Monotherapy with Intravenous Followed by Oral High-Dose Ciprofloxacin versus Combination Therapy with Ceftazidime plus Amikacin as Initial Empiric Therapy for Granulocytopenic Patients with Fever

ABSTRACT The aim of the present study was to obtain clinical experience with the use of high-dose ciprofloxacin as monotherapy for the treatment of febrile neutropenia episodes (granulocyte count, <500/mm3) compared to a standard regimen and to clarify whether ciprofloxacin administration may be switched to the oral route. In a prospective randomized study ciprofloxacin was given at 400 mg three times a day (t.i.d.) for at least 72 h followed by oral administration at 750 mg twice a day (b.i.d). That regimen was compared with ceftazidime given intravenously at 2 g t.i.d. plus amikacin given intravenously at 500 mg b.i.d. The frequency of successful clinical response without modification at the end of therapy was almost identical for ciprofloxacin (50% [62 of 124 patients]) compared with that for ceftazidime plus amikacin (50.8% [62 of 122 patients]) in an intent-to-treat analysis; the frequencies were 48.3% (57 of 118 patients) versus 49.6% (56 of 113 patients), respectively, in a per-protocol analysis (P values for one-sided equivalence, 0.0485 and 0.0516, respectively; δ = 10%), with no significant differences among patients with bacteremia and other microbiologically or clinically documented infections and fever of unknown origin. For 82 (66.1%) patients, it was possible to switch from parenteral ciprofloxacin to the oral ciprofloxacin, and the response was successful for 61 (74.4%) patients. The efficacies of the regimens against streptococcal bacteremias were 16.6% (one of six patients) for the ciprofloxacin group and 33.3% (one of three patients) for the combination group (it was not statistically significant), with one breakthrough streptococcal bacteremia observed among the ciprofloxacin-treated patients. Adverse events were mostly self-limited and were observed in 27 (20.6%) ciprofloxacin-treated patients and 26 (19.7%) patients who were receiving the combination. This study demonstrates that high-dose ciprofloxacin given intravenously for at least 3 days and then by the oral route is therapeutically equivalent to the routine regimen of intraveneous ceftazidime plus amikacin even in febrile patients with severe neutropenia (polymorphonuclear leukocyte count, <100 mm3). However, it is very important that before an empirical therapy is chosen each hospital determine bacteriologic predominance and perform resistance surveillance.

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Even “Moderate” Dose Cyclophosphamide for Severe Aplastic Anemia Is Associated with Significant Toxicities and Does Not Prevent Relapse and Clonal Evolution

Blood ◽

10.1182/blood.v120.21.1259.1259 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1259-1259

Author(s):

Phillip Scheinberg ◽

Danielle M. Townsley ◽

Bogdan Dumitriu ◽

Olga Rios ◽

Barbara Weinstein ◽

...

Keyword(s):

