Francesco Menichetti

Itraconazole Oral Solution as Prophylaxis for Fungal Infections in Neutropenic Patients with Hematologic Malignancies: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species.

A Multicenter, Double-Blind, Placebo-Controlled Trial Comparing Piperacillin-Tazobactam with and without Amikacin as Empiric Therapy for Febrile Neutropenia

In a prospective, multicenter, double-blind, randomized clinical trial, we compared the efficacy of piperacillin-tazobactam (4.5 g 3 times daily intravenously) plus placebo versus piperacillin-tazobactam plus amikacin (7.5 mg/kg twice daily intravenously) for the treatment of 760 febrile, adult patients with cancer with chemotherapy-induced profound (<500 neutrophils/mm3) and prolonged (>10 days) neutropenia. A total of 733 patients were assessable for efficacy of the drug regimens, and an overall successful outcome was reported in 49% (179 of 364) of the patients who received monotherapy, compared with 53% (196 of 369) of patients who received combination therapy (P=.2). Response rates were similar with both regimens, as were incidences of bacteremia and clinically documented and possible infections. In our epidemiological setting, the initial empiric combination therapy was not associated with improved outcomes when compared with initial monotherapy.

Preventing fungal infection in neutropenic patients with acute leukemia : fluconazole compared with oral amphotericin B

