Iron Dextran

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Steven Fishbane - One of the best experts on this subject based on the ideXlab platform.

  • sodium ferric gluconate complex in hemodialysis patients ii adverse reactions in Iron Dextran sensitive and Dextran tolerant patients
    Kidney International, 2003
    Co-Authors: Daniel W Coyne, Rajiv Agarwal, Steven Fishbane, Allen R Nissenson, Beckie Michael, Vaughn W Folkert, Joseph W Eschbach, Franklin N Adkinson, Daniel Batlle, Richard J Trout
    Abstract:

    Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in Iron Dextran-sensitive and Dextran-tolerant patients. Background Iron Dextran administration is associated with a high incidence of adverse reactions including anaphylaxis and death. Although Dextran, rather than Iron, is believed to be the cause of these reactions, it is not known whether Iron Dextran-sensitive patients can be safely administered another form of parenteral Iron, sodium ferric gluconate in sucrose (SFGC). Methods In a 69 center, prospective, double-blind, controlled trial of safety and tolerability of SFGC, the rate of reactions to SFGC and placebo in 144 Iron Dextran-sensitive patients was compared with 2194 patients who were previously tolerant to Iron Dextran preparations. Serum tryptase levels, a marker of mast cell degranulation, also were measured. Results Among 143 Iron Dextran-sensitive patients exposed to SFGC, three (2.1%) were intolerant. All three had suspected allergic events to SFGC, including one patient with a serious reaction (0.7%). One Dextran-sensitive patient (0.7%) had a suspected allergic reaction after placebo. In contrast, among 2194 Iron Dextran-tolerant patients, reactions to SFGC were significantly less common, with SFGC intolerance seen in seven patients (0.3%; P = 0.020), including five (0.2%) who had suspected allergic events ( P = 0.010), but none who had serious events (0.0%; P = 0.061). Two Iron Dextran-tolerant patients (0.09%) had allergic-like reactions following placebo injections. Two of the three suspected allergic events in the Iron Dextran-sensitive group were confirmed as mast cell dependent by a 100% increase in serum tryptase, while there were no confirmed allergic events in the Iron Dextran-tolerant group. Long-term exposure to SFGC in Iron Dextran-sensitive patients resulted in intolerance in only one additional patient and no serious adverse events. Conclusions Patients with a history of Iron Dextran sensitivity had approximately sevenfold higher rates of reaction to both placebo and SFGC compared to Iron Dextran tolerant patients. However, logistic regression analysis, performed to account for the higher reaction rate to placebo, suggests that this increased reactivity was not drug-specific nor immunologically mediated, but represented host idiosyncrasy. These results support the conclusions that reactions to SFGC can be attributed to pseudoallergy, and that SFGC is not a true allergen.

  • sodium ferric gluconate complex in hemodialysis patients adverse reactions compared to placebo and Iron Dextran
    Kidney International, 2002
    Co-Authors: Beckie Michael, Rajiv Agarwal, Steven Fishbane, Daniel W Coyne, Allen R Nissenson, Vaughn W Folkert, Robert I Lynn, Joseph W Eschbach, Stephen Z Fadem, Richard J Trout
    Abstract:

    Sodium ferric gluconate complex in hemodialysis patients: Adverse reactions compared to placebo and Iron Dextran. Background Parenteral Iron is often required by hemodialysis patients to maintain adequate Iron stores. Until recently, the only available form of intravenous Iron was Iron Dextran, which is associated with significant adverse reactions, including anaphylaxis and death. Sodium ferric gluconate complex (SFGC) was recently approved for use in the U.S. under FDA's priority drug review. This Phase IV study was designed to evaluate the safety of a single dose of intravenous SFGC as compared to placebo and a historical Iron Dextran control. Methods This multicenter, crossover, randomized, double blind, placebo-controlled prospective comparative study was performed in hemodialysis patients requiring at least 125mg of elemental Iron. The historical control was obtained from a meta-analysis of four publications examining outcomes in patients exposed to Iron Dextran. SFGC naive patients were administered SFGC without a test dose, undiluted, at a rate of 125mg over 10 minutes, and compared to placebo comprising bacteriostatic saline. Results A total of 2534 patients were enrolled. The incidence of drug intolerance (an adverse event precluding re-exposure) was significantly less [0.44%, confidence interval (CI) 0.21 to 0.71%] after SFGC as compared to the Iron Dextran control (2.47%, CI 1.87 to 3.07%, P Conclusion SFGC is well tolerated when given by intravenous push without a test dose. SFGC has a significantly lower incidence of drug intolerance and life-threatening events as compared to previous studies using Iron Dextran. The routine use of Iron Dextran in hemodialysis patients should be discontinued.