Aplastic Anemia ◽

Fungal Infections ◽

Clonal Evolution ◽

Randomized Study ◽

Antifungal Drugs ◽

Severe Aplastic Anemia ◽

Severe Neutropenia ◽

High Dose ◽

Moderate Dose ◽

Monosomy 7

Abstract Abstract 1259 Severe aplastic anemia (SAA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. As most patients lack a histocompatible donor, the majority of patients are treated with immunosuppressive therapy (IST) with horse anti-thymocyte globulin plus cyclosporine (h-ATG/CsA). The current limitations of IST in SAA are: 1) most responses are not complete; 2) 1/3 of patients are refractory to initial h-ATG/CsA; 3) hematologic relapses occur in 30–35% of responders following initial response ATG/CsA; 4) and clonal evolution is observed in about 15% of patients at 10 years after first therapy (Scheinberg and Young 2012). Efforts to improve initial IST in treatment-naïve patients with the addition of mycophenolate mofetil and sirolimus to standard h-ATG/CsA or use of lymphocytotoxic agents such as rabbit ATG or alemtuzumab have not yielded better outcomes when compared to standard h-ATG/CsA (Scheinberg and Young 2012). Cyclophosphamide (Cy) has been proposed as an alternative IST regimen to h-ATG/CsA. A pilot and single institution phase II study suggested that high dose Cy (200 mg/kg) yielded similar results to that observed for h-ATG/CsA but with fewer relapses and clonal evolutions (Brodsky, Chen et al. 2010). However, in a randomized study at NHLBI comparing high dose Cy (200 mg/kg) and h-ATG/CsA in treatment-naïve patients excess toxicity and deaths from invasive fungal infections were observed in the Cy arm, which led to the discontinuation of this regimen (Tisdale, Dunn et al. 2000). In a recent Chinese protocol introduced by Dr. Zhang (Institute of Hematology & Blood Disease Hospital, China), lower doses of Cy (30 mg/kg/d * 4 days, 120 mg/kg total) plus CsA, were reported to achieve similar results as with high-dose Cy at 200 mg/kg with reduced toxicity (Kojima, Nakao et al. 2011). Because of the marked improvement in survival in SAA, especially among patients who did not respond to IST, likely due at least in part to improved antifungal drugs (Valdez, Scheinberg et al. 2011), we considered it reasonable to investigate “moderate” dose Cy + CsA as proposed by the Chinese as first line in SAA. The main objective was to assess the safety and efficacy of Cy at 120 mg/kg + low dose CsA, at doses aimed to achieve plasma levels of 100 – 200 mg/L, in treatment-naïve SAA, and the primary hematologic endpoint was response, defined as no longer meeting criteria for SAA, at 6 months. The study was designed to show an increase in complete response rate > 30%, in our experience a surrogate for fewer late events. Prophylactic voriconazole was administered with target levels between 1 – 5.5 ug/L, with ciprofloxacin and Bactrim. From October 2010 to April 2012, 22 patients were accrued. Toxicity from Cy + CsA was considerable and in some cases unexpected, with absolute neutrophil levels of 0/uL universal regardless of pre-therapy blood counts. Granulocyte transfusions were required in 5 participants for uncontrolled infections, and to date 5 patients have died, all from infections. Confirmed fungal infections were documented in 4 participants. In 10 patients with a pre-treatment ANC > 500/uL, 5 remained with severe neutropenia at 6 months as salvage therapies were being sought. In a companion protocol using Cy at 60 mg/kg + fludarabine at 125 mg/m2, neutropenia was also prolonged and severe in a patient leading to pulmonary murcomycosis and need for frequent granulocyte transfusions. In total 9 patients responded to “moderate” dose Cy (120 mg/kg total dose) + CsA, with 4 complete and 5 partial responders. In the relative short follow-up period, cytogenetic abnormalities have been observed in 4 patients: 1 to monosomy 7, 1 del20q, 1 trisomy 15, and 1 del7q. We conclude that Cy at 120 mg/kg + CsA, while capable of producing meaningful hematologic responses in some cases, results in significant toxicity, despite maximum prophylactic and intensive supportive care. The regimen led to very prolonged hospitalizations and frequent bacterial and fungal infections. Hematologic relapses with a higher than expected number of clonal evolution events were observed in our cohort. Due to the high toxicity of Cy (120 mg/kg) + CsA, without likelihood of benefit from decreased relapse and clonal evolution, both protocols using “moderate” dose Cy were terminated by our data and safety monitoring board. Although Cy has activity in SAA, its toxicity is not justified when far less toxic alternatives, such as h-ATG, are available. Disclosures: Off Label Use: Cyclophosphamide in aplastic anemia.

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Prophylactic Antibiotics Reduce Morbidity from Septicemia during Intensive Treatment for Pediatric Acute Myelogenous Leukemia.

Blood ◽

10.1182/blood.v108.11.1919.1919 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1919-1919

Author(s):

Beth Kurt ◽

Patricia Flynn ◽

Jerry Shenep ◽

Raul Ribeiro ◽

Ching-Hon Pui ◽

...

Keyword(s):

