Meropenem-ANT3310, a unique ß-lactam-ß-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii.

ANT3310 is a novel broad-spectrum diazabicyclooctane serine ß-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the in vitro antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included Acinetobacter baumannii (n = 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) (n = 252) or Klebsiella pneumoniae carbapenemase (KPC) (n = 180) carbapenemases, and Pseudomonas aeruginosa (n = 502). MEM was poorly active against A. baumannii, as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC90 values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC90 value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat A. baumannii infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC90 values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of A. baumannii and 100% of OXA- and KPC-positive CREs, with ~90% of P. aeruginosa isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23 A. baumannii. This study demonstrates the potent in vitro activity of the MEM-ANT3310 combination against both carbapenem-resistant A. baumannii and Enterobacterales clinical isolates, a key differentiator to other ß-lactam/ß-lactamase combinations.

Higher levels of Pseudomonas aeruginosa LasB elastase expression are associated with early-stage infection in cystic fibrosis patients.

Pseudomonas aeruginosa is a common pathogen in cystic fibrosis (CF) patients and a major contributor to progressive lung damage. P. aeruginosa elastase (LasB), a key virulence factor, has been identified as a potential target for anti-virulence therapy. Here, we sought to differentiate the P. aeruginosa isolates from early versus established stages of infection in CF patients and to determine if LasB was associated with either stage. The lasB gene was amplified from 255 P. aeruginosa clinical isolates from 70 CF patients from the Toulouse region (France). Nine LasB variants were identified and 69% of the isolates produced detectable levels of LasB activity. Hierarchical clustering using experimental and clinical data distinguished two classes of isolates, designated as 'Early' and 'Established' infection. Multivariate analysis revealed that the isolates from the Early infection class show higher LasB activity, fast growth, tobramycin susceptibility, non-mucoid, pigmented colonies and wild-type lasR genotype. These traits were associated with younger patients with polymicrobial infections and high pFEV1. Our findings show a correlation between elevated LasB activity in P. aeruginosa isolates and early-stage infection in CF patients. Hence, it is this patient group, prior to the onset of chronic disease, that may benefit most from novel therapies targeting LasB.

Novel Specific Metallo-ß-Lactamase Inhibitor ANT2681 Restores Meropenem Activity to Clinically Effective Levels against NDM-Positive Enterobacterales.

The global dissemination of metallo-ß-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) is a serious public health concern. Specifically, NDM (New Delhi MBL) has been a major cause of carbapenem therapy failures in recent years, particularly as effective treatments for serine-ß-lactamase (SBL)-producing Enterobacterales are now commercially available. Since the NDM gene is carried on promiscuous plasmids encoding multiple additional resistance determinants, a large proportion of NDM-CREs are also resistant to many commonly used antibiotics, resulting in limited and suboptimal treatment options. ANT2681 is a specific, competitive inhibitor of MBLs with potent activity against NDM enzymes, progressing to clinical development in combination with meropenem (MEM). Susceptibility studies have been performed with MEM-ANT2681 against 1,687 MBL-positive Enterobacterales, including 1,108 NDM-CRE. The addition of ANT2681 at 8 µg/ml reduced the MEM MIC50/MIC90 from >32/>32 µg/ml to 0.25/8 µg/ml. Moreover, the combination of 8 µg/ml of both MEM and ANT2681 inhibited 74.9% of the Verona integron-encoded MBL (VIM)-positive and 85.7% of the imipenem hydrolyzing ß-lactamase (IMP)-positive Enterobacterales tested. The antibacterial activity of MEM-ANT2681 against NDM-CRE compared very favorably to that of cefiderocol (FDC) and cefepime (FEP)-taniborbactam, which displayed MIC90 values of 8 µg/ml and 32 µg/ml, respectively, whereas aztreonam-avibactam (ATM-AVI) had a MIC90 of 0.5 µg/ml. Particularly striking was the activity of MEM-ANT2681 against NDM-positive Escherichia coli (MIC90 1 µg/ml), in contrast to ATM-AVI (MIC90 4 µg/ml), FDC (MIC90 >32 µg/ml), and FEP-taniborbactam (MIC90 >32 µg/ml), which were less effective due to the high incidence of resistant PBP3-insertion mutants. MEM-ANT2681 offers a potential new therapeutic option to treat serious infections caused by NDM-CRE.

