Efectos colaterales de antibacilares en pacientes con enfermedad de Hansen / No disponible

Introducción: La Organización Mundial de la Salud (OMS) recomendó el uso de la poliquimioterapia (PQT) desde 1981, y desde 1998 esta pauta de tratamiento fue introducida en Paraguay. Desde ese entonces y hasta la actualidad el esquema Multibacilar (MB) comprende tres drogas: rifampicina, clofazimina y dapsona, y, el esquema Paucibacilar (PB), dos drogas: rifampicina y dapsona. Todas ellas relacionadas en mayor o menor medida a efectos colaterales. A pesar de ello, hay pocos estudios a nivel mundial, y ningún estudio en el Paraguay. Métodos: Estudio retrospectivo, observacional, de corte transversal con componente analítico, llevado a cabo en la Cátedra de Dermatología del Hospital de Clínicas - Universidad Nacional de Asunción, en San Lorenzo, Paraguay. En el periodo de enero de 2013 a octubre de 2017. Resultados: Fueron incluidos en el estudio 58 pacientes con enfermedad de Hansen, de los cuales 45 (78%) presentaron al menos un efecto colateral a la PQT, 3 pacientes presentaron más de un efecto colateral. De los 45, 25 (56%) fueron del sexo masculino y 20 (44%) del sexo femenino. En cuanto a la distribución por rango de edad: Dos (4%) en menores de 18 años, 8 (18%) de 19 a 30 años, 27 (18%) de 31 a 59 años y 8 (18%) 60 y más años. Seis (3%) pacientes de procedencia rural y 39 (87%) de procedencia urbana. Cuarenta y siete (98%) casos de efectos colaterales hematológicos (Anemia: 45; leucopenia: 1 y trombocitopenia: 1) y 1 (2%) caso de efecto colateral gastrointestinal (hepatitis). La conducta en casos de anemia: suplementación con hierro y ácido fólico: 40, suspensión de dapsona: 10 y ninguna conducta: 6 suspensión de la dapsona en 1 caso de leucopenia, suspensión de la dapsona en 1 caso de trombocitopenia y suspensión de la rifampicina en 1 caso de hepatitis. En 26 (58%) pacientes los efectos colaterales se presentaron al mes del inicio de la PQT, en 15 (33%) pacientes entre 2 y 5 meses del inicio y en 4 (9%) pacientes a los 6 y más meses del inicio. En 14 (31%) de los pacientes con efectos colaterales existía comorbilidad y en 31 (69%) casos, eran pacientes sanos. De los 45 pacientes, 41 (91%) estaban en tratamiento MB, 4 (9%) en tratamiento PB. Conclusión: La mayoría de los pacientes incluidos en el estudio presentaron efectos colaterales. Los hombres fueron los más afectados, el rango etario en el cual se presentaron con mayor frecuencia fue entre los 31 y 59 años. La mayoría procedían del medio urbano. Los efectos colaterales más frecuentes fueron los hematológicos y, de entre ellos, la anemia. Ante tal situación la medida más frecuentemente adoptada fue la suplementación con hierro y ácido fólico. En la mayoría de los casos los efectos colaterales aparecieron en el primer mes de recibir la medicación. Aquellos pacientes que recibieron PQT MB presentaron la mayor frecuencia de efectos colaterales

Introduction: The World Health Organization (WHO) recommends the implementation of multidrug (MDT) since 1981, and this régimen was introduced in Paraguay in 1998. The MDT administrate three drugs: rifampicin, clofazimine and dapsone to multibacillary patients (MB) and only two: rifampicina and dapsone to paucibacillary patients (PB). All the drugs have some adverse effects. But very few statistics have been carried out in the world on this matter and none at all in Paraguay. Methods: The work is a retrospective, observational, cross-sectional and analytical study carried out at Catedra de Dermatología del Hospital de Clínicas-Universidad Nacional de Asunción, San Lorenzo, Paraguay between January 2013 and October 2017. Results: Fifty eight leprosy patients were registered in the study and 45 (78%) presented at least one adverse effect to the MDT and 3 patients presented more tan one. 25/45 were men and 20 (44%) women. The age distributions were: Two (4%) less than 18 years old, 8 (18%) between 19-30 years old, 27(18%) 31-59 years old and 8 (18%) 60 and older. Six (3%) lived in rural setting and 39 (87%) urban. Forty seven (98%) presented adverse hematological effects (anemia: 45, leucopenia: 1 and thrombocytopenia:1) and 1 (2%) presented a gastrointestinal effect. Forty patients with anemia received iron and folic acid supplements and 6 cases with no modifications. There was 1 case leucopenia, 1 thrombocytopenia, and 1 hepatitis due to rifampicine. In 26 patients (58%) adverse effects were detected during first month of MDT, in 15 (33%) between 2-5 of treatment and in 4 (9%) patients after 6 or more months of treatment. Fourteen (31%) patients had comorbility and 31 (69%) were healthy patients. Forty one (91%) patients were receiving MB MDT and 4 (9%) PB MDT. Conclusions: The mayority of the patients in the study presented adverse effects. Men were the most affected and the mayority were in the 31-59 years age group and from urban settings. Most of the effects were hematological and among them, anemia the most frequent. These cases were supplemented with iron and folic acid. Most adverse effects appeared during the first month of treatment and MB MDT group was the most affected