  • Sodium ferric gluconate complex in the treatment ofIron deficiency for patients on dialysis
    American journal of kidney diseases : the official journal of the National Kidney Foundation, 2001
    Co-Authors: Steven Fishbane, John Wagner
    Abstract:

    Abstract Intravenous Iron has been found to be an important adjunctive therapy in the treatment of anemia for patients ondialysis. In the United States, Iron Dextran had been the only form available for parenteral use until 1999. This agent has been associated with a concerning number of severe adverse reactions, in some cases resulting In patients' deaths. Recently, a form of Iron used for many years in Europe, sodium ferric gluconate complex in sucrose, was approved for intravenous use in the United States. Because this agent does not contain the immunogenic Dextran component of Iron Dextran, it is expected that the safety profile of this drug should be superior to that of Iron Dextran. The purpose of this review is to critically appraise the relevant literature and to synthesize the information into a strategy for clinical use of this drug.

  • the comparative safety of intravenous Iron Dextran Iron saccharate and sodium ferric gluconate
    Seminars in Dialysis, 2000
    Co-Authors: Steven Fishbane, Edward A Kowalski
    Abstract:

    Intravenous Iron treatment is an important component of anemia therapy for patients on dialysis. Until recently Iron Dextran was the only parenteral form of Iron available in the United States. This drug has been associated with occasional serious adverse reactions, including full-blown anaphylaxis. In 1999 the Food and Drug Administration approved a second form of Iron for intravenous administration, sodium ferric gluconate in sucrose. It is expected that by the time of this publication, a third agent, Iron saccharate will also be approved. In this review the comparative safety of these three agents is critically evaluated.

  • the safety of intravenous Iron Dextran in hemodialysis patients
    American Journal of Kidney Diseases, 1996
    Co-Authors: Steven Fishbane, Virgiliudan Ungureanu, John K Maesaka, Charles J Kaupke, Victoria S Lim, Jay B Wish
    Abstract:

    The treatment of anemia in hemodialysis patients is frequently hindered by the presence of suboptimal Iron stores. Intravenous Iron Dextran is in common use to maintain Iron stores in this population, but there are little published data regarding the incidence and type of adverse events. The purpose of this study was to evaluate the safety of this medication. Charts from four hemodialysis centers of all 573 patients treated with intravenous Iron Dextran (INFeD; Schein Pharmaceutical, Inc, Florham Park, NJ) between July 1, 1993, and June 30, 1995, were studied. Twenty-seven patients (4.7%) had adverse reactions that were related to Iron Dextran. Four patients (0.7%) had reactions classified as serious (one cardiac arrest; three others required hospitalization). Ten patients (1.7%) had reactions classified as anaphylactoid. No patients died or developed permanent disability as a result of reactions. The most common adverse reactions included itching (1.5% of patients) and dyspnea or wheezing (1.5%); others included chest pain (1.0%), nausea (0.5%), hypotension (0.5%), swelling (0.5%), dyspepsia (0.5%), diarrhea (0.5%), skin flushing (0.3%), headache (0.3%), cardiac arrest (0.2%), and myalgias (0.2%). Five of all the reactions occurred during a test dose; four of these were anaphylactoid. Several factors were studied as possible predictors of adverse reactions. A positive history of drug allergy (odds ratio, 2.4; P = 0.03) and history of multiple drug allergy (odds ratio, 5.5; P = 0.0004) were significant predictors of reactions. In summary, we found serious adverse reactions to be uncommon in hemodialysis patients treated with intravenous Iron Dextran. Future prospective studies will help confirm this finding.

Glenn M. Chertow - One of the best experts on this subject based on the ideXlab platform.

