0.08). The viral load had an inverse relation with the degree of histological fibrosis (Light fibrosis: 4.5 +/- 0.8 log vs Severe fibrosis: 3.7 +/- 0.8 log) (p < 0.01) and a direct relation with the Knodell histological activity index (HAI), only with those patients with a lower fibrosis degree (p < 0.01). There was no relation between the viremia level of the HCV and the degree of immunosuppression measured by the CD4 lymphocyte count, at least in those patients in which it was higher than 200/mm3. We have not observed relations between the viral load and the age or the transaminases level. The evolution in time of the viremia tended to rise from 3.7 +/- 1.3 to 4.5 +/- 0.9 log in 14.8 months on the average, although there were some cases with tendency to decrease. We have not observed relation between its increase/month and the degree of histological damage or the CD4 lymphocyte count. CONCLUSIONS: The viral load of the HCV in HIV-infected patients seems to have an inverse relation with the degree of liver fibrosis and direct relation with the histological activity when the fibrosis light and so it could indirectly inform us about the liver aggression. The degree of immunosuppression measured by the CD4 lymphocyte count, when these are > 200/mm3, doesn't seem to influence the viremia level of the HCV. The evolution of the viral load in time tend to rise although there could be some cases with intermittent or descending evolution, without these tendencies have any clinical implications.

Pharmacokinetics and tissue distribution of intravenous ofloxacin for antibiotic prophylaxis in biliary surgery.

The plasma levels and tissue penetration of ofloxacin were studied after prophylactic administration in 17 patients undergoing elective biliary surgery. A single dose of ofloxacin 400mg given intravenously as an infusion was administered 1 hour before surgery. Adequate drug plasma levels [>/= minimum inhibitory concentration (MIC(90)) for Escherichia coli] were found throughout the procedure. Mean peak (1 hour) and last-determined (36 hours) ofloxacin serum levels were 7.97 +/- 3.79 mg/L and 0.19 +/- 0.13 mg/L, respectively. The elimination half-life (t((1/2)lambda)) was 8.86 +/- 3.07 hours, and the clearance and steady-state volume of distribution were 0.17 +/- 0.05 L/h.kg and 112.90 +/- 37.09L, respectively. The area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was 41.60 +/- 12.51 mg/L.h. In bile, ofloxacin levels were higher than in plasma and showed great variability. Adequate ofloxacin levels in subcutaneous cell tissue and gallbladder wall tissue were observed during the surgical procedure. Patients were observed daily throughout their hospital stay. This included examination of the surgical wound and recording of body temperature. No cases of anaerobic infection were noted in the study patients. Other constants such as hospitalisation stay and time of recuperation were normal for this type of surgery.

[Epidemic Kaposi's sarcoma. Apropos of 14 cases]. / Sarcoma de Kaposi epidémico. A propósito de 14 casos.

The epidemic Kaposi's sarcoma is the most common AIDS associated cancer. The lesions are located in any part of the organism. The skin affection is the most frequent. The risk group with a highest incidence is the "male homosexuals". Though the diagnosis of Kaposi's sarcoma doesn't determine "per se" the prognosis "quad vitam", there exist some analytic parameters at the time of the diagnosis that are useful for the prognosis of the HIV infection. We present 14 Kaposi's sarcoma and HIV infected cases analyzing some parameters and evaluating their prognosis and surviving hope.

Lipolytic effects of beta1, beta2 and beta3-adrenergic agonists in isolated human fat cells from omental and retroperitoneal adipose tissues.

The presence of beta1- and beta2-adrenoceptors has been clearly established in human fat cells. There is some controversy about the presence and function of beta3-adrenoceptors. It is well established that there are marked regional variations in catecholamine-induced lipolysis. In this work the possibility that a beta3-adrenoceptor plays a significant role in the control of lipid mobilization is studied and also its importance in comparison to beta1- and beta2-adrenoceptors in isolated human fat cells, is evaluated, by measuring the in vitro lipolysis induced by dobutamine, salbutamol, metaproterenol, BRL 37344 and CGP 12177A. Human adipocytes from omental and retroperitoneal fat deposits exhibited an "atypical" beta-adrenergic response but, given the small lipolytic effect initiated by BRL 37344 and CGP 12177A, they are probably poorly equipped in functional beta3-adrenoceptors.

[The study of contacts of tuberculosis patients]. / Estudio de contactos con enfermos tuberculosos.

The study and follow-up of contacts is one of the main goals of the battle against tuberculosis. We studied 640 contacts of 141 patients diagnosed of active pulmonary tuberculosis (PT) in our center between 1985 and June 1990. The average per index case (IC) was 4.5. Contacts were classified according to the IC bacteriology (positive bacilloscopy and culture: 448 cases; negative bacilloscopy and positive culture: 126 cases; and both tests negative: 66 cases). PPD was positive in 342 cases (53.4%) and the number of infected contacts was significant when IC showed positive bacilloscopy and culture (251 cases), cough (328 cases). Twelve new cases of tuberculosis (1.9%) were detected, with an average age of 29.6 years. Chemoprophylaxis was completed during one-year period by 121 contacts (43.5%). The systematic study of contacts allow us to detect new patients and infected cases, helping to break the epidemiological chain of transmission of the disease.

[Pulmonary tuberculosis: differences between patients seropositive and seronegative for the acquired immunodeficiency virus]. / Tuberculosis pulmonar: diferencias entre pacientes seropositivos y seronegativos para el virus de la inmunodeficiencia adquirida.

423 cases of pulmonary tuberculosis (PT) are described, dividing them into two major groups depending on the presence (Group 1:54 cases) or the absence (Group 2:369 cases) of infection by the Acquired Immunodeficiency Virus, in order to compare their clinical-epidemiological characteristics. 70.37% patients of Group 1 had an age between 15 and 30 years and 72.2% (39 cases) were parenterally drug addicts. In the Group 1, fever, general and digestive symptoms were predominant (p < 0.004, p < 0.01 and p, 0.00001); a miliar profile was observed in 8 cases (14.8%) and the radiology was normal in 7 cases (12.9%), with predominance of condensation semiology and cavitation in Group II (p < 0.003 and p < 0.00001). In addition, we observed extrapulmonary affection in 42.6% cases (23 patients) of Group I (p < 0.0004) and the diagnosis of tuberculosis determined the presence of AIDS in 26 cases (48.1%).

[Tuberculosis caused by Mycobacterium bovis: apropos of 2 cases]. / Tuberculosis causada por Mycobacterium bovis: a propósito de dos casos.

Infection by Mycobacterium bovis is currently a rare form of tuberculosis in developed countries, being its incidence lower than 1%. Its main mechanism of transmission is through the ingestion of contaminated milk. In this paper, two cases of tuberculosis by Mycobacterium bovis are described, one of lymphatic location by endogenous reactivation and another of pulmonary location, probably by a primary infection acquired through the inhalation route. We stress the risk of transmission of the disease through the respiratory route from infected animals and by person to person contagion.