Gerald R. Donowitz

Voriconazole Compared with Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Neutropenia and Persistent Fever

BACKGROUND Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative. METHODS In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy. RESULTS A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03). CONCLUSIONS Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

Treatment of Invasive Aspergillosis with Posaconazole in Patients Who Are Refractory to or Intolerant of Conventional Therapy: An Externally Controlled Trial

BACKGROUND Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. METHODS We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. RESULTS Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. CONCLUSIONS Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

Double-blind randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hematologic malignancies

In a double blind study, oral prophylactic trimethoprim/sulfamethoxazole was evaluated for its utility in preventing serious infections in patients with hematologic malignancy. Of 58 evaluated granulocytopenic episodes in 47 patients, acute leukemia was the underlying malignancy in 46 episodes. Trimethoprim/sulfamethoxazole prophylaxis resulted in fewer microbiologically documented infections (seven versus 15; p = 0.029). This was primarily the result of a reduction in episodes of bacteremia in the trimethoprim/sulfamethoxazole-treated group as compared with the placebo-treated group (three versus nine episodes; p = 0.05). The combined frequency of disseminated candidiasis, candidemia, and esophagitis of presumed fungal etiology was greater in the trimethoprim/sulfamethoxazole-treated group (six) than in the placebo-treated group (two) but not significantly so (p = 0.13). Similarly, there were no significant differences between groups in the overall incidence of infectious complications, number of febrile days, use of parenteral antibiotics, or number of days following randomization to first infectious episode. Throat and rectal surveillance cultures more frequently revealed trimethoprim/sulfamethoxazole-resistant gram-negative bacilli and yeasts in the trimethoprim/sulfamethoxazole-treated group. More frequent emergence of yeast isolates from previously culture-negative patients was documented (p = 0.033). Thus, in this study, trimethoprim/sulfamethoxazole prophylaxis during granulocytopenia reduced the incidence of microbiologically documented infections. However, the emergence of resistant bacteria and of fungi may limit the potential usefulness of this approach.

Triad of acute infusion-related reactions associated with liposomal amphotericin B: Analysis of clinical and epidemiological characteristics

We investigated the clinical characteristics and treatment of patients with a distinctive triad of acute infusion-related reactions (AIRRs) to liposomal amphotericin B (L-AMB) via single-center and multicenter analyses. AIRRs occurred alone or in combination within 1 of 3 symptom complexes: (1) chest pain, dyspnea, and hypoxia; (2) severe abdomen, flank, or leg pain; and (3) flushing and urticaria. The frequency of AIRRs in the single-center analysis increased over time. Most AIRRs (86%) occurred within the first 5 min of infusion. All patients experienced rapid resolution of symptoms after intravenous diphenhydramine was administered. The multicenter analysis demonstrated a mean overall frequency of 20% (range, 0%-100%) of AIRRs among 64 centers. A triad of severe AIRRs to L-AMB may occur in some centers; most of these reactions may be effectively managed by diphenhydramine administration and interruption of L-AMB infusion.

Opportunistic pneumonia: a clinicopathological study of five cases caused by an unidentified acid-fast bacterium.

Five patients had opportunistic pulmonary infection caused by acid-fast bacilli, unusual clinical presentations and a unique pathological picture. Clinically, these cases mimicked septic pulmonary emboli or bacterial pneumonia. The infection was temporally related to high-dose corticosteroid therapy, given for renal-transplant rejection in four patients and for therapy of lymphocytic lymphoma in one. Histologic sections of lung-biopsy or autopsy material showed an acute suppurative pneumonia with dense alveolar infiltration by neutrophils, without granuloma formation or caseous necrosis. Predominantly intracellular acid-fast bacilli were present. The organism failed to grow in culture on routine bacterial, fungal and mycobacterial mediums. This unusual and possibly new acid-fast organism is a probable cause of suppurative pneumonia in impaired hosts receiving corticosteroid therapy.

