[Show abstract][Hide abstract] ABSTRACT: Microbiologically influenced corrosion (MIC), also known as biocorrosion, is caused by corrosive biofilms. MIC is a growing problem, especially in the oil and gas industry. Among various corrosive microbes, sulfate reducing bacteria (SRB) are often the leading culprit. Biofilm mitigation is the key to MIC mitigation. Biocide applications against biofilms promote resistance over time. Thus, it is imperative to develop new biodegradable and cost-effective biocides for large-scale field applications. Using the corrosive Desulfovibrio vulgaris (an SRB) biofilm as a model biofilm, this work demonstrated that a cocktail of glyceryl trinitrate (GTN) and caprylic acid (CA) was very effective for biofilm prevention and mitigation of established biofilms on C1018 carbon steel coupons. The most probable number sessile cell count data and confocal laser scanning microscope biofilm images proved that the biocide cocktail of 25 ppm (w/w) GTN + 0.1 % (w/w) CA successfully prevented the D. vulgaris biofilm establishment on C1018 carbon steel coupons while 100 ppm GTN + 0.1 % CA effectively mitigated pre-established D. vulgaris biofilms on C1018 carbon steel coupons. In both cases, the cocktails were able to reduce the sessile cell count from 106 cells/cm2 to an undetectable level.
Full-text · Article · Feb 2016 · World Journal of Microbiology and Biotechnology
[Show abstract][Hide abstract] ABSTRACT: Background:
Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease.
This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893.
527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001).
Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease.
Astellas Pharma Global Development, Basilea Pharmaceutica International.
[Show abstract][Hide abstract] ABSTRACT: Objective:
Previously, we investigated a locally developed technique of bonding arterial grafts with three antimicrobials to protect against early (within 2 weeks) perioperative bacterial contamination encountered occasionally during aortic graft prosthetic reconstruction. Vascular graft infections are classified by their appearance time (early [<4 months] vs late [>4 months] after graft implantation), degree of incorporation into the surrounding vessel wall, connectivity to the postoperative wound, and extent of graft involvement. In the current phase of testing, we evaluated the ability of our novel triple antimicrobial-bonded graft to prevent infection in the first 8 weeks after implantation.
In nine Sinclair miniature pigs, we surgically implanted a 6-mm vascular Dacron patch graft in the infrarenal abdominal aorta. Five pigs received grafts chemically bonded with a 60-mg/mL solution of rifampin, minocycline, and chlorhexidine, and four pigs received unbonded grafts. Before implantation, the five bonded grafts and three of the unbonded grafts were immersed for 15 minutes in a 2-mL solution containing 1-2 × 10(7) colony-forming units (CFUs)/mL of Staphylococcus aureus (ATCC 29213); the fourth unbonded graft served as a control.
At week 9, all of the grafts were explanted. All S aureus-inoculated bonded grafts (n = 5) showed no bacterial growth. The unbonded, uninoculated graft (n = 1) showed low-level bacterial growth (<1.2 × 10(3) CFUs); S cohnii spp urealyticus, but not S aureus, was isolated, which suggested accidental direct perioperative contamination. Two pigs that received S aureus-inoculated, unbonded grafts were euthanized because of severe S aureus infection (<6.56 × 10(8) CFUs per graft). Results of histopathologic analysis were concordant with the microbiologic findings. Most intergroup differences were observed in the inflammatory infiltrate in the aortic wall at the site of graft implantation. In all pigs that received bonded grafts, Gram staining showed no bacteria.
Our triple-bonded aortic graft prevented perioperative aortic graft infection for at least 8 weeks in a porcine model. The synergistic antimicrobial activity of this graft was sufficient to prevent and/or eradicate infection during that period. Further studies are needed to assess the graft's ability to combat early-onset vascular graft infection for up to 4 months.
