Enfermedad de Graves en un paciente de 3 años con agranulocitosis asociada a fármacos antitiroideos: terapia ablativa con radioyodo como una alternativa eficaz / Graves’ disease in a 3 year-old patient with agranulocytosis due to anti-thyroid drugs: radioiodine ablation therapy as an effective alternative

Se presenta el caso de una niña de 3 años pluripatológica, con una enfermedad genética mitocondrial (encefalomiopatía necrosante subaguda o síndrome de Leigh), insuficiencia renal crónica estadio v por una esclerosis mesangial difusa y alteraciones del desarrollo, que fue diagnosticada de hipertiroidismo autoinmune por enfermedad de Graves-Basedow. A las 6 semanas del inicio terapéutico con neocarbimazol, la paciente presentó un cuadro de agranulocitosis severa que obligó a suspender la medicación con fármacos antitiroideos, motivo por el cual fue tratada de manera eficaz con terapia metabólica con 131I. La relevancia del artículo radica en la infrecuencia de la enfermedad de Graves en niños prepuberales (especialmente menores de 6 años), las complicaciones en el desarrollo derivadas de un posible diagnóstico tardío, la aparición de agranulocitosis como efecto adverso potencialmente grave tras el uso de antitiroideos y los pocos casos reportados de terapia ablativa con 131I a esta edad, que otorgan singularidad al caso (AU)

The case is presented of a 3 year-old girl with mitochondrial disease (subacute necrotizing encephalomyelopathy of Leigh syndrome), v-stage chronic kidney disease of a diffuse mesangial sclerosis, as well as developmental disorders, and diagnosed with hyperthyroidism Graves-Basedow disease. Six weeks after starting the treatment with neo-carbimazole, the patient reported a serious case of agranulocytosis. This led to stopping the anti-thyroid drugs, and was treated successfully with 131I ablation therapy. The relevance of the article is that Graves’ disease is uncommon in the paediatric age range (especially in children younger than 6 years old), and developing complications due to a possible late diagnosis. Agranulocytosis as a potentially serious adverse effect following the use of anti-thyroid drugs, and the few reported cases of ablation therapy with 131I at this age, makes this case unique (AU)

Clostridium difficile infection induced by pregabalin-associated agranulocytosis.

A 33-year-old man who had recently undergone surgery for cervical spondylotic myelopathy was prescribed pregabalin for neuralgia, and the dose was increased to 600 mg/day during hospitalization. However, the patient was diagnosed with a Clostridium difficile infection on day 34 after admission. A complete blood count showed agranulocytosis (neutrophil count: 105/µL). We did not observe any changes in vital signs, a relative increase in band cells, or intestinal edema. The patient's agranulocytosis resolved after withdrawing pregabalin. This is the first reported case of agranulocytosis associated with pregabalin. Periodic monitoring of the white blood cell count is therefore considered to be useful in patients receiving high-dose pregabalin therapy.

[Prophylactic efficacy of a basidiomycetes preparation AHCC against lethal Candida albicans infection in experimental granulocytopenic mice].

The prophylactic effects of a Basidiomycetes preparation, AHCC, against lethal Candida albicans infection were investigated in non treated or immunosuppressed mice. In the cyclophosphamide-or 5-fluorouracil (5-FU)-treated leukopenic mice and nontreated mice, the intraperitoneal administration of AHCC prior to C. albicans infection clearly prolonged the survival periods of the infected mice. In doxorubicin-treated mice, AHCC was less but significantly effective. On the other hand, in prednisolone-treated mice, AHCC was not effective. Oral administration of AHCC also protected the 5-FU-treated mice from lethal Candida infection, as indicated by prolongation of the survival periods and inhibition of Candida growth in the kidneys of these mice and by the increase in a number of neutrophils in their peripheral blood. These results suggested that AHCC may display a protective role against opportunistic fungal infection in leukopenic hosts.

The role of the gastrointestinal tract in hematogenous candidiasis: from the laboratory to the bedside.

The gastrointestinal (GI) tract is a frequent source of hematogenous candidiasis in humans. Animal models of GI and hematogenous candidiasis have provided insights into the nature of candidal infection of host mucosal tissue, mechanisms of fungal dissemination to body organs, and features of host response to candidal infections. Biological systems such as these that simulate human candidiasis can be used for testing novel antifungal drugs. We have focused on two murine models of candidiasis with similarities to this fungal disease in humans. The first model simulates a commensal association of Candida albicans with the GI tract of immunocompetent hosts; it has permitted studies of innate and immune cell response to long-term ( > 60 days) infection of the esophageal, gastric, and intestinal mucosa. The second model simulates candidal infection in granulocytopenic patients with invasive candidiasis that originated from sites of colonization in the gut. Both models are well suited for investigating new approaches to prevention and treatment of hematogenous candidiasis. A review of the data on the role of GI candidiasis in hematogenous candidal infections is presented.