Pharmacodynamics of the Novel Metallo-ß-Lactamase Inhibitor ANT2681 in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.

Enterobacteriaceae that produce metallo-ß-lactamases (MBLs) are an emerging threat to public health. The metallo-ß-lactamase inhibitor (MBLi) ANT2681 inhibits the enzymatic activity of MBLs through interaction with the dinuclear zinc ion cluster present in the active site that is common to these enzymes. ANT2681 is being codeveloped, with meropenem as the partner ß-lactam, as a novel combination therapy for infections caused by MBL-producing bacteria. The pharmacokinetics/pharmacodynamics of meropenem-ANT2681 were studied in a murine neutropenic thigh model of NDM-producing Enterobacteriaceae Dose-ranging studies were performed with both meropenem and ANT2681. Dose fractionation experiments were performed to identify the relevant pharmacodynamic index of ANT2681 when coadministered with meropenem. A background of meropenem at 50 mg/kg of body weight every 4 h (q4h) subcutaneously (s.c.) had minimal antibacterial effect. On this background, half-maximal effect was observed with an ANT2681 dose of 89 mg/kg q4h intravenously (i.v.). The dose fractionation study showed that area under the concentration-time curve (AUC) was the relevant pharmacodynamic index for the inhibitor. The magnitude of the meropenem-ANT2681 exposure required to achieve stasis was explored using 5 NDM-producing strains. A 3-dimensional surface fitted to the pharmacodynamic data from the 5 strains suggested that stasis was achieved with an fT > potentiated meropenem MIC of 40% and ANT2681 AUC of 700 mg · h/liter. These data and analyses provide the underpinning evidence for the combined use of meropenem and ANT2681 for clinical infections.

Discovery and development of first in class antifungal caspofungin (CANCIDAS®)--a case study.

Covering: 1985 to 2001.This paper describes a fifteen year journey from concept to clinical discovery and development of the first in class caspofungin acetate (CANCIDAS®) a parenteral antifungal agent. Caspofungin is a semisynthetic derivative of pneumocandin B0, a naturally occurring, lipophilic cyclic peptide isolated from the fungus, Glarea lozoyensis. While the echinocandins had been previously studied for antifungal activity by several organizations, the class was dropped for a variety of reasons. Merck subsequently initiated a research program leading to the discovery and development of caspofungin. The multitude of challenges that ensued during the discovery and development process and which were successfully resolved by multi-disciplinary teams constitute the content of this article. The article consists of five sections that describe the discovery and development of caspofungin in chronological order: (i) discovery of the natural product pneumocandin B0 from fungal fermentations, (ii) fermentation development to improve the titer of pneumocandin B0 to make it commercially viable, (iii) semisynthetic modification by medicinal chemistry to successfully improve the properties of pneumocandin B0 leading to the discovery of caspofungin, (iv) development of commercial semisynthesis and purification and formulation development to improve stability and (v) clinical development and approval of CANCIDAS® as an antifungal drug which subsequently saved thousands of lives.

Caspofungin exposure-response relationships in adult patients with mucosal or invasive candidiasis.