No preview · Article · Nov 2015 · Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
[Show abstract][Hide abstract] ABSTRACT: Gram-positive bacteria infections are an important cause of morbidity and mortality in cancer patients despite current therapy. In this case control study, we evaluated the clinical outcomes and safety of telavancin in cancer patients with uncomplicated gram-positive BSIs. Between March 2011 and May 2013, we enrolled cancer patients with uncomplicated gram-positive bloodstream infections (BSIs) to receive intravenous telavancin for at least 14 days for Staphylococcus aureus and 7 days for other gram-positive cocci. Patients with baseline creatinine clearance (Cr Cl) >50mL/min received 10mg/kg/day of telavancin, and those with Cr Cl between 30-49mL/min received 7.5mg/kg/day. Patients were compared with a retrospective cohort of 39 historical patients matched for underlying malignancy, infecting organism, and neutropenia status with gram-positive BSIs who were treated with vancomycin. A total of 78 patients were analyzed, 39 in each group. The most common pathogen causing BSI was S. aureus (51%), followed by alpha-hemolytic Streptococci (23%), Enterococci spp.(15%), coagulase-negative Staphylococci (8%), and beta-hemolytic Streptococci (3%). Sixty-two percent of patients had hematological malignancies, and 38% had solid tumors. 51% of patients were neutropenic. Overall response determined by clinical outcome and microbiological eradication at 72 hours following initiation of therapy, in the absence of relapse, deep-seated infections and infection-related mortality was better with telavancin compared to vancomycin (86% vs. 61%; P=0.013). Drug-related adverse events were similar in both groups (telavancin, 31% vs vancomycin, 23%; P = .79), with similar incidences of renal adverse events. Telavancin may provide a useful alternative to standard vancomycin therapy for gram-positive BSI in cancer patients.
No preview · Article · Oct 2015 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Background: Hepatitis C virus (HCV) infection is difficult to treat in cancer patients (pts). We report the educational experience from our center focused on HCV care of pts with various types of malignancies.
Methods: In 8/2009, a clinic devoted to managing HCV infection in cancer pts was started in our center by infectious diseases (ID) specialists in collaboration with hepatologists. Multidisciplinary educational activities were implemented to train nurses, mid-level providers, public health students, prospective internal medicine residents, ID fellows, and ID providers. To understand the strengths and limitations of diagnosis and management of this unique population and to establish best practices, all clinic pts were evaluated following a standardized approach.
Results: Between 8/2009 and 4/2015, 475 HCV-infected cancer pts were evaluated in the clinic. Pts were monitored for liver disease progression, eligibility for antiviral therapy (AVT), drug interactions, adverse events of AVT, and outcomes. Clinic nurses provided care to patients, facilitated insurance approval of treatment, assessed side effects of AVT, and educated pts/caregivers. Since 2009, 30 nurses have been trained and over 600 pts/caregivers educated on HCV infection. Seven mid-level providers were trained to deliver HCV care. In 2014, four ID fellows joined the clinic as an elective rotation. A formal training for managing HCV in cancer pts was begun in 2015 with a mandatory continuity clinic for ID fellows. Six research fellows have presented clinic data in more than 30 professional meetings, and published 15 articles in peer-reviewed journals including various aspects of epidemiology, oncogenesis, complications, and treatment outcomes. Future plans include evaluation of pt/caregivers knowledge and attitudes regarding HCV and AVT. Management guidelines are being developed for HCV-infected cancer patients related to rapidly changing standard of care.
Conclusion: Educational efforts focused on HCV care in cancer pts provide transdisciplinary learning opportunities for nurses, mid-level providers, public health students, and physicians in training. This training experience could be replicated in other academic centers in the US.
[Show abstract][Hide abstract] ABSTRACT: Isolates from patients who acquired vancomycin-resistant enterococci (VRE) were examined for the frequency of genetically indistinguishable strains on leukemia and stem cell transplant units at a major cancer center for 1 year. A total of 14 strains recurred, primarily on the same floor and in the same service unit an average of 49 days apart.
Infect. Control Hosp. Epidemiol.
Full-text · Article · Sep 2015 · Infection Control and Hospital Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Procalcitonin (PCT) and Interleukin-6 (IL-6) have emerged as biomarkers for different inflammatory conditions. The purpose of the study was to evaluate the role of PCT and IL-6 as biomarkers of cancer and its progression in a large cohort of patients. This cross-sectional study included residual plasma samples collected from cancer patients, and control subjects without cancer. Levels of PCT and IL-6 were determined by Kryptor compact bioanalyzer. We identified 575 febrile cancer patients, 410 non-febrile cancer patients, and 79 non-cancer individuals. The median PCT level was lower in control subjects (0.029 ng/ml) compared to cancer patients with stage I-III disease (0.127 ng/ml) (p<0.0001) and stage IV disease (0.190 ng/ml) (p<0.0001). It was also higher in febrile cancer patients (0.310 ng/ml) compared to non-febrile cancer patients (0.1 ng/ml) (p<0.0001). Median IL-6 level was significantly lower in the control group (0 pg/ml) than in non-febrile cancer patients with stages I-III (7.376 pg/ml) or stage IV (9.635 pg/ml) (p<0.0001). Our results suggest a potential role for PCT and IL-6 in predicting cancer in non-febrile patients. In addition, PCT is useful in detecting progression of cancer and predicting bacteremia or sepsis in febrile cancer patients.