Bacterial Infections ◽

Prophylactic Antibiotic ◽

Empiric Therapy ◽

Prophylactic Antibiotics ◽

Myelogenous Leukemia ◽

High Dose ◽

Antibiotic Regimen ◽

Front Line ◽

Prophylactic Use ◽

Oral Ciprofloxacin

Abstract Patients with acute myeloid leukemia (AML) who receive intensive chemotherapy regimens containing high-dose cytarabine are at high risk for bacterial sepsis due to prolonged neutropenia and severe mucositis. To determine if the use of prophylactic antibiotics during periods of neutropenia reduced bacterial infections and viridans streptococcal infections (VSI) in particular, we reviewed the charts of 66 AML patients who were treated on our front line protocol (AML02) from October 2002 to June 2006. During this time, several consecutive prophylactic antibiotic strategies were implemented for use after intensive myelosuppressive therapy. All patients also received prophylactic antifungal therapy. Overall, patients who received any prophylactic antibiotic regimen had an 86% (95% CI: 66–95%) reduction in VSI (P<0.001) and a 76% (95% CI: 62–85%) reduction in all bacterial infections (P<0.001), compared to those who did not receive prophylactic antibiotics. Oral cephalosporins were used initially and were found to be ineffective at preventing overall bacterial infections (P=0.97) or VSI (P=0.70). Intravenous cefepime was then implemented and completely prevented VSI. Furthermore, there was an 84% (95% CI: 52–94%) reduction in all bacterial infections (P<0.001). However, because we observed the emergence of life-threatening resistant gram-negative infections in two patients receiving cefepime, we instituted the prophylactic use of intravenous vancomycin with oral ciprofloxacin. The use of a vancomycin regimen resulted in an 84% (95% CI: 66–92%) decrease in total bacterial infections (P<0.001) and a 97% (95 CI: 78–100%) decrease in VSI (P<0.001). Importantly, fungal infection rates were similar in patients who received prophylactic antibiotics compared to those who did not (0.9 vs. 1.0 infection per 1000 patient days). Patients who received prophylactic antibiotics had shorter lengths of hospital stay (LOS), with a median (range) of 7 days (0–39) vs. 15 days (0–56) for each course of chemotherapy. After adjusting for course of therapy, this represented a 38% (95% CI: 24–50%) reduction in total LOS. Patients who received a vancomycin regimen had a 46% (95% CI: 28–59%) reduction in LOS (P<0.001) and those who received intravenous cefepime a 31% (95% CI: 9–47%) reduction (P=0.008) compared to patients who did not receive prophylactic antibiotics. Overall, there was only one death from septicemia; this occurred in a patient who was not receiving prophylactic antibiotics. In conclusion, this study suggests that supportive care with antibiotic prophylaxis during periods of neutropenia may dramatically decrease the incidence of septicemia and length of hospitalization. While intravenous cefepime was found to be effective prophylaxis for VSI and other bacterial infections, we have avoided its use because of concern for emerging resistance to our front-line empiric therapy for fever and neutropenia. Thus, intravenous vancomycin with oral ciprofloxacin is our prophylactic antibiotic regimen of choice. We did not administer ciprofloxacin alone, as this has previously been shown to increase the risk of infections with gram positive organisms. Further research is needed to determine the most effective antibiotic regimen for prevention of bacterial infection in pediatric patients with AML.

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Antibody Dependent Enhancement of Infections after High Dose Chemotherapy

Blood ◽

10.1182/blood-2019-122236 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1047-1047 ◽

Cited By ~ 1

Author(s):

Jens Magnus Bernth-Jensen ◽

Bjarne Kuno Møller ◽

Steffen Thiel ◽

Anette Tarp Hansen

Keyword(s):