Caspofungin is an echinocandin antifungal agent administered once daily as an intravenous infusion. Relationships between caspofungin exposure and clinical efficacy and safety were investigated. End-of-infusion (CEOI ) and trough (C24 hours ) concentrations were obtained in 218 patients with mucosal (i.e., esophageal and/or oropharyngeal) candidiasis (MC) receiving caspofungin 35, 50, or 70 mg/day and 278 patients with invasive candidiasis (IC) receiving 50, 100, or 150 mg/day. Area under the plasma concentration-time curve (AUC0-24 hours ) was obtained in a subset of MC patients (n = 99). Odds ratios were estimated for the association between log-transformed PK and efficacy response and the occurrence of common adverse events. No pharmacokinetic or hybrid parameter (ratio of AUC:MIC, CEOI :MIC, C24 hours :MIC) was significantly correlated with overall treatment outcome in either MC or IC, although this patient population may exhibit confounding factors which masked a potential pharmacokinetic/pharmacodynamic relationship. An exploratory evaluation of MC identified significant pharmacokinetic correlations with endoscopic response, but not symptom response. Statistically significant associations were identified for IC patients with C. parapsilosis infections. Occurrence of clinical adverse events and/or laboratory abnormalities did not appear to be increased by higher caspofungin plasma concentrations. Caspofungin concentrations achieved with 50 mg/day are generally within the therapeutic window for the treatment of candidiasis.

Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial.

OBJECTIVES: Avibactam, a novel non-ß-lactam ß-lactamase inhibitor, restores the in vitro activity of ceftazidime against class A, C and some class D ß-lactamase-producing pathogens, including those commonly associated with complicated intra-abdominal infections (cIAIs). This randomized, active-controlled, double-blind, Phase II trial (NCT00752219) aimed to evaluate the safety and efficacy of ceftazidime/avibactam plus metronidazole compared with meropenem in hospitalized patients with cIAI. METHODS: Adults with confirmed cIAI requiring surgical intervention and antibiotics were randomized 1 : 1 to receive intravenously either (i) 2000 mg of ceftazidime plus 500 mg of avibactam plus a separate infusion of 500 mg of metronidazole or (ii) 1000 mg of meropenem plus placebo every 8 h for a minimum of 5 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 2 weeks after the last dose of study therapy. RESULTS: Overall, 101 patients received ceftazidime/avibactam plus metronidazole; 102 received meropenem. The median duration of treatment was 6.0 and 6.5 days, respectively. Favourable clinical response at the TOC visit in the ME population was observed in 91.2% (62/68) and 93.4% (71/76) of patients in the ceftazidime/avibactam plus metronidazole and meropenem groups, respectively (observed difference: -2.2%; 95% CI: -20.4%, 12.2%). The incidence of treatment-emergent adverse events was similar for ceftazidime/avibactam plus metronidazole (64.4%) and meropenem (57.8%). CONCLUSIONS: Ceftazidime/avibactam plus metronidazole was effective and generally well tolerated in patients with cIAI, with a favourable clinical response rate in the ME population of >90%, similar to that of meropenem.

Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study.

OBJECTIVES: The aim of this prospective phase II, randomized, investigator-blinded study (NCT00690378) was to compare the efficacy and safety of ceftazidime-avibactam and imipenem-cilastatin in hospitalized adults with serious complicated urinary tract infection (cUTI) due to Gram-negative pathogens. PATIENTS AND METHODS: Patients aged between 18 and 90 years with cUTI were enrolled and stratified by infection type (acute pyelonephritis or other cUTI) and randomized 1:1 to receive intravenous ceftazidime 500 mg plus avibactam 125 mg every 8 hours or imipenem-cilastatin 500 mg every 6 hours. Patients meeting pre-specified improvement criteria after 4 days could be switched to oral ciprofloxacin. Patients were treated for a total of 7-14 days. The primary efficacy objective was a favorable microbiological response at the test-of-cure (TOC) visit 5-9 days post-therapy in microbiologically evaluable (ME) patients. RESULTS: Overall, 135 patients received study therapy (safety population); 62 were included in the ME population (ceftazidime-avibactam, n = 27; imipenem-cilastatin, n = 35). The predominant uropathogen was Escherichia coli. Favorable microbiological response was achieved in 70.4% of ME patients receiving ceftazidime-avibactam and 71.4% receiving imipenem-cilastatin at the TOC visit (observed difference -1.1% [95% CI: -27.2%, 25.0%]). Among ME patients with ceftazidime-resistant uropathogens, response was observed in 6/7 (85.7%) receiving ceftazidime-avibactam. Adverse events were observed in 67.6% and 76.1% of patients receiving ceftazidime-avibactam and imipenem-cilastatin, respectively. Limitations of the study include the small number of patients in the ME population. CONCLUSION: The results suggest that the efficacy and safety of ceftazidime-avibactam may be similar to that of imipenem-cilastatin.