[Show abstract][Hide abstract] ABSTRACT: Antimicrobial peripherally inserted central catheters (PICCs) might reduce the incidence of central line-associated bloodstream infections (CLABSI). We tested the biocompatibility of a novel gendine-coated (combination of chlorhexidine [CHX] and gentian violet [GV]) PICC in a rabbit intravascular model and tested antimicrobial efficacy in comparison with commercially available minocycline/rifampin (M/R)- and CHX-treated PICCs in an in vitro biofilm colonization model. Gendine-coated and uncoated control PICCs were inserted in the jugular veins of rabbits for 4 days. Histopathological analysis was performed at the end of the 4-day period, and circulating levels of CHX and GV in the blood were measured at different time points using liquid chromatography-mass spectrometry. The antimicrobial efficacy of the PICCs was tested following simulated intravascular indwells of 24 h and 1 week against clinical isolates of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Enterobacter cloacae, Candida albicans, and Candida glabrata. Rabbits implanted with gendine-coated PICCs exhibited reduced levels of thrombosis and inflammation compared to those of the rabbits with uncoated controls. No GV was detected in blood samples over the entire study period, and trace concentrations of CHX were detected. The gendine-coated PICCs completely prevented the adherence of all pathogens from 24 h to 1 week (P ≤ 0.001), while M/R-treated, CHX-treated, and control PICCs did not. Gendine-coated PICCs were highly effective in preventing biofilm formation of multidrug-resistant pathogenic bacteria and fungi. Gendine-coated PICCs were biocompatible in an intravascular setting. Further, the pharmacokinetic testing established that acute systemic exposures of CHX and GV from the gendine-coated catheters were well within safe levels.
No preview · Article · Jun 2015 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Alpha-fetoprotein (AFP) is a diagnostic marker for hepatocellular carcinoma (HCC). A direct relationship between poor prognosis and the concentration of serum AFP has been observed. Telomerase, an enzyme that stabilizes the telomere length, is expressed by 90% of HCC. The aim of this study was to investigate the effect of telomerase inhibition on AFP secretion and the involvement of the PI3K/Akt/mTOR signaling pathway. Proliferation and viability tests were performed using tetrazolium salt. Apoptosis was determined through the Annexin V assay using flow cytometry. The concentrations of AFP were measured using ELISA kits. The AFP mRNA expression was evaluated using RT-PCR, and cell migration was evaluated using a Boyden chamber assay. The in vivo effect of costunolide on AFP production was tested in NSG mice. Telomerase inhibition by costunolide and BIBR 1532 at 5 and 10 μM decreased AFP mRNA expression and protein secretion by HepG2/C3A cells. The same pattern was obtained with cells treated with hTERT siRNA. This treatment exhibited no apoptotic effect. The AFP mRNA expression and protein secretion by PLC/PRF/5 was decreased after treatment with BIBR1532 at 10 μM. In contrast, no effect was obtained for PLC/PRF/5 cells treated with costunolide at 5 or 10 μM. Inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP concentration. In contrast, the MAPK/ERK pathway appeared to not be involved in HepG2/C3A cells, whereas ERK inhibition decreased the AFP concentration in PLC/PRF/5 cells. Modulation of the AFP concentration was also obtained after the inhibition or activation of PKC. Costunolide (30 mg/kg) significantly decreased the AFP serum concentration of NSG mice bearing HepG2/C3A cells. Both the inhibition of telomerase and the inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP production of HepG2/C3A and PLC/PRF/5 cells, suggesting a relationship between telomerase and AFP expression through the PI3K/Akt/mTOR pathway.
[Show abstract][Hide abstract] ABSTRACT: In patients with malignancy, the major barrier to achieving complete response is emergence of resistance to current chemotherapeutic agents. One of the major mechanisms by which tumor cells become resistant to therapies is by altering cellular drug targets through mutations and/or deletions. Resistance by this mechanism is achieved more easily if the drug has limited cellular targets and/or processes. We hypothesized that since Pseudomonas aeruginosa ExoT targets six proteins that are required for cancer cell survival and proliferation, it is highly unlikely for cancer cells to develop resistance to this toxin. We assessed ExoT's cytotoxicity against multiple invasive and highly resistant tumor cell lines in order to evaluate its potential as a chemotherapeutic agent. Our data demonstrate that ExoT induces potent cytotoxicity in all tumor cell lines that we examined. Collectively, our data highlights the potential of ExoT as a possible chemotherapeutic candidate for the treatment of cancer.