[Chemoprophylaxis of bacterial infections in granulocytopenic patients with new quinolone: a comparison of trimethoprim-sulfamethoxazole (ST) alone with ST plus ciprofloxacin].

Fifty-three granulocytopenic patients were studied in a randomized trial comparing trimethoprim-sulfamethoxaxole (ST) alone with ST + ciprofloxacin (CPFX) for prevention of bacterial infections. Seventeen febrile episodes occurred in 24 patients receiving ST alone, and 9 febrile episodes occurred in 29 patients receiving ST + CPFX. ST + CPFX was significantly effective than ST alone (p < 0.005). Although ST alone was effective to prevent infections in moderately granulocytopenic patients, it could not prevent infections in severely granulocytopenic patients whose minimal granulocyte count was less than 250/microliters during prophylactic treatment. In contrast, ST + CPFX was effective in severely as well as in moderately granulocytopenic patients. Clinically significant adverse reactions were not observed in both regimens. These results suggest that combination with ST and CPFX is more efficacious than ST alone for the prevention of bacterial infections in granulocytopenic patients.

Comparison of ciprofloxacin, ofloxacin and pefloxacin for the prevention of the bacterial infection in neutropenic patients with haematological malignancies.

The efficacy of oral prophylaxis with ciprofloxacin, ofloxacin or pefloxacin was assessed in preventing bacterial infection in neutropenic patients with treatment being allocated randomly before beginning chemotherapy. Bacteraemia developed in six of 78 episodes (8%) treated with ciprofloxacin, in eight of 80 (10%) allocated to ofloxacin and in 12 of 77 (16%) when pefloxacin was given. However, there were no episodes involving Gram-negative bacilli among those given ciprofloxacin whereas three and seven episodes occurred in patients given ofloxacin or pefloxacin respectively (P = 0.013). With the exception of Pseudomonas aeruginosa, all potential pathogens isolated were resistant to all three fluoroquinolones. Faecal anaerobes were not affected by treatment with pefloxacin whereas their total numbers were reduced in 12 cases who had received ofloxacin and in nine cases who had been given ciprofloxacin (P = 0.002). Fourteen patients (18%) were colonized with pefloxacin resistant P. aeruginosa at the end of treatment with this agent compared with only two and five of those given ciprofloxacin or ofloxacin respectively. A similar trend was seen with other resistant Gram-negative bacilli colonizing 14%, 20% and 23% of patients for ciprofloxacin, ofloxacin and pefloxacin, respectively. Ciprofloxacin was therefore superior to the other two fluoroquinolones in preventing infections due to Gram-negative bacteria in this population of neutropenic patients.

Efficacy of unilamellar liposomal amphotericin B in treatment of pulmonary aspergillosis in persistently granulocytopenic rabbits: the potential role of bronchoalveolar D-mannitol and serum galactomannan as markers of infection.

A model of primary pulmonary aspergillosis in rabbits was developed to reproduce the persistent levels of profound granulocytopenia and the histopathologic features of bronchopneumonia, vascular invasion, and hemorrhagic infarction encountered in humans. D-mannitol was detectable in bronchoalveolar lavage fluid by gas-liquid chromatography/mass spectroscopy, and galactomannan was measurable in serum by latex agglutination immunoassay. A pharmacokinetically distinctive unilamellar vesicle formulation of liposomal amphotericin B, 5 mg/kg/day intravenously, compared with high-dose conventional desoxycholate amphotericin B, 1 mg/kg/day intravenously, was more effective in preventing nephrotoxicity, increasing survival, reducing the number of viable organisms, and decreasing tissue injury due to Aspergillus organisms. Thus, D-mannitol in lavage fluid and galactomannan in serum may be useful markers of pulmonary aspergillosis, and liposomal amphotericin B was significantly more effective and safer than desoxycholate amphotericin B for treatment of pulmonary aspergillosis in profoundly granulocytopenic rabbits.

Therapy with cefoperazone plus sulbactam against disseminated infection due to cefoperazone-resistant Pseudomonas aeruginosa and Escherichia coli in granulocytopenic mice.