Incorporation of amphotericin B in tuftsin-bearing liposomes showed enhanced efficacy against systemic cryptococcosis in leucopenic mice.

OBJECTIVES: The role of the immunomodulator tuftsin in enhancing the antifungal activity of liposomal amphotericin B against Cryptococcus neoformans in leucopenic mice was assessed. METHODS: In the present study, we investigated the antifungal activity of amphotericin B liposomes with tuftsin grafted on the surface. Mice were treated with free amphotericin B as well as liposomal formulations after C. neoformans infection. For prophylactic studies, mice were pre-treated with liposomal tuftsin (50 microg/mL) for three consecutive days prior to C. neoformans infection (7 x 10(5) cfu/mouse). Chemotherapy, with tuftsin-free and tuftsin-bearing amphotericin B liposomes, was started 24 h post C. neoformans infection. The role of tuftsin in immunoaugmentative therapy was assessed by survival and cfu of treated mice. RESULTS: Amphotericin B entrapped in tuftsin-bearing liposomes showed increased anticryptococcal activity in the murine model. Moreover, tuftsin pre-treatment further augmented the antifungal activity of liposomal amphotericin B in leucopenic mice. Incorporation of tuftsin in liposomes resulted in increased anticryptococcal activity of liposomal amphotericin B compared with amphotericin B deoxycholate and conventional liposomal amphotericin B formulations. CONCLUSIONS: The enhanced anticryptococcal activity of amphotericin B in tuftsin-liposomes can be attributed to the immune-stimulating property of tuftsin. Tuftsin activates the key immune cells, due to the presence of its receptors on macrophages and neutrophils, for a better fight against pathogens. Simultaneous liposome-mediated delivery of amphotericin B to the site of infection kills the pathogens more effectively.

Prophylactic role of immunomodulators in treatment of systemic candidiasis in leukopenic mice.

In the present study, we have evaluated prophylactic role of various immunomodulators viz. lipopolysachharide, protein A and tuftsin to impart protection against experimental candidiasis in leukopenic mice. Both free as well as liposomised form of nystatin was not effective enough in offering complete cure against less susceptible isolate of Candida albicans (JNMCR) infection in immunodebilitant mice. Interestingly, the pretreatment of leukopenic mice with immunomodulators before challenging them with C. albicans increased therapeutic efficacy of the nystatin against systemic candidiasis. Efficacy of the treatment was evaluated on the basis of survival of the animals as well as fungal load in systemic circulation and various organs viz. liver, kidney, spleen and lungs of the treated animals.

Leucopenia como efecto secundario de la paroxetine / Leukopenia as side effect of paroxetine

No disponible

Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area.

Chemotherapy doses are sometimes reduced because of obesity in patients. This study examines the effect of parameters reflecting the body size, body weight and height, body mass index (BMI), and body surface area (BSA) on the depth of the blood leukocyte nadir in breast cancer patients receiving adjuvant chemotherapy, when drug dosing was based on the BSA. Three hundred and forty patients with node positive breast cancer without distant metastases were treated with 6 cycles of adjuvant postoperative CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and 5-fluorouracil 600 mg/m2 i.v. every 3 weeks). Patients within the highest BMI had the highest leukocyte nadir values (Spearman correlation coefficient 0.3, p < 0.001). A high body weight and a large BSA were also associated with high leukocyte nadirs. We conclude that when the blood leukocyte nadir is used as a surrogate marker for the drug effect, obese patients receiving intravenous CMF have higher leukocyte nadirs than the lean ones. Therefore, the drug doses should not be reduced because of obesity, and even when obese patients are treated according to the scheduled doses they may remain slightly underdosed.