Superficial and systemic fungal infections are a major problem among neutropenic patients with acute leukemia [1] or those having bone marrow transplantation [2]. It remains a leading cause of morbidity and mortality, and many centers administer amphotericin B empirically to patients with neutropenia and fever refractory to antibacterial treatment [3, 4]. Antifungal prophylaxis is also used widely, but its efficacy in reducing systemic fungal infection is debated [5]. However, oral polyene antibiotics, usually poorly tolerated because of their bitter taste, have been shown to reduce oral candidiasis, and, in a placebo-controlled study, oral amphotericin B was shown to decrease autopsy-proven systemic candidiasis [6]. Among the imidazoles, ketoconazole and miconazole have been used with contrasting results in the prevention of systemic fungal infections, but because of their toxicities and the emergence of fungal-resistant strains, they are rarely used. Fluconazole, an oral triazole with systemic activity, tested in placebo-controlled trials in a daily oral dose of 400 mg, was found to be effective in reducing systemic fungal infections in marrow recipients [7] but did not show the same benefit in patients with acute leukemia receiving therapy to induce remission [8]. Our aim was to clarify the role of systemic and topical antifungal prophylactic agents in neutropenic patients with acute leukemia by doing a large, randomized, multicenter trial that compared the efficacy and tolerability of oral fluconazole with high-dose amphotericin B suspension. Methods Eligible patients included consecutive adults who had acute leukemia, were hospitalized at participating centers, and were receiving cytotoxic therapy likely to induce neutropenia (neutrophil count < 1000/mm3) within 7 days. Patients received remission-induction or reinduction therapy according to the GIMEMA protocols [9, 10]. We excluded from the study before randomization patients younger than 14 years, patients with a history of hypersensitivity to triazoles, patients treated with antifungal therapy in the previous 15 days, patients with evidence of a preexisting systemic fungal infection, and patients who had nasal colonization with Aspergillus spp. Study Protocol After informed consent was obtained, the patients were randomly assigned to receive either fluconazole, 150 mg as a once-daily capsule, or amphotericin B suspension, 500 mg every 6 hours. Patients were randomly assigned to treatments using random permuted blocks of 10 containing different and balanced sequences of the two regimens. Antifungal prophylaxis was started 1 to 3 days before the administration of cytotoxic chemotherapy and continued until the neutrophil count returned to 1000/L or a systemic fungal infection was proved or suspected. All patients received oral ciprofloxacin, 500 mg twice daily, as antibacterial prophylaxis [11]; antiviral prophylaxis and central venous catheters were used according to autonomous decisions made at each participating center. The patients were treated under conventional ward conditions or in single rooms, depending on the center. Prophylactic granulocyte transfusions and colony-stimulating factors were not used. All patients were examined daily for clinical signs of fungal infection. When axillary temperature increased to more than 38 C or infection was suspected, samples for microbiological cultures, including at least three separate blood specimens, were obtained, prophylactic therapy with ciprofloxacin was discontinued, and treatment with amikacin, ceftazidime, and a glycopeptide antibiotic (teicoplanin or vancomycin) was started; if fever persisted despite 4 to 6 days of systemic antibiotics, empiric intravenous amphotericin B was administered. Documented systemic fungal infections were treated with systemic antifungal agents (mainly intravenous amphotericin B), and superficial fungal infections were treated with topical antifungal agents. To compare the efficacy and tolerability of the two prophylactic regimens, the following variables were measured: documented systemic fungal infection; suspected systemic fungal infection; superficial fungal infection; the interval to the development of documented systemic fungal infection or to the use of empiric antifungal therapy; compliance; treatment interruption caused by side effects; and mortality. Definition of Fungal Infection Superficial fungal infection was defined as clinically apparent infection of the oropharynx or skin, along with positive cultures; a suspected case of systemic fungal infection was defined as any episode of fever that persisted despite 4 to 6 days of empiric antibiotic therapy, for which empiric intravenous amphotericin B therapy was administered; definite systemic fungal infection was defined as one in which there was both clinical evidence of blood or tissue infection and a culture or biopsy specimen from the involved site showing a pathogenic fungal organism [7]. Compliance Compliance was monitored by the nurse who counted capsules of fluconazole and measured the volume of amphotericin B oral suspension each day and recorded these data on the clinical report form. Compliance was defined as excellent if the patient took all the drug doses, as good if the patient missed fewer than three consecutive doses or took more than 80% of the total number of doses, and as poor if the patient missed more than three consecutive doses or took less than 80% of the total number of doses. Statistical Analysis Statistical analysis was done at the GIMEMA Infection Program Data Center with the SAS package (SAS Institute, Inc., Cary, North Carolina). Results are reported for all patients enrolled in the study (intention-to-treat analysis). Except for three patients randomly assigned to fluconazole and two patients assigned to amphotericin B who did not receive the study drugs and six additional patients in the fluconazole group and five in the amphotericin B group who had a duration of neutropenia of less than 7 days, all other patients were evaluable for the clinical efficacy analysis. The chi-square test with a correction for continuity, or the Fisher exact test when appropriate, was used to compare differences in proportions between the two groups. The log-rank test was used to compare the Kaplan-Meier survival curves. The Student unpaired t-test was used to compare the means. Confidence intervals (CIs) of 95% are given where appropriate. Results A total of 820 patients with acute leukemia and neutropenic episodes from 30 centers were studied; 420 were randomly assigned to receive fluconazole, and 400 were randomly assigned to receive oral amphotericin B. The two groups of patients were similar in sex, age, underlying diseases, type of chemotherapy, protective environment, use of central venous catheters, and duration and severity of neutropenia. Patients receiving first-induction chemotherapy were equally distributed in the two treatment groups (Table 1). Table 1. Patient Characteristics according to Treatment Group Systemic Fungal Infection Proven systemic fungal infection occurred in 11 (2.6%) fluconazole recipients and in 10 (2.5%) amphotericin B recipients (P > 0.2). The distribution of fungal isolates was similar in both groups (Table 2): Candida spp. caused 55% of systemic infections in fluconazole recipients and 70% in amphotericin B recipients; no difference was found in the isolation of different Candida spp., including C. krusei, between the two groups. Rates of infections caused by Aspergillus spp. were 45% in fluconazole recipients and 30% in amphotericin B recipients, a difference of 15 percentage points (95% CI for difference, 25% to 56%, P > 0.2), and the Aspergillus isolates were equally distributed. Fungemia caused by Candida spp. was documented in five patients receiving fluconazole and in three treated with amphotericin B. The characteristics of the patients with proven cases of systemic fungal infection and their clinical outcomes are summarized in Table 3. Table 2. Types of Fungi Isolated in Systemic Infections according to Treatment Group* Table 3. Characteristics and Outcomes of the Definite Cases of Systemic Fungal Infection according to Treatment Group Overall, the sites of infection between the two treatment groups were similar (P > 0.2). Simple fungemia caused by Candida isolates was documented in three patients in each group (two cases of C. krusei and one of C. parapsilosis in fluconazole recipients; one case each of C. albicans, C. krusei, and C. parapsilosis in amphotericin B recipients), and tissue infection was documented in three fluconazole recipients (C. tropicalis, C. albicans, and C. parapsilosis), and two amphotericin recipients (Candida spp., C. albicans). In patients receiving amphotericin B, esophagitis caused by Candida spp. and urinary tract infection caused by C. tropicalis were also documented. Tissue infection caused by Aspergillus spp. occurred in five fluconazole recipients (four cases of pneumonia and one disseminated infection) and in three amphotericin B-treated patients (two cases of pneumonia and one case of disseminated infection). Deaths from fungal infection were similar. Candida krusei fungemia and C. albicans and C. parapsilosis tissue infections caused death in three fluconazole recipients; C. albicans fungemia and Candida spp. tissue infection caused death in two amphotericin B recipients. Aspergillus pneumonia caused two deaths in the fluconazole group and one death in the amphotericin B group. The interval to the documented systemic fungal infection was 21 days in fluconazole recipients and 15 days in amphotericin B recipients, a nonstatistically significant difference (95% CI for difference, 3 to 15 days; P = 0.15). Superficial Fungal Infection Superficial infections were reported in 7 of the 420 patients receiving fluconazole (1.7%) and in 11 of 400 of those receiving amphotericin B (2.7%), a difference of 1 percentage point (CI for di

Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial

Amphotericin B, despite its intrinsic servere toxicity, is the most commonly used empirical antifungal therapy in cancer patients with unexplained fever not responding to empirical antibacterial therapy. The aim of this study was to show whether fluconazole was as effective as, and less toxic than, amphotericin, with no effort made to compare the antifungal activity of the two drugs. A group of 112 persistently febrile (> 38 degrees C) and granulocytopenic (< 1000 cells/mm3) cancer patients, not receiving any absorbable antifungal antibiotic for prophylaxis, with a mean age of 27 years (range 1-73 years), undergoing chemotherapy for a variety of malignancies and with a diagnosis of unexplained fever after at least 96 h of empirical antibacterial therapy, were randomised to receive either fluconazole (6 mg/kg/day up to 400 mg/day) or amphotericin B (0.8 mg/kg/day) as empirical antifungal treatment. Patients were required to have normal chest X-rays at randomisation, no previous history of aspergillosis and negative surveillance cultures for Aspergillus. The intention-to-treat analysis showed defervescence and survival without treatment modification in 42 of 56 patients (75%) in the fluconazole group and in 37 of 56 (66%) in the amphotericin B group (P = 0.4). Duration of therapy was 6 days (95% CI = 4-8 days) in both groups. Death occurred in 3 patients (5%) in the fluconazole and in 2 (4%) in the amphotericin B group. No fungal death was documented in either group. Adverse events developed in 18 of 56 patients (32%) in the fluconazole group and in 46 of 56 (82%) in the amphotericin B group (P < 0.001). In the amphotericin B group, 5 patients had treatment discontinued because of toxicity, versus none in the fluconazole group, a difference which approached statistical significance (P = 0.06). This study shows that fluconazole is by far less toxic than amphotericin B and suggests that it might be as effective as amphotericin B, in pragmatical terms and for this specific indication. However, numbers are too small to allow definitive conclusions about efficacy, and the use of fluconazole for this indication remains experimental. Future studies should try to identify patients more at risk of fungal infections, with the aim of individualising antifungal approaches.

mcr-1.2, a New mcr Variant Carried on a Transferable Plasmid from a Colistin-Resistant KPC Carbapenemase-Producing Klebsiella pneumoniae Strain of Sequence Type 512.

ABSTRACT A novel mcr variant, named mcr-1.2, encoding a Gln3-to-Leu functional variant of MCR-1, was detected in a KPC-3-producing ST512 Klebsiella pneumoniae isolate collected in Italy from a surveillance rectal swab from a leukemic child. The mcr-1.2 gene was carried on a transferable IncX4 plasmid whose structure was very similar to that of mcr-1-bearing plasmids previously found in Escherichia coli and K. pneumoniae strains from geographically distant sites (Estonia, China, and South Africa).