Using a granulocytopenic murine model, we evaluated the efficacy of cefoperazone plus sulbactam against disseminated infection due to isolates of beta-lactamase-producing, cefoperazone-resistant (MIC, > or = 50 micrograms/ml) Escherichia coli and Pseudomonas aeruginosa. Both isolates were susceptible in vitro to cefoperazone plus sulbactam (MIC, < or = 6.3 micrograms/ml). Mice rendered granulocytopenic with cyclophosphamide were divided into three groups: group A--infected, untreated mice (controls); group B--infected, cefoperazone-treated mice (700 mg/kg of body weight); and group C--infected, cefoperazone-plus-sulbactam-treated mice (700 mg plus 350 mg). In the E. coli experiment, survival rates in groups A, B, and C were 25, 46, and 73%, respectively. In the experiment with P. aeruginosa, survival rates in groups A, B, and C were 0, 10, and 50%, respectively (P < 0.001). Highly significant differences also were noted for colony counts in the blood, liver, and spleen of group C mice versus group A or B mice in both experiments. Thus, cefoperazone plus sulbactam appears to be a promising combination for the treatment of infections due to certain cefoperazone-resistant gram-negative bacilli, including P. aeruginosa.

Chemoprophylaxis of bacterial infections in granulocytopenic patients with ciprofloxacin vs ciprofloxacin plus amoxicillin.

Ciprofloxacin was compared to ciprofloxacin plus amoxicillin as antibacterial prophylaxis in 53 evaluable patients with neutropenic episodes, because an oral penicillin may help to decrease the incidence of gram-positive infections. The two groups were randomized and evaluated in a number of febrile episodes, in days at fever/at risk, in mean interval of first febrile episode, in duration of antibiotic therapy and in causative organisms in febrile episodes. In conclusion, no significant difference was observed between the two groups in prevention of gram-positive bacteremias.

[Fungal infections in granulocytopenic and immunocompromised patients]. / Pilzinfektionen bei granulozytopenischen und immunsupprimierten Patienten.

Opportunistic fungus infections in neutropenic immunocompromised patients have strikingly increased, especially with the improvement of antibiotic treatment. Their outcome is often fatal because of the difficulties in diagnosis and treatment. Therefore a rationale of surveillance diagnostics and empiric treatment in risk patients is necessary. In these patients a continuous weekly mycotic diagnosis of mouth, throat, faeces, urine, vagina, as well as of the blood is necessary. During an aggressive neutropenia-producing chemotherapy an antimycotic prophylaxis with the aim of reducing fungal colonization in the gastrointestinal tract (sometimes in the respiratory pathways, too) should be performed. Fever of unknown origin lasting longer than 4-5 days in spite of broad spectrum antibiotic treatment and/or positive diagnostic findings must lead to treating risk patients empirically using amphotericin B 1 mg/kg/d or a combination of amphotericin B 0.3-0.5 mg/kg/d together with flucytosin (Ancotil) 150 mg/kg/d. In case of a beginning candidiasis, patients can first be treated with fluconazol (Diflucan). The dose is 400 mg/d, later on 200 mg/d. It is pointed out that, much more often than usual, in risk patients with fever, atypical pneumonia, meningoencephalitis or other organ symptoms fungal infections should be taken into consideration. The most common opportunistic fungal diseases are presented and details concerning the different antimycotic drugs are given.

Selective oral antimicrobial prophylaxis for the prevention of infection in acute leukaemia-ciprofloxacin versus co-trimoxazole plus colistin. The EORTC-Gnotobiotic Project Group.

230 leukaemic patients were entered into a randomised, prospective, multicentre trial of either ciprofloxacin (1 g/day) or co-trimoxazole (1920 mg/day) plus colistin (800 mg/day) for the prevention of infection during granulocytopenia. Bacteraemia due to resistant gram-negative rods occurred only in the co-trimoxazole-colistin group though both regimens were effective for selective gastrointestinal tract decontamination. However, there were fewer patients without any infective complications (31% vs. 18%: P = 0.02), fewer febrile days [mean (S.D.) 5.9 (1.1) vs. 8.2 (1.4): P = 0.0242], a lower proportion of infective events (0.9 (0.16) vs. 1.2 (0.18): P = 0.005) and fever occurred later (median 19 vs. 14 days: 0.025 less than P less than 0.05) in the co-trimoxazole-colistin group. The choice of prophylactic regimen therefore appears to depend upon whether or not protection against gram-negative infection is required or better systemic prophylaxis overall.

Ciprofloxacin plus vancomycin versus ceftazidime plus gentamicin in the treatment of pneumonia in granulocytopenic patients with or without venous catheters. Short communication.