Ciprofloxacin plus Piperacillin Compared with Tobramycin plus Piperacillin as Empirical Therapy in Febrile Neutropenic Patients: A Randomized, Double-Blind Trial

Context Hospitalized patients with neutropenia have high risks for opportunistic gram-negative infections. An aminoglycoside in combination with an antipseudomonas -lactam, a traditional empirical therapy for febrile neutropenic patients, is limited by potential nephrotoxicity. Contribution This large randomized trial showed that ciprofloxacin plus piperacillin and tobramycin plus piperacillin were equally effective empirical therapies for hospitalized patients with fever and neutropenia. Side effects, including nephrotoxicity, were common with both regimens and did not differ significantly. Implications Combination therapy with the -lactam piperacillin plus a quinolone (ciprofloxacin) or an aminoglycoside (tobramycin) is a viable option for neutropenic febrile patients. The Editors Empirical therapy with antibiotic combinations aimed at gram-negative bacilli has been used in febrile neutropenic patients for more than 30 years (1). Aminoglycosides have remained an essential component of this combination therapy, although gram-positive organisms have emerged as major sources of infection (2-6). Ongoing concerns about aminoglycoside-induced ototoxicity and nephrotoxicity and the need for monitoring of serum drug levels have led to studies of other potentially useful agents. Ciprofloxacin is one of the most potent of the presently available quinolones against Pseudomonas aeruginosa; has excellent activity against most Enterobacteriaceae; and provides coverage against many strains of Staphylococcus aureus, coagulase-negative staphylococci, and some strains of streptococci. Synergy with -lactams against some strains of gram-negative bacilli has been demonstrated (7-11). Ciprofloxacin has been used as part of combination therapy, as modified monotherapy, and as true monotherapy in febrile neutropenic patients (12-22). Unfortunately, previous studies have involved relatively small numbers of patients and heterogeneous populations; thus, no clear conclusions have been drawn about efficacy. Therefore, we undertook a randomized, double-blind study to determine whether ciprofloxacin was equivalent to tobramycin when used as part of combination therapy with piperacillin as empirical therapy for neutropenic fever. Methods Patients The study groups were hospitalized patients with cancer and granulocytopenia (absolute granulocyte counts < 1 109 cells/L within 24 hours of study onset). The patients were 16 years of age or older and required antibiotic therapy for fever and presumed infection (a clinically documented infection defined by signs and symptoms compatible with infection in the presence or absence of fever or a microbiologically documented infection with or without fever). Fever was defined as an oral temperature of at least 38 C. Patients could be enrolled in the trial more than once as long as each entry represented a different neutropenic episode. Seven university-affiliated hospitals and a private research center (the Scripps Institute in La Jolla, California) participated in this study from June 1992 to July 1995. We excluded patients with allergy to aminoglycosides, quinolones, or penicillin; infections caused by bacteria presumed to be resistant to the study drugs; high probability of death within 24 hours; or creatinine clearance of 30 mL/min or less. We also excluded those who were pregnant or nursing. Patients receiving any systemic antimicrobial therapy within 7 days before initiation of the study drug were excluded, except the following drugs: antifungal or antiviral agents, trimethoprimsulfamethoxazole prophylaxis (to be discontinued when the study began), and cefazolin prophylaxis for placement of indwelling venous catheters. The institutional review boards at each participating center approved the study protocol. Patients or their guardians provided written informed consent to participate in the study. Random Assignment to Antibiotic Regimen Randomization was stratified according to the nature of the underlying disease (acute leukemia or bone marrow transplantation vs. lymphoma or solid tumor) and the use of recombinant colony-stimulating factors during the neutropenic episode (Figure 1). Patients were randomly assigned to receive piperacillin, 50 mg/kg of body weight intravenously every 4 hours, plus ciprofloxacin, 400 mg intravenously every 8 hours, or tobramycin, 2 mg/kg intravenously every 8 hours. Administration of antibiotics was double-blinded; only the pharmacists dispensing the medication were unblinded. Placebo was administered when necessary to maintain blinding with regard to study drug assignment when renal impairment led to changes in dosing intervals. Figure 1. Randomization schema. Evaluation and Monitoring At baseline, we performed cultures, laboratory tests, and radiography on all patients at the onset of fever. When possible, audiometry was performed within 24 hours of starting the study drug and