A web-based endpoint adjudication system for interim analyses in clinical trials.

BACKGROUND: A data monitoring committee (DMC) is often employed to assess trial progress and review safety data and efficacy endpoints throughout a trail. Interim analyses performed for the DMC should use data that are as complete and verified as possible. Such analyses are complicated when data verification involves subjective study endpoints or requires clinical expertise to determine each subject's status with respect to the study endpoint. Therefore, procedures are needed to obtain adjudicated data for interim analyses in an efficient manner. In the past, methods for handling such data included using locally reported results as surrogate endpoints, adjusting analysis methods for unadjudicated data, or simply performing the adjudication as rapidly as possible. These methods all have inadequacies that make their sole usage suboptimal. PURPOSE: For a study of prophylaxis for invasive candidiasis, adjudication of both study eligibility criteria and clinical endpoints prior to two interim analyses was required. Because the study was expected to enroll at a moderate rate and the sponsor required adjudicated endpoints to be used for interim analyses, an efficient process for adjudication was required. METHODS: We created a web-based endpoint adjudication system (WebEAS) that allows for expedited review by the endpoint adjudication committee (EAC). This system automatically identifies when a subject's data are complete, creates a subject profile from the study data, and assigns EAC reviewers. The reviewers use the WebEAS to review the subject profile and submit their completed review form. The WebEAS then compares the reviews, assigns an additional review as a tiebreaker if needed, and stores the adjudicated data. RESULTS: The study for which this system was originally built was administratively closed after 10 months with only 38 subjects enrolled. The adjudication process was finalized and the WebEAS system activated prior to study closure. Some website accessibility issues presented initially. However, once these issues were resolved, the reviewers found the system user-friendly and easy to navigate. LIMITATIONS: Web-based data adjudication depends upon expeditious data collection and verification. Further, ability to use web-based technologies, in addition to clinical expertise, must be considered in selecting EAC members. CONCLUSION: The automated nature of this system makes it a practical mechanism for ensuring timely endpoint adjudication. The authors believe a similar approach could be useful for handling endpoint adjudication for future clinical trials.

Advances in antifungal therapy.

The prevalence of invasive fungal infections (IFIs) has increased over the past three decades owing to the increasing numbers of immunocompromised hosts. These infections are associated with significant morbidity and mortality. Recent significant advances in antifungal therapy include the broad-spectrum triazoles (voriconazole and posaconazole) and a new class of antifungals, the echinocandins (caspofungin, micafungin, and anidulafungin). New treatment strategies, such as combination therapy and pre-emptive therapy, are being investigated. There have also been significant improvements in diagnostics; the galactomannan enzyme immunoassay and the beta-glucan test are now part of the EORTC/MSG criteria for diagnosis of IFI. Despite these advances, there remain a number of unanswered questions regarding optimal management of serious fungal infections, and research continues to discover and develop new therapies and evaluate new management strategies.

Invasive candidiasis treated in the intensive care unit: observations from a randomized clinical trial.