In vivo activity and pharmacokinetics of ziracin (SCH27899), a new long-acting everninomicin antibiotic, in a murine model of penicillin-susceptible or penicillin-resistant pneumococcal pneumonia.

The effectiveness of ziracin (SCH27899), a novel everninomicin, was at first investigated against lethal pneumonia caused by a penicillin-susceptible Streptococcus pneumoniae strain. A single intravenous injection of ziracin at a dose of 60 mg/kg of body weight given at 18 h postinfection protected 100% mice and led to the complete clearance of bacteria from their lungs. The activity of ziracin was observed to be the same as that of ceftriaxone: the 50% protective doses (PD(50)s) of ziracin and ceftriaxone were 24.8 and 24.6 mg/kg, respectively. Evaluation of this therapy with leukopenic mice showed that a single injection of ziracin protected 75% of these mice. A delay in therapy with ziracin, which was initiated at 48 h postinfection with 30 mg/kg given once daily for 3 days, resulted in an 83% survival rate of immunocompetent mice. The efficacy of ziracin was further compared to that of vancomycin against lethal pneumonia caused by a penicillin-resistant S. pneumoniae strain in leukopenic mice. The PD(50)s of ziracin and vancomycin were 40.5 and 44.2 mg/kg, respectively. Treatment with ziracin at 30 mg/kg once daily for 2 days (initiated 18 h postinfection) yielded an 83% survival rate and achieved complete eradication of the bacteria. The results were the same as those obtained with vancomycin administered at 15 mg/kg twice daily for 2 days. It is notable that the high survival rates for mice treated with ziracin were associated with effective eradication of the bacteria and rapid recovery of pulmonary tissues from pneumonia. The pharmacokinetic properties of ziracin, ceftriaxone, and vancomycin were estimated following intravenous administration of a single dose of 30 mg/kg to immunocompetent mice. The half-life of ziracin was observed to be longer than those of ceftriaxone and vancomycin (2.3 h versus 1.0 and 0.36 h in the bloodstream and 3 h versus 1.9 and 0. 45 h in lung tissues). The areas under the concentration-time curves (AUCs) in lung tissue for ziracin versus those for ceftriaxone and vancomycin were 36 microg. h/g versus 20 and 9.5 microg. h/g. The prolonged half-life and high AUC for ziracin in tissue contributed to its excellent in vivo activities.

Nitric oxide synthase inhibition by L-NAME in leukocytopenic patients with severe septic shock.

OBJECTIVES: To investigate the effects of nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester (L-NAME) on hemodynamics and outcome in leukocytopenic (< 1000/microliter) patients with severe septic shock requiring strong vasopressor support. DESIGN: Prospective clinical study. SETTING: Medical intensive care unit. PATIENTS: 10 patients with hematologic malignancies in chemotherapy-induced leukocytopenia with severe septic shock and high-dose vasopressor requirement. INTERVENTION: Continuous intravenous infusion of L-NAME (0.3 mg/ kg per hour) for a study period of 24 h with prolongation for up to 96 h according to individual requirements. MEASUREMENTS AND RESULTS: Compared to baseline values, an increase in mean arterial pressure (p = 0.0021), systemic vascular resistance (p = 0.0001), and left ventricular stroke work index (p = 0.023) with a concomitant decrease in vasopressor requirement (p < 0.05) was observed during the first 24 h of L-NAME treatment. Cardiac output data were unchanged during the study period (p = 0.49). L-NAME was tapered off in five patients who again became responsive to vasopressor medication. Two patients survived the episode of septic shock and vasoactive medication was stopped. CONCLUSIONS: The data demonstrate that inhibition of nitric oxide synthase may be beneficial for the treatment of severe septic shock in leukocytopenic patients as indicated by an increase in systemic vascular resistance, mean arterial pressure, and left ventricular stroke work index.

The Spanish experience with high-dose infusional 5-fluorouracil (5-FU) in colorectal cancer. The Spanish Cooperative Group For Gastrointestinal Tumor Therapy (TTD).