Added Value of 99mTc-HMPAO–Labeled Leukocyte SPECT/CT in the Characterization and Management of Patients with Infectious Endocarditis

The clinical performance of the Duke Endocarditis Service criteria to establish the diagnosis of infectious endocarditis (IE) can be improved through functional imaging procedures such as radiolabeled leukocytes (99mTc-hexamethylpropyleneamine oxime [HMPAO]–labeled white blood cells [WBC]). Methods: We assessed the value of 99mTc-HMPAO-WBC scintigraphy including SPECT/CT acquisitions in a series of 131 consecutive patients with suspected IE. Patients with permanent cardiac devices were excluded. 99mTc-HMPAO-WBC scintigraphy results were correlated with transthoracic or transesophageal echocardiography, blood cultures, and the Duke criteria. Results: Scintigraphy was true-positive in 46 of 51 and false-negative in 5 of 51 cases (90% sensitivity, 94% negative predictive value, and 100% specificity and positive predictive value). No false-positive results were found, even in patients with early IE evaluated within the first 2 mo from the surgical procedure. In 24 of 51 patients with IE, we also found extracardiac uptake, indicating septic embolism in 21 of 24. Despite the fact that septic embolism was found in 11 of 18 cases of Duke-definite IE, most of the added value from the 99mTc-HMPAO-WBC scan for decision making was seen in patients in whom the Duke criteria yielded possible IE. The scan was particularly valuable in patients with negative or difficult-to-interpret echocardiographic findings because it correctly classified 11 of 88 of these patients as having IE. Furthermore, 3 patients were falsely positive at echocardiography but correctly negative at 99mTc-HMPAO-WBC scintigraphy: these patients had marantic vegetations. Conclusion: Our results demonstrate the ability of 99mTc-HMPAO-WBC scintigraphy to reduce the rate of misdiagnosed cases of IE when combined with standard diagnostic tests in several situations: when clinical suspicion is high but echocardiographic findings are inconclusive; when there is a need for differential diagnosis between septic and sterile vegetations detected at echocardiography; when echocardiographic, laboratory, and clinical data are contradictory; and when valve involvement (especially of a prosthetic valve) needs to be excluded during febrile episodes, sepsis, or postsurgical infections.

Carbapenem-Sparing Antibiotic Regimens for Infections Caused by Klebsiella pneumoniae Carbapenemase–Producing K. pneumoniae in Intensive Care Unit

A carbapenem-sparing regimen of tigecycline plus gentamicin or colistin was effective for treating 24 of 26 (92%) Klebsiella pneumoniae carbapenemase-producing K. pneumoniae infectious episodes in 22 polytrauma intensive care unit patients without comorbidities. The 30-day crude mortality rate was 14%. Regimens were considered appropriate in 12% of episodes according to the Vitek 2 System and in 100% based on E-test.

Effects of teicoplanin and those of vancomycin in initial empirical antibiotic regimen for febrile, neutropenic patients with hematologic malignancies. Gimema Infection Program.