Full-text · Article · Jan 2015 · Journal of Medical Microbiology
[Show abstract][Hide abstract] ABSTRACT: Background: Hepatitis C virus (HCV) infection is a neglected disease in patients with cancer. Therefore, this study examined the impact of HCV infections in these patients.
Methods: The records of HCV-infected patients with cancer seen at The University of Texas MD Anderson Cancer Center (2008–2011) were reviewed. The outcomes of those who underwent HCV treatment were analyzed.
Results: Of 1291 patients who had positive test results for an antibody to HCV (anti-HCV), 744 (58%) were tested for HCV-RNA; 642 (86%) of which had chronic HCV infections. Most had solid tumors (72%) and genotype-1 (G-1) infections (66%). HCV therapy was administered in 348 patients (98 of them after cancer diagnosis). Sustained virologic response (SVR) occurred in 27 (35%) of the 78 patients treated for whom outcome data were available. Compared with patients who experienced an SVR, more patients who did not were black (29% vs 4%; P=.007), had G-1 infections (72% vs 6%; P<.0001), and had higher baseline aspartate aminotransferase (78 vs 47 IU/L; P=.006) and alanine aminotransferase levels (71.1 vs 43.3 IU/L; P=.009). Overall, progression to cirrhosis (hazard ratio [HR], 0.38; P=.03) and portal hypertension (HR, 0.19; P=.009) was less common in those treated, irrespective of the treatment outcome (SVR or non-SVR). Hepatocellular carcinoma (HCC) developed as a second primary malignancy in 7% of patients with non-HCC cancer.
Conclusions: This is the largest series to analyze HCV infections in patients with cancer. HCV therapy is feasible and prevents liver disease progression in this forgotten population. A treatment algorithm is provided.
Full-text · Article · Jan 2015 · Journal of the National Comprehensive Cancer Network: JNCCN
[Show abstract][Hide abstract] ABSTRACT: Different types of central venous catheters (CVCs) have been used in clinical practice to improve the quality of life of chronically and critically ill patients. Unfortunately, indwelling devices are usually associated with microbial biofilms and eventually lead to catheter-related bloodstream infections (CLABSIs).
An estimated 250,000–400,000 CLABSIs occur every year in the United States, at a rate of 1.5 per 1,000 CVC days and a mortality rate of 12–25 %. The annual cost of caring for patients with CLABSIs ranges from 296 million to 2.3 billion dollars.
Biofilm formation occurs on biotic and abiotic surfaces in the clinical setting. Extensive studies have been conducted to understand biofilm formation, including different biofilm developmental stages, biofilm matrix compositions, quorum-sensing regulated biofilm formation, biofilm dispersal (and its clinical implications), and multi-species biofilms that are relevant to polymicrobial infections.
When microbes form a matured biofilm within human hosts through medical devices such as CVCs, the infection becomes resistant to antibiotic treatment and can develop into a chronic condition. For that reason, many techniques have been used to prevent the formation of biofilm by targeting different stages of biofilm maturation. Other methods have been used to diagnose and treat established cases of CLABSI.
Catheter removal is the conventional management of catheter associated bacteremia; however, the procedure itself carries a relatively high risk of mechanical complications. Salvaging the catheter can help to minimize these complications.
In this article, we provide an overview of microbial biofilm formation; describe the involvement of various genetic determinants, adhesion proteins, organelles, mechanism(s) of biofilm formation, polymicrobial infections, and biofilm-associated infections on indwelling intravascular catheters; and describe the diagnosis, management, and prevention of catheter-related bloodstream infections.
No preview · Article · Jan 2015 · Advances in Experimental Medicine and Biology
[Show abstract][Hide abstract] ABSTRACT: Invasive aspergillosis (IA) is a life-threatening infection in severely immunocompromised haematological malignancy patients. In this study, the efficacy and safety of caspofungin, voriconazole or the combination as primary and salvage therapy in patients with IA were compared. The study included 181 patients with haematological malignancies and IA who received primary or salvage therapy with caspofungin, voriconazole or the combination. In total, 138 patients who received treatment for ≥7 days were analysed; 86 underwent primary antifungal therapy (15 with caspofungin, 38 with voriconazole and 33 with both). Among the salvage therapy patients, 17 received caspofungin, 24 received voriconazole and 35 received both. In the primary therapy group, no difference in therapy response was found, but caspofungin was associated with higher IA mortality rates. A multivariate competing risk analysis of primary antifungal therapy revealed that voriconazole was independently associated with lower IA-associated mortality rates than caspofungin (hazard ratio = 0.2, 95% confidence interval 0.06–0.96; P = 0.04). In the salvage therapy group, the three treatment groups had similar responses and IA-associated mortality rates. The combination of voriconazole and caspofungin did not result in better outcomes compared with voriconazole alone, as primary or salvage therapy, in haematological malignancy patients. However, voriconazole was associated with a lower Aspergillus-associated mortality rate compared with caspofungin monotherapy.