OBJECTIVES: The objectives of this study were to contrast risk factors, microbiology, and outcomes in patients with invasive candidiasis treated in an intensive care unit (ICU) with those in patients with invasive candidiasis treated outside an ICU and to describe therapeutic results with caspofungin in ICU patients. MATERIALS AND METHODS: We retrospectively identified patients with documented invasive candidiasis who received their first dose of the study drug in the ICU as part of a double-blind randomized trial. Participants were not stratified at entry by their ICU status. Patients received caspofungin (50 mg/d after a 70-mg loading dose) or conventional amphotericin B (0.6-1.0 mg/kg per day) for 10 to 14 days. A favorable response required resolution of signs and symptoms as well as eradication of Candida pathogens. RESULTS: Of the 224 patients, 97 (43%) received their first dose of the study drug in the ICU. Most patients had well-recognized risk factors for invasive candidiasis, including broad-spectrum antibiotics, central venous catheters, and hyperalimentation. Recent surgery was more common whereas malignancy, neutropenia, and immunosuppression were less common among ICU patients than among non-ICU patients. Candidemia was demonstrated in 81% of ICU patients and in 84% of non-ICU patients. Favorable response rates in the ICU patients vs the non-ICU patients were 68% (95% confidence interval [CI] = 53%, 82%) vs 77% (95% CI = 67%, 87%) for caspofungin and 56% (95% CI = 43%, 69%) vs 67% (95% CI = 55%, 79%) for amphotericin B. After accounting for differences in APACHE (Acute Physiology and Chronic Health Evaluation) II score, neutropenia status, and geographic region, we found that patients initiating the study therapy in an ICU were still more likely to die than patients initiating study therapy outside an ICU. For ICU patients, all-cause mortality rates were 45% (95% CI = 30%, 60%) for caspofungin recipients and 40% (95% CI = 28%, 53%) for amphotericin B recipients, whereas candidiasis-attributable mortality rates were 5% (95% CI = 0%, 12%) for caspofungin recipients and 11% (95% CI = 3%, 19%) for amphotericin B recipients. Overall, drug-related adverse events were reported less often among the ICU patients than among the non-ICU patients. CONCLUSIONS: In ICU patients treated with antifungal therapy, invasive candidiasis is associated with substantial mortality, but most deaths cannot be directly attributed to this infection.

Caspofungin for the treatment of less common forms of invasive candidiasis.

OBJECTIVES: Caspofungin has demonstrated efficacy in invasive candidiasis. However, in a comparative study, most patients (>83%) had candidaemia. Therefore, we performed a study in patients with non-fungaemic invasive candidiasis. PATIENTS AND METHODS: Adults with proven non-fungaemic invasive candidiasis or probable chronic disseminated candidiasis (CDC) received caspofungin primary or salvage monotherapy. Most patients received 50 mg daily following a 70 mg loading dose. Patients with endocarditis, osteomyelitis or septic arthritis received caspofungin at 100 mg daily and were allowed dose escalation up to 150 mg. Primary efficacy endpoint was the overall response at end of caspofungin therapy. A favourable overall response required complete resolution of symptoms and either eradication of Candida or radiographic resolution. RESULTS: All 48 patients enrolled had confirmed infection and received>or=1 dose of caspofungin. At study entry, 8% were neutropenic. The mean APACHE II score was 14.3. Most infections were due to Candida albicans (60%) or Candida glabrata (14%). The overall success at end of caspofungin therapy was 81%. Success by site of infection was as follows: peritonitis 77% (10/13), abdominal abscess 89% (8/9), CDC 88% (7/8), osteomyelitis/septic arthritis 100% (4/4), endocarditis 33% (1/3) and multiple sites 75% (6/8). Outcomes were similar across Candida spp. None of the patients had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Overall mortality until 12 week follow-up was 23%. CONCLUSIONS: In deep-seated invasive candidiasis, including peritonitis, abdominal abscesses, CDC and arthritis, caspofungin was effective and safe at regular doses and up to 100 mg daily.

Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis.