The efficacy and toxicity of teicoplanin and vancomycin in the initial empirical antibiotic regimen in febrile, neutropenic patients with hematologic malignancies were compared in a prospective, randomized, unblinded, multicenter trial in the setting of 29 hematologic units in tertiary-care or university hospitals. A total of 635 consecutive febrile patients with hematologic malignancies and chemotherapy-induced neutropenia were randomly assigned to receive intravenously amikacin plus ceftazidime plus either teicoplanin at 6 mg/kg of body weight once daily or vancomycin at 1 g twice daily. An efficacy analysis was done for 527 evaluable patients: 275 treated with teicoplanin and 252 treated with vancomycin. Overall, successful outcomes were recorded for 78% of patients who received teicoplanin and 75% of those who were randomized to vancomycin (difference, 3%; 95% confidence interval [CI], -10 to 4%; P = 0.33). A total of 102 patients presented with primary, single-agent, gram-positive bacteremia. Coagulase-negative staphylococci accounted for 42%, Staphylococcus aureus accounted for 27%, and streptococci accounted for 21% of all gram-positive blood isolates. The overall responses to therapy of gram-positive bacteremias were 92 and 87% for teicoplanin and vancomycin, respectively (difference, 5%; CI, -17 to 6%; P = 0.22). Side effects, mainly represented by skin rash, occurred in 3.2 and 8% of teicoplanin- and vancomycin-treated patients, respectively (difference, -4.8%; CI, 0.7 to 8%; P = 0.03); the rate of nephrotoxicity was 1.4 and 0.8% for the teicoplanin and vancomycin groups, respectively (difference, 0.6%; CI, -2 to 1%; P = 0.68). Further infections were caused by gram-positive organisms in two patients (0.7%) treated with teicoplanin and one patient (0.4%) who received vancomycin (difference, 0.3%; CI, -0.9 to 1.0%; P = 0.53). Overall mortalities were 8.5 and 11% for teicoplanin- and vancomycin-treated patients, respectively (difference, -2.5%; CI, - 2 to 7%; P = 0.43); death was caused by primary gram-positive infections in three patients (1%) in each treatment group. When used for initial empirical antibiotic therapy in febrile, neutropenic patients, teicoplanin was at least as efficacious as vancomycin, but it was associated with fewer side effects.

Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria

The antibiotic pipeline continues to diminish and the majority of the public remains unaware of this critical situation. The cause of the decline of antibiotic development is multifactorial and currently most ICUs are confronted with the challenge of multidrug-resistant organisms. Antimicrobial multidrug resistance is expanding all over the world, with extreme and pandrug resistance being increasingly encountered, especially in healthcare-associated infections in large highly specialized hospitals. Antibiotic stewardship for critically ill patients translated into the implementation of specific guidelines, largely promoted by the Surviving Sepsis Campaign, targeted at education to optimize choice, dosage, and duration of antibiotics in order to improve outcomes and reduce the development of resistance. Inappropriate antimicrobial therapy, meaning the selection of an antibiotic to which the causative pathogen is resistant, is a consistent predictor of poor outcomes in septic patients. Therefore, pharmacokinetically/pharmacodynamically optimized dosing regimens should be given to all patients empirically and, once the pathogen and susceptibility are known, local stewardship practices may be employed on the basis of clinical response to redefine an appropriate regimen for the patient. This review will focus on the most severely ill patients, for whom substantial progress in organ support along with diagnostic and therapeutic strategies markedly increased the risk of nosocomial infections.

Synergistic activity of colistin plus rifampin against colistin-resistant KPC-producing Klebsiella pneumoniae.

ABSTRACT Infections caused by carbapenem-resistant KPC-producing Klebsiella pneumoniae are responsible for high rates of mortality and represent a major therapeutic challenge, especially when the isolates are also resistant to colistin. We used the checkerboard method to evaluate the synergistic activity of 10 antibiotic combinations against 13 colistin-resistant KPC-producing K. pneumoniae isolates (colistin MIC range of 8 to 128 mg/liter). Colistin plus rifampin was the only combination that demonstrated consistent synergistic bacteriostatic activity against 13/13 strains tested, reducing the colistin MIC below the susceptibility breakpoint (MIC ≤ 2 mg/liter) in 7/13 strains at rifampin concentrations ranging from 4 to 16 mg/liter. Bactericidal synergistic activity was also documented for 8/13 tested strains. Other antimicrobial combinations with carbapenems, gentamicin, and tigecycline showed variously synergistic results. Colistin plus rifampin also exhibited bacteriostatic synergistic activity against 4/4 colistin-susceptible KPC-producing K. pneumoniae isolates (colistin MIC range of 0.5 to 2 mg/liter) and 4/4 ertapenem-resistant extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae isolates (ertapenem MIC range of 16 to 32 mg/liter). Collectively, our data suggest that colistin plus rifampin is the most consistently synergistic combination against KPC-producing K. pneumoniae isolates, including colistin-resistant strains. Colistin-rifampin combinations may have a role in the treatment of multidrug-resistant K. pneumoniae and may possibly slow the selection of heteroresistant subpopulations during colistin therapy.