  • Original Article Update on adverse drug events associated with parenteral Iron
    2015
    Co-Authors: Glenn M. Chertow, Phillip D. Mason, Odd Vaage-nilsen
    Abstract:

    Background. We previously compared the safety pro-file of three formulations of intravenous Iron used during 1998–2000 and found higher rates of adverse drug events (ADEs) associated with the use of higher molecular weight Iron Dextran and sodium ferric gluconate complex compared with lower molecular weight Iron Dextran. Since that time, Iron sucrose has become widely available and clinicians have gained additional experience with sodium ferric gluconate complex. Methods. We obtained data from the United States Food and Drug Administration (FDA) on ADEs attributed to the provision of four formulations of intravenous Iron during 2001–2003, including highe

  • Original Article On the relative safety of parenteral Iron formulations
    2014
    Co-Authors: Glenn M. Chertow, Phillip D. Mason, Odd Vaage-nilsen
    Abstract:

    Background. Intravenous Iron is usually required to optimize the correction of anaemia in persons with advanced chronic kidney disease and end-stage renal disease. Randomized clinical trials may have insuffi-cient power to detect differences in the safety profiles of specific formulations. Methods. We obtained data from the US Food and Drug Administration on reported adverse drug events (ADEs) related to the provision of three formulations of intravenous Iron during 1998–2000. We estimated the relative risks [odds ratios (OR)] of ADEs asso-ciated with the use of higher molecular weight Iron Dextran and sodium ferric gluconate complex com-pared with lower molecular weight Iron Dextran usin

  • high molecular weight Iron Dextran a wolf in sheep s clothing
    Journal of The American Society of Nephrology, 2008
    Co-Authors: George M. Rodgers, Daniel W Coyne, Glenn M. Chertow, Michael Auerbach, David Cella, John A Glaspy, David H Henry
    Abstract:

    Parenteral Iron is given to patients in a variety of formulations, including two Iron Dextran products known as high- (HMW) or low- (LMW) molecular weight Iron Dextran. Despite more risk of adverse events, HMW Iron Dextran is sometimes substituted for LMW Iron Dextran without physician knowledge for

  • update on adverse drug events associated with parenteral Iron
    Nephrology Dialysis Transplantation, 2006
    Co-Authors: Glenn M. Chertow, Phillip D. Mason, Odd Vaagenilsen, Jarl Ahlmen
    Abstract:

    Background. We previously compared the safety profile of three formulations of intravenous Iron used during 1998–2000 and found higher rates of adverse drug events (ADEs) associated with the use of higher molecular weight Iron Dextran and sodium ferric gluconate complex compared with lower molecular weight Iron Dextran. Since that time, Iron sucrose has become widely available and clinicians have gained additional experience with sodium ferric gluconate complex. Methods. We obtained data from the United States Food and Drug Administration (FDA) on ADEs attributed to the provision of four formulations of intravenous Iron during 2001–2003, including higher and lower molecular weight Iron Dextran, sodium ferric gluconate complex and Iron sucrose. We estimated the odds of intravenous Iron-related ADEs using 2 � 2 tables and the 2 test. Results. The total number of reported parenteral Ironrelated ADEs was 1141 among approximately 30 063 800 doses administered, yielding a rate of 3.8 � 10 � 5 , or roughly 38 per million. Eleven individuals died in association with the ADE. Relative to lower molecular weight Iron Dextran, total and lifethreatening ADEs were significantly more frequent among recipients of higher molecular weight Iron Dextran and significantly less frequent among recipients of sodium ferric gluconate complex and Iron sucrose. The absolute rates of life-threatening ADEs were 0.6, 0.9, 3.3 and 11.3 per million for Iron sucrose, sodium ferric gluconate complex, lower molecular weight Iron Dextran and higher molecular weight Iron Dextran, respectively. Based on differences in the average wholesale price of Iron sucrose and lower molecular weight Iron Dextran in the US, the cost to prevent one life-threatening ADE related to the use of lower molecular weight Iron Dextran was estimated to be $5.0–7.8 million. The cost to prevent one lower molecular weight Iron Dextran-related death was estimated to be $33 million. Conclusions. The frequency of intravenous Ironrelated ADEs reported to the FDA has decreased, and overall, the rates are extremely low. This is the fourth report suggesting increased risks associated with the provision of higher molecular weight Iron Dextran. Life-threatening and other ADEs appear to be lower with the use of non-Dextran Iron formulations, although the cost per ADE prevented is extremely high.