BACKGROUND: Caspofungin inhibits synthesis of beta-1,3-glucan, an essential component of the Aspergillus cell wall. This echinocandin has demonstrated efficacy (45% success) as salvage monotherapy of invasive aspergillosis (IA). Interest remains as to whether caspofungin, in combination with other antifungal classes, can improve the efficacy against IA. METHODS: The study involved 53 adults with documented IA who were refractory to or intolerant of standard antifungal therapy and received caspofungin and 1 other mold-active antifungal agent (at the investigator's discretion). Efficacy was assessed by signs, symptoms, and radiographs at the end of combination therapy and Day 84 after combination therapy initiation. Favorable (complete or partial) responses required significant clinical and radiographic improvement. Diagnoses and outcomes were assessed by an independent expert. RESULTS: Among the 53 patients enrolled the most common underlying diseases were acute leukemia (53%), lymphoma (11%), and chronic leukemia (6%). Pulmonary aspergillosis (81%) was the most common site, and most patients (87%) were refractory to prior therapy. Success at the end of combination therapy and Day 84 was 55% (29/53) and 49% (25/51), respectively. Fifty-seven percent of patients with neutropenia and 54% who received an allogeneic hematopoietic stem cell transplant responded favorably. Survival at Day 84 was 55%. Combination therapy, dosed on average for 31.3 days, was well tolerated. Two (4%) serious drug-related adverse events, both attributed to voriconazole, occurred. None of the patients discontinued caspofungin due to toxicity. CONCLUSIONS: Caspofungin in combination with a triazole or polyene was an effective alternative as salvage therapy for patients with recalcitrant Aspergillus infections.

Efficacy of caspofungin against invasive Candida or invasive Aspergillus infections in neutropenic patients.

BACKGROUND: Neutropenia is an indicator of poor prognosis in patients with fungal infections. All available clinical trial experience from the caspofungin development program was reviewed to ascertain the efficacy of caspofungin in neutropenic patients with documented invasive aspergillosis (IA) or invasive candidiasis (IC). METHODS: The review was limited to neutropenic patients with proven IC or proven/probable IA at caspofungin onset. Data were available from four clinical trials. All patients had an absolute neutrophil count < 500/mm(3) at the initiation of caspofungin. In all cases caspofungin was administered as monotherapy at a dose of 50 mg/day, after a 70-mg loading dose. In all patients efficacy was assessed at the completion of caspofungin therapy. Success included complete and partial responses. RESULTS: Sixty-eight neutropenic patients were identified with documented invasive infection, including 27 with IC and 41 with IA. Most patients had acute or chronic leukemia. A favorable response was noted in 63% (17 of 27 patients) of patients with IC, including a 58% (14 of 24 patients) response as first-line therapy and a 100% (3 of 3 patients) response as salvage therapy. Success in candidemia was 68% (17 of 25 patients). Outcomes across the different Candida species were similar. Favorable responses were noted in 39% (16 of 41 patients) of patients with IA, including a 42% (5 of 12 patients) response as first-line therapy and 38% (11 of 29 patients) response as salvage therapy. Success by site of IA was 40% for pulmonary (12 of 30 patients), 43% for sinus (3 of 7 patients), and 25% for skin/disseminated site (1 of 4 patients). CONCLUSIONS: A review of the caspofungin database demonstrates that this echinocandin is effective in neutropenic patients with documented cases of IC or IA.

Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents.