Stem Cell ◽

Serum Sample ◽

Unknown Origin ◽

High Dose Chemotherapy ◽

Severe Neutropenia ◽

High Dose ◽

Serum Concentrations ◽

Risk Of Infection ◽

Increased Risk ◽

Pathogen Survival

Background: High dose chemotherapy (HDT) burdens patients with a high risk of serious infections while neutropenic. The role of host antibodies as risk factors for infections is unclear. Our aim was to investigate if pre-HDT levels of IgG antibodies against terminal Galα3Gal (anti-αGal) predict infections. Anti-αGal is reported to be the most abundant antibody in human plasma and is able to recognize most sepsis-causing Gram-negative bacteria. The antibody exerts poor complement activation, which promotes pathogen survival by blocking access of more effective complement activators. This may be particularly problematic in neutropenic patients. Thus, we hypothesized that patients with high anti-αGal serum concentrations are particularly prone to suffer infections following HDT. Methods: We conducted a clinical cohort study on patients ≥16 years receiving HDT with autologous stem cell transplantation for myelomatosis (MM) or non-Hodgkin lymphoma (NHL) at Department of Hematology, Aarhus University Hospital, Denmark from 25 November 2009 through 26 June 2015. Of eligible patients (N=308), we excluded previous transplanted (N=14), those without a pre-HDT serum sample available for anti-αGal quantification (N=115), and recipients of plasma transfusion/IgG substitutions within 90 days before the pre-HDT serum sample and until end of follow-up (N=9). All included received prophylactic antimicrobial therapy (levofloxacin and fluconazol) and filgrastim. Serum anti-αGal was quantified using an in-house Time-resolved Immuno-Fluoremetric Assay. We ascertained infectious episodes within 30 days following the date of autologous stem cell re-infusion through review of all medical charts and data retrieval from the laboratory information systems, blinded for anti-αGal concentrations. Infectious episodes were defined as fever (≥38.5°C) or hypothermia (<36°C) prompting antibiotic treatment and CRP > 21 mg/L preceded by at least 24 hours without any of these. We used a Cox proportional hazards model to investigate the association between anti-αGal concentrations and risk of infection, with adjustment for total plasma IgG concentrations, ABO blood group, comorbidity, and underlying disease (MM or NHL) in the adjusted hazard ratios (HR). Optimum cutoff for dichotomizing was determined from ROC analysis applying Youden´s J statistic and groups were compared by Kaplan-Meier method. Results: We included 170 patients (MM, 55%; males, 58%; median age 62 years). Severe neutropenia was transient in all, with blood neutrophils increasing to above 500/µL on median day 11 (range 8-18). We identified one infectious episode in 103 patients (61%) and two episodes in six (3.5%) patients. The infectious episodes began during severe neutropenia in 92% of the patients. The infection types were fever of unknown origin (FUO) (72%), pneumonia (19%), catheter related (4.3%), typhlitis (1.7%), C. difficile colitis (1.7%), and hypothermia of unknown origin (0.87%). None died from infections. Pre-HDT serum was collected on median day -31 (range -142- -16). Anti-αGal was detectable in all but one sample, averaging 0.51 mg/dL (range: 0.016-12). Overall, anti-αGal concentrations predicted infectious episodes (all types), crude HR 1.2 (95% confidence interval (CI) 1.1-1.4), adjusted HR 1.1 (95% CI: 1.0-1.3). Using anti-αGal at 1.3 mg/dL as cut-off, we identified that patients with higher concentrations (N=41) experienced considerably increased risk of infectious episodes (crude estimates): all types, HR 1.7 (95% CI: 1.3-3.2); FUO, HR 2.0 (95%CI: 1.5-4.5); and pneumonia HR 2.1 (95%CI: 0.83-8.7). Discussion: We found that high anti-αGal serum concentrations predict an increased risk of infection after HDT. These findings support that anti-αGal may critically enhance pathogen-survival in the neutropenic host. Studies of other cohorts and mechanistic studies are required. Our findings may pave the way for future optimized risk stratification and therapeutic measures. Disclosures No relevant conflicts of interest to declare.

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High-dose Aprotinin in Cardiac Surgery—A Prospective, Randomized Study

Anaesthesia and Intensive Care ◽

10.1177/0310057x9402200505 ◽

1994 ◽

Vol 22 (5) ◽

pp. 529-533 ◽

Cited By ~ 20

Author(s):

M. J. Swart ◽

P. C. Gordon ◽

P. B. Hayse-Gregson ◽

R. A. Dyer ◽

A. L. Swanepoel ◽

...

Keyword(s):

Cardiac Surgery ◽

Placebo Group ◽

Blood Loss ◽

Artery Bypass ◽

Randomized Study ◽

Postoperative Blood Loss ◽

High Dose ◽

Maintenance Infusion ◽

Transfusion Requirements ◽

High Dose Aprotinin

Fifty patients undergoing primary coronary artery bypass surgery and 50 patients undergoing valve surgery received either high-dose aprotinin (2 million units loading dose, 2 million units added to the CPB prime, and 500,000 units/hr maintenance infusion) or placebo. Mean postoperative blood loss in the first six hours was reduced from 321 ml in the placebo group to 172 ml in the aprotinin group (95% confidence interval (CI) for difference = 95 to 189 ml). Seven patients in the placebo group and 16 patients in the aprotinin group did not require transfusion with homologous blood. This study adds to the growing body of evidence that the administration of high-dose aprotinin reduces blood loss and blood transfusion requirements associated with primary cardiac surgery.

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Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

Pediatric Rheumatology ◽

10.1186/s12969-020-00488-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ekaterina Alexeeva ◽

Gerd Horneff ◽

Tatyana Dvoryakovskaya ◽

Rina Denisova ◽

Irina Nikishina ◽

...