58 granulocytopenic patients with confirmed bronchopneumonia were divided retrospectively into two groups for this pilot study: group 1 included neutropenic patients with venous catheters who were treated with ciprofloxacin (CIP; 200-300 mg, i.v. b.i.d.) + vancomycin (VAN; 0.5-1 g, i.v. b.i.d.), and group 2, which included patients without venous catheters treated with ceftazidime (2 g, i.v. t.i.d.) + gentamicin (1 mg/kg, i.v. t.i.d.). Pneumonia was diagnosed clinically and radiologically in all patients; 92.3% in group 1 and 46.8% in group 2 were also microbially confirmed. Mixed infections were present in most patients. 3 of 26 patients (11.5%) in group 1 and 9 of 32 (20.1%) in group 2 did not recover while 88.5% in group 1 and 71.9% in group 2 recovered. CIP + VAN seems to be more effective in treating pneumonia in neutropenic patients, with only 1 patient in the group suffering an adverse effect compared with 5 in group 2.

Beta-lactam antibiotic therapy in febrile granulocytopenic patients. A randomized trial comparing cefoperazone plus piperacillin, ceftazidime plus piperacillin, and imipenem alone.

OBJECTIVE: To compare the efficacy, toxicity, and cost-effectiveness of double beta-lactam therapy with monotherapy. DESIGN: A randomized, controlled trial. PATIENTS: Febrile, granulocytopenic patients (429). INTERVENTIONS: Patients were randomly assigned to receive iv cefoperazone (3 g every 12 hours) plus piperacillin (75 mg/kg body weight every 6 hours), ceftazidime (2 g every 8 hours) plus piperacillin (75 mg/kg every 6 hours), or imipenem alone (1.0 g or 0.5 g every 6 hours). Patients also received prophylactic vitamin K. MEASUREMENTS: Clinical improvement, eradication of the infecting organism, and toxicity in 403 evaluable patients with one or more infections. MAIN RESULTS: Cefoperazone and ceftazidime, when given in combination with piperacillin, were equally effective (response rates of 75% (104 of 138 patients) and 74% (101 of 137 patients), respectively). Monotherapy with imipenem had a response rate of 82% (111 of 136 patients) and was as effective as double beta-lactam therapy. Overall antibiotic-related toxicity was minimal, although seizures were associated with high doses of imipenem. Seizures occurred in 3 of 29 patients (10.3%) who were receiving 4 g/d of imipenem, in 3 of 136 patients (2.2%) who were receiving cefoperazone plus piperacillin, in 0 of the 132 patients who were receiving ceftazidime plus piperacillin, and in 1 of 106 patients (0.9%) who were receiving 2 g/d of imipenem (P less than 0.005). The 2-g daily dose of imipenem was as effective as the 4-g daily dose. Diarrhea was more frequent in patients receiving cefoperazone, whereas nausea occurred more often with imipenem. No antibiotic-related hemorrhage or nephrotoxicity was observed. Superinfections caused by beta-lactam-resistant, gram-negative bacilli were uncommon but occurred more frequently with double beta-lactam therapy than with imipenem monotherapy (11 of 268 patients compared with 1 of 135 patients; P = 0.06). Xanthomonas maltophilia superinfections occurred only in patients receiving imipenem (3 of 135 patients compared with 0 of 268 patients; P = 0.03). Imipenem monotherapy was the least expensive therapy. CONCLUSIONS: Cefoperazone and ceftazidime were equally effective when used in combination antibiotic therapy with piperacillin. Twice-daily cefoperazone is less expensive than ceftazidime given three times daily. Monotherapy with imipenem, at a daily dose of 2 g, is as efficacious as double beta-lactam therapy and costs less than combination therapy.

Prospective randomized evaluation of ciprofloxacin versus piperacillin plus amikacin for empiric antibiotic therapy of febrile granulocytopenic cancer patients with lymphomas and solid tumors. The European Organization for Research on Treatment of Cancer International Antimicrobial Therapy Cooperative Group.