Caspofungin is a parenteral antifungal that inhibits beta-1,3-D-glucan synthesis. Although licensed for adult use, the appropriate caspofungin dosing regimen in pediatric patients is not yet known. We therefore investigated the pharmacokinetics and safety of caspofungin in pediatric patients. Thirty-nine children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) with neutropenia were administered caspofungin using either a weight-based regimen (1 mg/kg of body weight/day) or a body surface area regimen (50 mg/m2/day or 70 mg/m2/day). Plasma samples for caspofungin profiles were collected on days 1 and 4. These results were compared to those from adults treated with either 50 or 70 mg/day for mucosal candidiasis. In children receiving 1 mg/kg/day (maximum, 50 mg/day), the area under the concentration-time curve over 24 h (AUC(0-24)) was significantly smaller (46% after multiple doses) than that observed in adults receiving 50 mg/day (P < 0.001). In children and adolescents receiving 50 mg/m2/day (maximum, 70 mg/day), the AUC(0-24) following multiple doses was similar to that for the exposure in adults receiving 50 mg/day. The AUC(0-24) and concentration trough (at 24 h) in pediatric patients receiving the 50-mg/m2 daily regimen were consistent across the range of ages. Caspofungin was generally well tolerated in this study. None of the patients developed a serious drug-related adverse event or were discontinued for toxicity. These results demonstrate that caspofungin at 1 mg/kg/day in pediatric patients is suboptimal. Caspofungin administration at 50 mg/m2/day provides a comparable exposure to that of adult patients treated with 50 mg/day.

Caspofungin susceptibility testing of isolates from patients with esophageal candidiasis or invasive candidiasis: relationship of MIC to treatment outcome.

The caspofungin clinical trial database offers an opportunity to assess susceptibility results for Candida pathogens obtained from patients with candidiasis and allows for correlations between efficacy outcomes and MICs. Candida isolates have been identified from patients enrolled in four studies of esophageal candidiasis and two studies of invasive candidiasis. The MICs of caspofungin for all baseline isolates were measured at a central laboratory using NCCLS criteria (document M-27A); MICs for caspofungin were defined as the lowest concentration inhibiting prominent growth at 24 h. MICs were then compared to clinical and microbiological outcomes across the two diseases. Susceptibility testing for caspofungin was performed on 515 unique baseline isolates of Candida spp. obtained from patients with esophageal candidiasis. MICs for caspofungin ranged from 0.008 to 4 microg/ml; the MIC50 and MIC90 were 0.5 and 1.0 microg/ml, respectively. Susceptibility testing was also performed on 231 unique baseline isolates of Candida spp. from patients with invasive candidiasis. The majority (approximately 96%) of MICs were between 0.125 and 2 microg/ml, with MIC50 and MIC90 for caspofungin being 0.5 and 2.0 microg/ml, respectively. Overall, caspofungin demonstrated potent in vitro activity against clinical isolates of Candida species. A relationship between MIC for caspofungin and treatment outcome was not seen for patients with either esophageal candidiasis or invasive candidiasis. Patients with isolates for which the MICs were highest (>2 microg/ml) had better outcomes than patients with isolates for which the MICs were lower (<1 microg/ml). Additionally, no correlation between MIC and outcome was identified for specific Candida species.

Evaluation of serum sandwich enzyme-linked immunosorbent assay for circulating galactomannan during caspofungin therapy: results from the caspofungin invasive aspergillosis study.

There has been minimal clinical experience with the use of the Aspergillus galactomannan enzyme-linked immunosorbent assay (ELISA) for patients receiving echinocandin therapy. We reviewed the experience with the galactomannan ELISA for 17 patients in a study of caspofungin treatment for invasive aspergillosis. The rate of successful outcomes for these patients was similar to that overall for participants in the study. Trends in antigenemia levels correlated with clinical and radiographic findings.

Invasive candidiasis in cancer patients: observations from a randomized clinical trial.