No preview · Article · Oct 2014 · International Journal of Antimicrobial Agents
[Show abstract][Hide abstract] ABSTRACT: Background:
Procalcitonin (PCT) and Interleukin-6 (IL-6) have emerged as biomarkers for different inflammatory conditions, including cancer and infection. The purpose of the study was to evaluate the role of PCT and IL-6 as biomarkers of cancer and its progression in a large cohort of patients with and without infection.
This prospective, observational study included residual plasma samples collected from febrile and non-febrile cancer patients, and control subjects without cancer. Levels of PCT and IL-6 were determined by Kryptor compact bioanalyzer and ELISA respectively.
We identified a total of 1064 patients, including 575 febrile cancer patients, 410 non-febrile cancer patients, and 79 non-cancer individuals. The median PCT level was lower in control subjects (0.029 ng/ml) compared to cancer patients with stage I-III disease (0.127 ng/ml) (p<0.0001) and stage IV disease (0.190 ng/ml) (p<0.0001). It was also higher in febrile cancer patients (0.310 ng/ml) compared to non-febrile cancer patients (0.1 ng/ml) (p<0.0001). PCT was also higher in febrile cancer patients with sepsis or bacteremia (0.490 ng/ml) compared to those without microbiological documented infection (0.310 ng/ml) (p=0.003). Median IL-6 level was significantly lower in the control group (0 pg/ml) than in non-febrile cancer patients with stages I-III (7.376 pg/ml) or stage IV (9.635 pg/ml) (p<0.0001), but did not differ in patients with stage IV cancer from those with stage I-III.
Our results suggest a potential role for PCT and IL-6 in predicting cancer in non-febrile patients. PCT is also useful in detecting cancer and its progression in non-febrile patients. However, in febrile cancer patients, PCT predicts bacteremia or sepsis.
[Show abstract][Hide abstract] ABSTRACT: Background: Isavuconazole (ISA) is a novel broad-spectrum triazole antifungal available as a water-soluble prodrug in IV and oral formulations for treatment of invasive fungal disease. A Phase 3 trial assessed the efficacy and safety of ISA vs. voriconazole (VRC) in patients with IMD. Here we report outcomes in a pre-specified subset of patients from this non-inferiority trial, who had proven, probable, or possible pulmonary mold disease (PMD) without other site involvement (lower respiratory tract disease only).
Methods: Patients were randomized 1:1 to receive ISA or VRC for up to 84 days. Dosing regimens were: ISA 200mg IV TID for 2 days, followed by 200mg QD (IV or PO); VRC 6mg/kg IV BID on Day 1, 4mg/kg IV BID on Day 2, then either 4mg/kg IV BID or 200mg PO BID. Eligibility criteria and pre-specified outcomes are available at clinicaltrials.gov, NCT00412893. The primary efficacy endpoint was all-cause mortality by Day 42. All-cause mortality on Day 84, overall success (complete + partial response) at end of treatment (EOT) determined by an independent blinded data review committee were recorded. Safety and tolerability were also assessed, as reported by the Investigator.
Results: Overall 412 patients with proven/probable/possible PMD, primarily caused by Aspergillus spp. (n=224), were enrolled. Patient characteristics, outcomes, and adverse events (AEs) are presented in Table 1. Outcomes in patients with proven/probable cases were similar to those with proven/probable/possible infections.
Table 1.Efficacy and safety in patients with PMD
Adjusted difference* % (95% CI)
All-cause mortality on Day 42
−2.9 (−10.4, 4.6)
All-cause mortality on Day 84
−3.8 (−12.4, 4.8)
Overall success at EOT
−1.8 (−11.1, 7.4)
Study drug-related AEs
Study drug-related serious AEs
AE leading to permanent discontinuation
Conclusion: ISA had comparable efficacy to VRC for the primary treatment of PMD patients, but had a lower rate of drug-related AEs vs. VRC