Background In a previous phase I to II trial, we have shown that the maximum tolerable dose (MTD) of 5-Fluorouracil (5-FU) in 48-hour continuous infusion (CI) weekly was 3.5 gr/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained and the median survival reached was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with Leucovorin. On this basis we tried to modulate high-dose 5-FU (3 gr/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned. Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. Overall response rate was 37.5% (95% CI, 28% to 46.8%). Median time to progression has been 7.4 months, and median survival 14.4 months. WHO grade 3 diarrhea was seen in 27 patients (24.5%). Grade 3 mucositis was also seen in 9 (8.1%) patients, and grade 4 was observed in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients. Grade 3 hand-foot syndrome was detected in only 5 (4.5%) patients. Grade 4 leukopenia was observed in 1 case and grade 3 to 4 thrombocytopenia was observed in two cases, respectively. Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as main limiting toxicities. Its antitumor activity does not seem superior to that obtained with a weekly 48 hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.

Protective effects of sparfloxacin in experimental pneumonia caused by Chlamydia pneumoniae in leukopenic mice.

The in vivo antichlamydial activities of sparfloxacin and reference drugs were examined in a experimental model of pneumonia caused by Chlamydia pneumoniae in leukopenic mice; their in vitro activities were also examined. The most potent agents in vitro were sparfloxacin (MICs for C. pneumoniae Kajaani and IOL 207, (0.031 and 0.031 micrograms/ml, respectively), clarithromycin (0.031 and 0.031 micrograms/ml, respectively), and minocycline (0.031 and 0.031 micrograms/ml, respectively); these were followed by tosufloxacin (0.063 and 0.125 micrograms/ml, respectively) and ofloxacin (0.5 and 0.5 micrograms/ml, respectively). The MBCs of sparfloxacin, tosufloxacin, ofloxacin, clarithromycin, and minocycline for these two strains were 0.063 and 0.063 micrograms/ml, 0.125 and 0.25 micrograms/ml, 1.0 and 1.0 micrograms/ml, 0.125 and 0.125 micrograms/ml, and 0.25 and 0.25 micrograms/ml, respectively. Fatal pneumonia was induced by intranasal inoculation of cyclophosphamide-treated leukopenic mice with C. pneumoniae IOL 207; infiltration of neutrophils and lymphocytes was observed in the lungs of these mice by histopathological examination. The 50% effective dose of sparfloxacin (oral dose of 0.97 mg/kg of body weight) against the pneumonia was the lowest among the drugs tested; this was followed by those of minocycline (2.22 mg/kg), tosufloxacin (3.47 mg/kg), clarithromycin (4.66 mg/kg), and ofloxacin (16.6 mg/kg). The results indicate that it may be worthwhile to use sparfloxacin against C. pneumoniae infections in humans.

Efficacies of amphotericin B-desoxycholate (Fungizone), liposomal amphotericin B (AmBisome) and fluconazole in the treatment of systemic candidosis in immunocompetent and leucopenic mice.

The in-vitro activities of amphotericin B-desoxycholate (AmB-DOC), liposomal amphotericin B (L-AmB) and fluconazole were determined against a single strain of Candida albicans. In addition, the efficacies of these agents in the treatment of systematic candidosis in both immunocompetent and leucopenic mice were compared. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of AmB-DOC and L-AmB were similar, but on the basis of time-kill studies, the fungicidal activity of L-AmB was significantly less than that of AmB-DOC. In immunocompetent mice, the dosage of AmB-DOC was limited by toxicity, resulting in a maximum tolerated dosage (MTD) of 0.4 mg/kg/day during treatment for 5 days; L-AMB was less toxic, the MTD being 7 mg/kg/day following a treatment period of the same duration. Both AmB-DOC and L-AmB led to significant reductions in the numbers of C. albicans in the kidneys of these mice and prevented relapse of infection after completion of treatment. Fluconazole in dosages of 0.4 and 64 mg/kg/day resulted in initial reductions in the numbers of cfu but failed to prevent relapse. In leucopenic mice, treatment for 5 days with AmB-DOC in a dosage of 0.3 mg/kg/day resulted in survival of the animals and a significant reduction in the numbers of cfu in the liver, spleen and lungs. However, there was no reduction in the number of cfu in the kidneys and this led to relapse of infection once therapy was terminated. Fluconazole in a dosage of 64 mg/kg/day produced effects which were similar to those of AmB-DOC; prolonged treatment with fluconazole for 18 days did not improve the efficacy of this agent. Only treatment with high-dosage (7 mg/kg/day) L-AmB was effective in significantly reducing the numbers of cfu of C. albicans in the kidneys and other organs of leucopenic mice, as well as preventing relapse, even in severely infected animals.