BACKGROUND: Invasive candidiasis is a common and serious complication of cancer and its therapy. METHODS: We retrospectively identified patients with malignancies enrolled in a double-blind randomized trial of caspofungin (50 mg/day after a 70 mg loading dose) vs. conventional amphotericin B (0.6-1.0 mg/kg/day) as treatment of documented invasive candidiasis. A favorable response required complete resolution of signs and symptoms plus eradication of the Candida pathogen(s). The primary efficacy analysis used a modified intention-to-treat (MITT) approach that included all patients with a confirmed diagnosis of invasive candidiasis who received > or =1 dose of study medication. RESULTS: 74/224 (33%) patients in the MITT population had active malignancies. 25/30 (83%) hematological malignancies were acute or chronic leukaemias. 22/44 (50%) solid tumors were related to the gastrointestinal tract. Patients with hematological malignancies tended to be younger (median [range] age: 49 [19-74] vs. 59 [19-81] years) and have higher baseline acute physiology and chronic health evaluation (APACHE) II scores (mean [range]: 17 [0-28] vs. 15 [5-35]) than patients with solid tumors. Neutropenia [< or =500/microl] was present on entry in 23 (77%) patients with hematological malignancies and in one (3%) patient with a solid tumor. Candidemia was demonstrated in 56 (88%) cancer patients. C. albicans was the single most frequent isolate in cancer patients, although the majority of cases were caused by non-albicans species. Cancer patients in the caspofungin arm had more hematological malignancies (55 vs. 29%), higher baseline APACHE II scores (>20 in 36 vs. 15%), more frequent neutropenia (42 vs. 24%), and less C. albicans infections (27 vs. 49%) than the amphotericin B-treated cancer patients. Favorable response rates were 11/18 (61%) and 6/12 (50%) for patients with hematological malignancies treated with caspofungin or amphotericin B, respectively; the corresponding outcomes in patients with solid tumors were 12/15 (80%) and 17/29 (59%) for the 2 treatment arms. 7/14 (50%) caspofungin- and 4/10 (40%) amphotericin B-treated patients who were neutropenic on entry responded favorably. All-cause mortality rates during the study for caspofungin recipients were 11/18 (61%) with hematological malignancies and 6/15 (40%) with solid tumors, and for amphotericin recipients were 4/12 (33%) with hematological malignancies and 6/29 (21%) with solid tumors. CONCLUSIONS: Underlying cancers, most commonly leukaemias and gastrointestinal tumors, were present in one-third of patients enrolled in this study of invasive candidiasis. Overall, 70% of caspofungin-treated and 56% of amphotericin B-treated cancer patients responded favorably. Response rates were lower for neutropenic leukaemic patients than for non-neutropenic patients with solid tumors in both treatment groups.

Salvage therapy with caspofungin for invasive aspergillosis: results from the caspofungin compassionate use study.

OBJECTIVES: The objective was to prospectively assess the efficacy and safety of caspofungin as salvage therapy for invasive aspergillosis in patients enrolled in the caspofungin compassionate-use study. METHODS: Forty-eight patients with invasive Aspergillus infections (36 with pulmonary infection, 12 with extrapulmonary or disseminated infection) were enrolled in this study. All patients were refractory to or intolerant of intravenous amphotericin B or a lipid amphotericin formulation(s). Efficacy was assessed at end of intravenous caspofungin therapy based on the clinical (symptom/sign and radiographic) response. RESULTS: Underlying diseases included hematological malignancy (69%), organ transplant (8%), and AIDS (6%). Forty-three (90%) patients were refractory to prior antifungal treatment, including 25 patients refractory to multiple agents. Sixteen (33%) were neutropenic at study entry. Following caspofungin therapy, a favorable response was noted in 44% (20/45) of the patients, including nine (20%) and 11 (24%) patients with complete and partial responses, respectively. Caspofungin was generally well tolerated one serious drug-related adverse event was reported. CONCLUSIONS: In this study, caspofungin was an effective alternative for patients with refractory Aspergillus infections.

Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy.

BACKGROUND: Invasive aspergillosis (IA) is an important cause of morbidity and mortality among immunocompromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo activity against Aspergillus species. METHODS: We investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin. RESULTS: Efficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received >or=1 dose of study drug. Common underlying conditions included hematologic malignancy (48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently. CONCLUSION: Caspofungin demonstrated usefulness in the salvage treatment of IA.