Keyword(s):

Combination Therapy ◽

Controlled Trial ◽

Randomized Study ◽

Primary Objective ◽

Disease State ◽

Inactive Disease ◽

Open Label ◽

Standard Regimen ◽

Double Blind ◽

Early Combination Therapy

Abstract Background Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease. Methods A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit. Results By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients. Conclusions Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

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Current Nanocarrier Strategies Improve Vitamin B12 Pharmacokinetics, Ameliorate Patients’ Lives, and Reduce Costs

Nanomaterials ◽

10.3390/nano11030743 ◽

2021 ◽

Vol 11 (3) ◽

pp. 743

Author(s):

Marco Fidaleo ◽

Stefano Tacconi ◽

Carolina Sbarigia ◽

Daniele Passeri ◽

Marco Rossi ◽

...

Keyword(s):

Side Effects ◽

Vitamin B12 ◽

Memory Performance ◽

Oral Route ◽

High Dose ◽

Human Beings ◽

Inborn Errors ◽

Essential Nutrient

Vitamin B12 (VitB12) is a naturally occurring compound produced by microorganisms and an essential nutrient for humans. Several papers highlight the role of VitB12 deficiency in bone and heart health, depression, memory performance, fertility, embryo development, and cancer, while VitB12 treatment is crucial for survival in inborn errors of VitB12 metabolism. VitB12 is administrated through intramuscular injection, thus impacting the patients’ lifestyle, although it is known that oral administration may meet the specific requirement even in the case of malabsorption. Furthermore, the high-dose injection of VitB12 does not ensure a constant dosage, while the oral route allows only 1.2% of the vitamin to be absorbed in human beings. Nanocarriers are promising nanotechnology that can enable therapies to be improved, reducing side effects. Today, nanocarrier strategies applied at VitB12 delivery are at the initial phase and aim to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients’ lives. The safety of nanotechnologies is still under investigation and few treatments involving nanocarriers have been approved, so far. Here, we highlight the role of VitB12 in human metabolism and diseases, and the issues linked to its molecule properties, and discuss how nanocarriers can improve the therapy and supplementation of the vitamin and reduce possible side effects and limits.

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Idiopathic granulomatous mastitis: challenges of treatment in iranian women

BMC Surgery ◽

10.1186/s12893-021-01210-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Leyla Shojaee ◽

Nasrin Rahmani ◽

Siavash Moradi ◽

Asieh Motamedi ◽

Gholamali Godazandeh

Keyword(s):

Recurrence Rate ◽

Low Dose ◽

Unknown Origin ◽

Surgical Excision ◽

Chronic Inflammatory Disease ◽

High Dose ◽

Granulomatous Mastitis ◽

Idiopathic Granulomatous Mastitis ◽

Results Of Treatment ◽

Information Treatment

Abstract Background and objective As a chronic inflammatory disease of an unknown origin, the treatment of granulomatous mastitis has always been controversial. According to some researchers, surgical treatment and certain medications, especially steroids, are more effective in treating the disease. This study aimed at evaluating the results of treatment in a group of patients with granulomatous mastitis. Materials and methods This longitudinal cohort study evaluated the treatment outcomes of 87 patients with pathology-confirmed granulomatous mastitis referred to the surgical clinic of Central Hospital in Sari, Iran. Demographic, clinical, and pathological information, treatment methods and results, and the recurrence rate were analyzed. Findings A total of 87 female patients with granulomatous mastitis aged 22–52 years with a mean age of 34 years were evaluated. All patients had palpable masses; the breast masses were painful in 48.3% of patients, and 55.2% of patients suffered from erythema and inflammation, and8% had fistulas and ulcers at the inflammation site. The patients were followed-up for an average duration of 26 months (8–48 months) after treatment and recovery. The overall recurrence rate was 24.1%, and the recurrence rate was 29.4% in patients underwent surgery, 34.8% in patients received high-dose prednisolone, and 17% in those received low-dose prednisolone together with drainage (p < 0.001). Conclusions According to the results, the low-dose prednisolone plus drainage was more effective with a lower recurrence rate than only surgical excision or high-dose prednisolone. In fact, the use of minimally invasive methods such as drainage plus low-dose steroids is a more effective method with fewer side effects than the other two methods.

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