Granulocyte colony-stimulating factor (G-CSF) with or without a quinolone in the prevention of infection in cancer patients.

59 patients who had earlier developed an infection following antineoplastic chemotherapy were randomised to receive either granulocyte colony-stimulating factor (G-CSF) alone or G-CSF+quinolone as prophylaxis during subsequent identical chemotherapy courses. 30 patients received 48 courses of G+CSF, while 29 patients received 44 courses of G-CSF+ofloxacin or ciprofloxacin. The overall infection rate was 23%. Patients with WHO grade IV leukopenia at the onset of prophylactic treatment developed infection in 61% of cases when on G-CSF, but only in 22% when on G-CSF+quinolone (P = 0.002). Patients with initial leukopenia of grade WHO III-I had only a 11% infection rate showing no significant difference between the treatment groups. The median duration of leukopenia < 1 x 10(9)/l was 4 days for patients receiving G-CSF alone and 3.5 days for those receiving additional quinolone. Patients developing infection had grade IV leukopenia for a median of 5 days. Both prophylactic treatments were well tolerated. We conclude that when prophylactic G-CSF is initiated at WHO grade IV leukopenia, addition of an oral quinolone reduces the risk of infection.

Protective effect of ren-shen-yang-rong-tang (Ninjin-youei-to) in mice with drug-induced leukopenia against Pseudomonas aeruginosa infection.

When 200 mg/kg of cyclophosphamide (CY) or 5-fluorouracil (5-FU) were given subcutaneously to mice, severe reduction of leukocyte numbers in the peripheral blood was observed on day 4 and from day 4 to day 8 after the treatment, respectively. Daily administration of ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NYT), (1 g/kg/day) and recombinant human granulocyte-colony stimulating factor (rhuG-CSF, 2 micrograms/mouse/day) either from day 0 to day 4 after treatment with CY or from day 0 to day 8 after treatment with 5-FU accelerated the recovery of peripheral leukocytes. Administration of NYT and rhuG-CSF inhibited decreases in the number of colony forming units in the spleen (CFU-S) in drug-treated mice. In mice infected intraperitoneally with a virulent strain of Pseudomonas aeruginosa 4 days and 8 days after treatment with CY and 5-FU, respectively, lethal doses were much lower (approximately 1/1000) than that in normal mice. Administration of NYT and rhuG-CSF to drug-treated mice inhibited the enhanced bacterial growth in the peritoneal cavity. Administration of NYT or rhuG-CSF to drug-treated mice enhanced the recovery of accumulation of leukocytes into the infected peritoneal cavity from their depressed state. Administration of NYT was more effective for improving the host resistance of 5-FU-treated mice than for improving that of CY-treated mice in contrast to rhuG-CSF which exhibited stronger effect in CY-treated mice than in 5-FU treated mice.

Impact of the duration of infection on the activity of ceftazidime, gentamicin and ciprofloxacin in Klebsiella pneumoniae pneumonia and septicemia in leukopenic rats.

An experimental Klebsiella pneumoniae pneumonia and septicemia in leukopenic rats was used to study the impact of the duration of infection on the bactericidal activity of ceftazidime, gentamicin and ciprofloxacin. It appeared that the number of bacteria persisting after a single intravenous injection progressively increased with delay of antibiotic administration up to 3 h after bacterial inoculation with each of the drugs tested. This effect was most pronounced for ciprofloxacin. An inoculum effect could not explain this decrease in bacterial killing. It was also observed that a single injection with a particular dose of each of the respective drugs did not kill all the Klebsiella pneumoniae organisms in the lung. Persisting bacteria did not represent a preexisting less susceptible subpopulation selected after antibiotic administration. In further experiments the impact of delay of the start of treatment on the efficacy of ceftazidime or ciprofloxacin after administration for a period of four days with intramuscular injections at 6 h intervals was investigated. Treatment was started at 5, 12 or 24 h after bacterial inoculation. The therapeutic efficacy of both drugs decreased with the increase of duration of infection, which may be at least in part due to the progressive number of bacteria persisting after antibiotic administration. These data underline the need to start antimicrobial treatment as soon as possible.

Comparative therapy with cefpirome alone and in combination with rifampin and/or gentamicin against a disseminated Pseudomonas aeruginosa infection in leukopenic mice.