Empiric therapy for febrile granulocytopenic patients is mandatory, but whether monotherapy is a safe alternative and whether fluoroquinolones are useful agents for this indication are still controversial issues. The use of monotherapy with intravenous ciprofloxacin (200 to 300 mg every 12 h) was evaluated against combined therapy with piperacillin plus amikacin in febrile granulocytopenic patients with solid tumor or lymphoma. The study was discontinued prematurely because patients treated with ciprofloxacin had a significantly lower overall success rate than patients treated with piperacillin plus amikacin (31 of 48 patients [65%] versus 48 of 53 patients [91%], P = 0.002). Patients with gram-positive coccal bacteremia had a particularly poor outcome: therapy failed for six of eight patients (75%) treated with ciprofloxacin, while therapy failed for none of four patients treated with piperacillin plus amikacin. Death from primary infection during initially randomized protocol therapy occurred in 7 of 48 patients (14.5%) treated with ciprofloxacin and in 3 of 53 (6%) treated with piperacillin plus amikacin. This study does not support the use of this dose of intravenous ciprofloxacin as empiric monotherapy for fever in granulocytopenic patients.

Ciprofloxacin for infection prophylaxis in granulocytopenic patients with acute leukemia.

Forty consecutive neutropenic patients with acute leukemia receiving oral ciprofloxacin (500 mg twice daily) and ketoconazole (200 mg daily) for selective intestinal decontamination were compared retrospectively with 33 comparable patients treated with polymyxin E (1,500,000 U x 3/day) and nystatin (1,000,000 U x 3/day). The incidence of febrile episodes was slightly lower in ciprofloxacin treated patients (87.5% vs 100%). No gram-negative sepsis was observed in this group compared with seven cases in patients receiving polymyxin E (p less than 0.01). Furthermore, eight patients in ciprofloxacin group (20%) had gram-positive sepsis, compared with five (15.5%) in the polymyxin E group. The incidence of documented fungal infections was similar in the two groups. Ciprofloxacin appears to be an effective agent for the prevention of gram-negative infections in granulocytopenic patients with acute leukemia, but may contribute to a shift in the type of infections in these patients towards those caused by gram-positive microorganisms, intrinsically fairly sensitive or with acquired drug resistance.

Ceftazidime versus imipenem-cilastatin as initial monotherapy for febrile neutropenic patients.

One hundred febrile episodes in 89 neutropenic patients after cytotoxic chemotherapy were randomized to be treated with either ceftazidime or imipenem as initial monotherapy. The clinical characteristics of the two groups of patients were comparable. The response of the fever in patients who received imipenem was significantly better than that in those who received ceftazidime (77 versus 56%, respectively; P = 0.04), especially in those with microbiologically documented infection (81 versus 33%, respectively; P = 0.02). The in vitro susceptibilities and the clinical responses suggested that, with the possible exception of Pseudomonas spp., imipenem was more effective than ceftazidime in treating neutropenic infections caused by both gram-positive and -negative organisms. An additional 23 and 21% of the patients in the ceftazidime and imipenem groups, respectively, responded to the addition of cloxacillin and amikacin following failure of monotherapy. The majority of the treatment failures, relapses, and superinfections were related to resistant infective organisms such as methicillin-resistant Staphylococcus spp. and Pseudomonas spp. or disseminated fungal infections.

Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa.

A monoclonal antibody directed against murine tumor necrosis factor-alpha (TNF) was studied in a neutropenic rat model to determine its efficacy in protecting animals from lethal infection with Pseudomonas aeruginosa. Anti-TNF monoclonal antibody at a dose of 20 mg/kg given intravenously at 0 and 120 h resulted in a 53% survival rate (8/15) compared with no survival in control animals (0/15) (P less than .005). The combination of anti-TNF monoclonal antibody and oral ciprofloxacin at a suboptimal dose of 2.5 mg/kg/day resulted in a 100% survival rate in neutropenic animals (16/16), while ciprofloxacin alone produced only a 67% survival rate (10/15) during the 7-day period of neutropenia (P less than .05). Thus anti-TNF monoclonal antibody alone or in addition to antimicrobial agents improved survival in neutropenic animals after infection with P. aeruginosa.

Ceftriaxone vs. azlocillin and netilmicin in the treatment of febrile neutropenic children.

Efficacy of the cephalosporin, ceftriaxone, was compared with that of the combination of the aminoglycoside, netilmicin, and the penicillin, azlocillin, in the treatment of febrile episodes in immunocompromised neutropenic children undergoing chemotherapy for neoplastic disease. During 100 separate febrile episodes, 40 strains of bacteria were isolated from the blood of 34 patients and a further 55 strains from other sites. Nine strains (four of which were staphylococci) to both netilmicin and azlocillin. There was no difference in clinical response between the two therapeutic regimens as assessed 4 and 7 days after treatment began. Ceftriaxone had the considerable practical advantages of once daily dosage without a need for blood monitoring. Ceftriaxone would appear to be effective as initial monotherapy in the treatment of bacterial infections in severely neutropenic children.