  • on the relative safety of parenteral Iron formulations
    Nephrology Dialysis Transplantation, 2004
    Co-Authors: Glenn M. Chertow, Phillip D. Mason, Odd Vaagenilsen, Jarl Ahlmen
    Abstract:

    BACKGROUND Intravenous Iron is usually required to optimize the correction of anaemia in persons with advanced chronic kidney disease and end-stage renal disease. Randomized clinical trials may have insufficient power to detect differences in the safety profiles of specific formulations. METHODS We obtained data from the US Food and Drug Administration on reported adverse drug events (ADEs) related to the provision of three formulations of intravenous Iron during 1998-2000. We estimated the relative risks [odds ratios (OR)] of ADEs associated with the use of higher molecular weight Iron Dextran and sodium ferric gluconate complex compared with lower molecular weight Iron Dextran using 2 x 2 tables. RESULTS The total number of reported parenteral Iron-related ADEs was 1981 among approximately 21,060,000 doses administered, yielding a rate of 9.4 x 10(-5), or approximately 94 per million. Total major ADEs were significantly increased among recipients of higher molecular weight Iron Dextran (OR 5.5, 95% CI 4.9-6.0) and sodium ferric gluconate complex (OR 6.2, 95% CI 5.4-7.2) compared with recipients of lower molecular weight Iron Dextran. We observed significantly higher rates of life-threatening ADEs, including death, anaphylactoid reaction, cardiac arrest and respiratory depression among users of higher molecular weight compared with lower molecular weight Iron Dextran. There was insufficient power to detect differences in life-threatening ADEs when comparing lower molecular weight Iron Dextran with sodium ferric gluconate complex. CONCLUSIONS Parenteral Iron-related ADEs are rare. Using observational data, overall and most specific ADE rates were significantly higher among recipients of higher molecular weight Iron Dextran and sodium ferric gluconate complex than among recipients of lower molecular weight Iron Dextran. These data may help to guide clinical practice, as head-to-head clinical trials comparing different formulations of intravenous Iron have not been conducted.

Daniel Sperling - One of the best experts on this subject based on the ideXlab platform.

  • comparative efficacy of two parenteral Iron containing preparations Iron gleptoferron and Iron Dextran for the prevention of anaemia in suckling piglets
    Veterinary Record Open, 2018
    Co-Authors: Daniel Sperling, Barbara Freudenschuss, Aruna Shrestha, Barbara Hinney, Hamadi Karembe, Anja Joachim
    Abstract:

    Iron-deficiency anaemia (IDA) is a serious health problem in neonatal piglets and is controlled by routine application of Iron in various formulations. The efficacy and safety of two Iron-containing products for the prevention of IDA in suckling piglets were compared in a randomised, parallel study. Newborn piglets were treated with 200 mg Iron supplied by intramuscular injection in the neck as either Forceris (gleptoferron; n=13) or Uniferon 200 (Iron Dextran; n=12) 24–48 hours after birth. Blood samples were collected before and after treatment (2nd, 18th and 31st day of life) for complete haematology. The treatments were well tolerated with only mild transient swelling observed in two piglets (Forceris group). Piglets treated with Forceris had significantly higher haemoglobin, haematocrit, mean corpuscular volume and haemoglobin concentration values, as well as significantly higher plasma Iron and transferritin saturation and a lower total Iron binding capacity than those treated with Uniferon. No animals in the Forceris group but 17 per cent of piglets in the Uniferon group had haemoglobin levels

  • comparison of an injectable toltrazuril gleptoferron forceris and an oral toltrazuril baycox injectable Iron Dextran for the control of experimentally induced piglet cystoisosporosis
    Parasites & Vectors, 2018
    Co-Authors: Anja Joachim, Barbara Freudenschuss, Aruna Shrestha, Barbara Hinney, Hamadi Karembe, Nicola Palmieri, Daniel Sperling
    Abstract:

    Cystoisospora suis causes diarrhoeal disease and reduced weight gain in suckling piglets, and a toltrazuril-based oral suspension is available for treatment. Recently a combinatorial product with toltrazuril plus Iron has been developed for parenteral application. In this study we compared the efficacy of the injectable product with the oral suspension against experimentally induced piglet cystoisosporosis. In a randomised controlled study, three groups of piglets (n = 10–13) were treated either with a fixed dose of 45 mg toltrazuril + 200 mg gleptoferron i.m. per piglet (Forceris®) on the second day of life (study day 2; SD 2) or with 20 mg toltrazuril/kg body weight as an oral suspension (Baycox® 5%) on SD 4 or left untreated (Control group). The Baycox® and the Control group received 200 mg of Iron Dextran/piglet on SD 2. All piglets were infected with 1000 sporulated C. suis oocysts on SD 3. Faecal samples were taken daily from SD 7 to SD 20 to determine faecal consistency, oocyst shedding and other diarrhoeal pathogens. Body weight was recorded on SD 1 and then weekly until SD 29. Animals were observed daily for general health and after treatment for possible adverse events. In the Control group all animals shed oocysts for 3.1 days on average and all animals showed diarrhoea for an average of five days. Excretion peaked on SD 9 (max. 48,618 oocysts per gram of faeces). Treatment with Forceris® completely suppressed oocyst excretion. In the Baycox® group, low levels of excretion could be detected. Diarrhoea was reduced to single piglets in the treated groups. Body weight development was reduced in the Control group compared to the treated groups. Enteropathogenic bacteria (Escherichia coli, Clostridium perfringens) could be detected. All parameters related to oocyst excretion, faecal consistency and weight gain were significantly improved in the treated groups compared to the Control group without significant differences between the treated groups. Both products were safe to use. Treatment with both the injectable (Forceris®) and the oral (Baycox®) formulation of toltrazuril in the prepatent period were safe and highly effective against experimental infection with C. suis in newborn piglets.