Treatment of disseminated Pseudomonas aeruginosa infection in leukopenic mice was evaluated using cefpirome alone and in combination with gentamicin and/or rifampin. Mice were made leukopenic with cyclophosphamide and infected through a skin incision with an inoculum of 1250 organisms (13 LD50). Antibiotics were administered subcutaneously for 48 h. Although the addition of cefpirome to gentamicin and/or rifampin improved survival significantly at 48 h compared with untreated controls (84.6%-100% vs. 38.5%), therapy with these combinations did not improve survival significantly from that achieved with cefpirome alone. Quantitative blood and tissue (liver, spleen, kidney, lung) cultures in mice treated with cefpirome alone or including rifampin were lower than in infected controls or groups receiving therapy that excluded cefpirome. Highest counts were observed in mice receiving cefpirome plus gentamicin. Except for the cefpirome plus gentamicin group, which demonstrated areas of acute tubular necrosis, the cefpirome group had less tissue pathology than infected controls.

In vitro and in vivo activities of Sch 39304, fluconazole, and amphotericin B against Histoplasma capsulatum.

The antifungal activities of amphotericin B and two triazoles, Sch 39304 and fluconazole, were tested against Histoplasma capsulatum. In this study Sch 39304 compared favorably with amphotericin B in treating histoplasmosis in normal and leukopenic mice, whereas fluconazole was much less active. The differences in the efficacies of the triazoles appeared to be due to differences in their pharmacokinetics and the dosage schedule that was used. For amphotericin B there was a good correlation between in vitro and in vivo efficacy, but this was not true of the triazole derivatives. These results further demonstrate that, with the methods used in this study, in vitro susceptibility testing of triazoles may not be predictive of in vivo activity against isolates of H. capsulatum.

Cartilage proteoglycan depletion in acute and chronic antigen-induced arthritis.

We examined the kinetics of proteoglycan (PG) depletion in rabbits with antigen-induced arthritis. There was a rapid loss of PG from arthritic cartilage, reaching 35-40% at day 7. Thereafter, the rate of PG depletion declined, and by day 42, the maximum loss was 55-60%. The initial loss of PG was accompanied by the appearance of large amounts of sulfated glycosaminoglycans (GAGs) in the joint fluid (measured as total sulfated GAGs by dye binding and as keratan sulfate by radioimmunoassay). However, by day 14, the levels of sulfated GAGs in arthritic joint fluid declined to control levels, even though the cartilage demonstrated a sustained depletion of PG. The cartilage PG degradation observed in antigen-induced arthritis could also be produced in normal animals by a single intraarticular injection of recombinant interleukin-1. The acute loss of cartilage PG occurred independently of neutrophil accumulation, both in the case of antigen-induced arthritis and after injection of interleukin-1.

Continuous versus intermittent administration of ceftazidime in experimental Klebsiella pneumoniae pneumonia in normal and leukopenic rats.

Experimental Klebsiella pneumoniae pneumonia was used to study the influence of cyclophosphamide-induced leukopenia on the relative therapeutic efficacy of continuous and intermittent (6-h intervals) administration of ceftazidime. The antimicrobial response was evaluated with respect to the calculated daily dose that protected 50% of the animals from death (PD50) until 16 days after the termination of a 4-day treatment. When ceftazidime was administered intermittently to leukopenic rats, the PD50 was 24.37 mg/kg per day, 70 times (P less than 0.001) the PD50 of 0.35 mg/kg per day for normal rats. Continuous administration of ceftazidime to leukopenic rats resulted in a PD50 of 1.52 mg/kg per day, four times (P less than 0.001) the PD50 of 0.36 mg/kg per day for normal rats. Continuous administration of ceftazidime in daily doses that protected 100% of normal and leukopenic rats from death resulted in serum levels of 0.06 and 0.38 micrograms/ml, respectively, whereas the MIC for the infecting K. pneumoniae strain was 0.2 micrograms of ceftazidime per ml. The effect of the duration of ceftazidime treatment by continuous infusion on the therapeutic efficacy in relation to the persistence of leukopenia was then investigated in leukopenic rats. The administration of 3.75 mg of ceftazidime/kg per day for 4 days protected all leukopenic rats from death, provided the circulating leukocytes returned at the end of antibiotic treatment. When leukopenia persisted for 8 days this ceftazidime treatment schedule resulted in the mortality of rats (P less than 0.05). However, when ceftazidime treatment was continued for 8 days, until the return of the leukocytes, there was no significant mortality (P greater than 0.05).