again at the end of therapy. Peak and trough concentrations of serum tobramycin were determined serially in all patients until renal function stabilized. All drug concentrations were reported directly to an unblinded pharmacist who calculated dosages to maintain the 30-minute postdose serum concentration (peak) above 6 g/mL and the 30-minute predose serum concentration (trough) below 2 g/mL. Patients were monitored prospectively for signs of drug toxicity and adverse events. Definitions of expected toxicities were established and included in the protocol before the start of the study. Toxicity was reported to be probably related to antibiotics if it followed a consistent temporal sequence with drug administration, abated after discontinuation of drug use, and was not clearly attributable to other causes. Toxicity was judged to be possibly related to antibiotics if it followed a consistent temporal sequence with drug use but could have been produced by the patients underlying disease or other drug exposures. For ototoxicity and nephrotoxicity, antibiotic association was judged to be probable if patients had not received other potential toxins and considered possible if other potential toxins were concurrently administered. Primary Outcome Variable The primary outcome variable in this study was success or failure of treatment of infection. Patients in the intention-to-treat group and those in the subgroup meeting the criteria for being clinically evaluable were examined. Patients were considered clinically evaluable if they 1) met the inclusion criteria [and did not satisfy the exclusion criteria] and 2) received study drugs for at least 4 days or received study drugs for fewer than 4 days because of treatment failure or an adverse event. For treatment success, patients had to satisfy all of the following criteria: 1) normal body temperature on 4 consecutive days, 2) eradication of any isolated pathogen from the bloodstream or local site of infection, 3) resolution of clinical signs of infection, and 4) no modification of antimicrobial therapy. Failure was defined as not meeting all of the criteria for success or death from infection. Secondary Outcome Variables Secondary outcome variables included survival during the neutropenic period and subsequent infection, superinfection, or relapse. Survival during the neutropenic period was defined as surviving from when the absolute neutrophil count decreased to less than 1 109 cells/L until when it reached 0.5 109 cells/L or higher. We considered subsequent infection to be an infection at a site other than the primary site of infection occurring more than 72 hours after the patient started taking the study medication. Superinfection was considered a second infection at the initial site caused by an organism other than the initial pathogen and occurring more than 72 hours after the patient started taking the study medication. Relapse was defined as recurrence of an infection at the initial site with the original pathogen. Statistical Analysis We estimated that a sample size of 568 episodes was necessary for meaningful evaluation of the primary outcome variable (defined as treatment success). This estimate was based on the goal of demonstrating treatment equivalence, with a of 15% and with the assumption that 50% of patients would have documented infections. Assuming a size per treatment group of 142 patients with documented infections, we estimated that the study would have 80% power to demonstrate equivalence. We used chi-square tests to evaluate for differences between the categorical baseline and medical characteristics of the treatment groups. For continuous baseline variables, we conducted two-way analyses of variance (with one term for study site and one term for treatment). For the variable of treatment of infection, we constructed a 95% confidence interval around the treatment-group differences for the clinically evaluable patients and the intention-to-treat patients. We used a MantelHaenszel weighting scheme for this interval, in which the weights were the sample sizes from each participating center. Four of the eight centers each enrolled at least 113 patients, while the other four centers each enrolled 17 or fewer patients. To avoid possible nonrepresentation of a treatment group in the confidence interval construction, we pooled the four small centers while the study was still blinded and treated them as one center. Centers were pooled only for the confidence interval for the treatment-of-infection variable; this was justified by the similarity of results between small and large centers. We used KaplanMeier curves to estimate the distribution of time to fever response by using a Wilcoxon rank-sum test to determine whether the curves differed significantly. Chi-square tests were used to evaluate for differences between treatment groups in incidence of adverse events. We planned additional safety and efficacy analyses to account for the re-entry of the same patient into the study for multiple independent neutropenic episodes. We used only

Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study

Community-acquired pneumonia remains an important infectious disease problem, with more than 4 million cases occurring in the United States annually. Although Streptococcus pneumoniae remains the most commonly identified organism, a variety of bacterial and nonbacterial pathogens may be involved. Hospitalization is unnecessary in most cases, and oral antibiotic therapy is common. In the majority of cases, the etiology of pneumonia is unknown at the time of presentation, necessitating the use of empiric therapy. Quinolones have not been utilized in this setting in the past because of their inconsistent coverage of S pneumoniae. Sparfloxacin (RP 64206) is a broad-spectrum fluoroquinolone with excellent activity in vitro against the majority of bacteria involved in community-acquired pneumonia, including pneumococcus. We therefore studied the efficacy and safety of sparfloxacin compared with the second-generation cephalosporin cefaclor as empiric therapy for patients with community-acquired pneumonia in a double-masked, double-dummy, multicenter trial. Three hundred thirty patients aged 18 years or older with community-acquired pneumonia suspected of being bacterial in etiology were enrolled at 74 centers in the United States from June 1, 1992, to March 4, 1995. Patients meeting the inclusion criteria were randomized to receive 10 days of either sparfloxacin 400 mg orally once followed by sparfloxacin 200 mg orally daily (n = 168), or cefaclor 500 mg orally every 8 hours (n = 162). There were no significant differences between groups with regard to baseline characteristics. Patients were followed up serially at 4 +/- 1 days, 20 +/- 3 days, and 38 +/- 7 days after the beginning of therapy. Patients were evaluated for clinical response, clinical recurrence of infection, and eradication of baseline pathogens. The primary efficacy variable was the clinical response (cured or improved) in the subgroup of patients meeting the definition of clinically assessable. Responses were also evaluated in the intent-to-treat population. In the intent-to-treat population, 35.7% of patients receiving sparfloxacin were clinically cured, compared with 32.1% of patients receiving cefaclor. Clinical successes (patients clinically cured plus improved) were also comparable (72.6% of patients in the sparfloxacin group and 71.0% of patients in the cefaclor group). Similar clinical success rates were noted using only the clinically assessable population (primary efficacy variable). Forty-four percent of patients receiving sparfloxacin and 39.1% of patients receiving cefaclor were clinically cured. In the sparfloxacin group, 86.6% of patients were clinical successes, compared with 84.4% of patients in the cefaclor group. Microbiologic cures were comparable in both groups. There was no difference in the incidence of recurrence of infection or superinfection. Adverse events thought to be due to study drug occurred equally in both groups (14.3% in the sparfloxacin group vs 14.8% in the cefaclor group). Results show that sparfloxacin is a safe and effective empiric therapy for patients with community-acquired pneumonia and is comparable to cefaclor.

A controlled study of ticarcillin plus clavulanic acid versus piperacillin as empiric therapy for fever in the immunocompromised host

Clavulanic acid, a potent beta-lactamase inhibitor, was studied in fixed combination with ticarcillin and used with tobramycin as empiric therapy for fever in the immunocompromised host. Fifty febrile episodes were evaluated in patients with hematologic malignancy and/or neutropenia. Eighty-one percent of evaluable infections treated with the study regimen of ticarcillin, clavulanic acid, and tobramycin responded. Seventy-four percent of evaluable infections treated with the control regimen of piperacillin, tobramycin, and vancomycin responded (p = 0.4). Resistance to piperacillin and ticarcillin were noted in 23.8 percent of 21 isolated organisms. Resistance to ticarcillin and clavulanic acid was noted in only one (4.7 percent) of the isolated organisms (p = 0.092). Untoward reactions, including rash, nephrotoxicity, and superinfection, were unusual and occurred with equal frequency in the study and control groups. Clavulanic acid in combination with ticarcillin was effective and safe in treating fever in the immunocompromised host.

Algorithm-based decision rules to safely reduce laboratory test ordering

PURPOSE Our study develops decision rules to define appropriate intervals at which repeat tests might be indicated for commonly ordered laboratory tests for hospitalized patients. METHODS The final data set includes 5,632 adult patients admitted to the University of Virginia Hospital between July 1995 and December 1999. These patients had a hospital length of stay of five days or more and had results recorded for three routinely ordered laboratory tests for each of the first five days of their hospitalization. We use the serum potassium test to illustrate our algorithm-based decision rule methodology. RESULTS Our decision rule begins with testing on the first two days of hospitalization and allows for repeat testing after observation of any non-normal values. The results show that the algorithm-based decision rule would lead to a 34% reduction for serum potassium tests for the first five days of hospitalization. Only one out of the 5,632 patients in our sample had a critical value that occurred only on a non-test day and, thus, was missed by the algorithm. CONCLUSIONS The algorithm results are encouraging. We demonstrate that the number of tests can be reduced while missing critical values in only a small fraction of patients. Testing algorithms such as these can be used to reduce laboratory test ordering without compromising the quality of patient care.

TATLOCK Bacterium (Pittsburgh Pneumonia Agent) Presumptively Identified in Five Cases of Pneumonia

Excerpt Recently Rogers and co-workers (1) described five cases of pneumonia caused by a bacterium that could not be isolated on routine bacteriologic media. They suggested that the organism might ...