  • Comparison of an injectable toltrazuril-gleptoferron (Forceris®) and an oral toltrazuril (Baycox®) + injectable Iron Dextran for the control of experimentally induced piglet cystoisosporosis
    BMC, 2018
    Co-Authors: Anja Joachim, Barbara Freudenschuss, Aruna Shrestha, Barbara Hinney, Hamadi Karembe, Nicola Palmieri, Daniel Sperling
    Abstract:

    Abstract Background Cystoisospora suis causes diarrhoeal disease and reduced weight gain in suckling piglets, and a toltrazuril-based oral suspension is available for treatment. Recently a combinatorial product with toltrazuril plus Iron has been developed for parenteral application. In this study we compared the efficacy of the injectable product with the oral suspension against experimentally induced piglet cystoisosporosis. Methods In a randomised controlled study, three groups of piglets (n = 10–13) were treated either with a fixed dose of 45 mg toltrazuril + 200 mg gleptoferron i.m. per piglet (Forceris®) on the second day of life (study day 2; SD 2) or with 20 mg toltrazuril/kg body weight as an oral suspension (Baycox® 5%) on SD 4 or left untreated (Control group). The Baycox® and the Control group received 200 mg of Iron Dextran/piglet on SD 2. All piglets were infected with 1000 sporulated C. suis oocysts on SD 3. Faecal samples were taken daily from SD 7 to SD 20 to determine faecal consistency, oocyst shedding and other diarrhoeal pathogens. Body weight was recorded on SD 1 and then weekly until SD 29. Animals were observed daily for general health and after treatment for possible adverse events. Results In the Control group all animals shed oocysts for 3.1 days on average and all animals showed diarrhoea for an average of five days. Excretion peaked on SD 9 (max. 48,618 oocysts per gram of faeces). Treatment with Forceris® completely suppressed oocyst excretion. In the Baycox® group, low levels of excretion could be detected. Diarrhoea was reduced to single piglets in the treated groups. Body weight development was reduced in the Control group compared to the treated groups. Enteropathogenic bacteria (Escherichia coli, Clostridium perfringens) could be detected. All parameters related to oocyst excretion, faecal consistency and weight gain were significantly improved in the treated groups compared to the Control group without significant differences between the treated groups. Both products were safe to use. Conclusions Treatment with both the injectable (Forceris®) and the oral (Baycox®) formulation of toltrazuril in the prepatent period were safe and highly effective against experimental infection with C. suis in newborn piglets

Paul A Gulig - One of the best experts on this subject based on the ideXlab platform.

  • genotype is correlated with but does not predict virulence of vibrio vulnificus biotype 1 in subcutaneously inoculated Iron Dextran treated mice
    Infection and Immunity, 2011
    Co-Authors: Patrick C Thiaville, Keri L Bourdage, Anita C Wright, Melissa Farrellevans, Cynthia Garvan, Paul A Gulig
    Abstract:

    Vibrio vulnificus is the leading cause of reported deaths from infections related to consumption of seafood in the United States. Affected predisposed individuals frequently die rapidly from sepsis. Otherwise healthy people can experience severe wound infection, which can lead to sepsis and death. A question is why, with so many people consuming contaminated raw oysters, the incidence of severe V. vulnificus disease is low. Molecular typing systems have shown associations of V. vulnificus genotypes and the envIronmental or clinical source of the strains, suggesting that different genotypes possess different virulence potentials. We examined 69 V. vulnificus biotype 1 strains that were genotyped by several methods and evaluated them for virulence in a subcutaneously inoculated Iron Dextran-treated mouse model. By examining the relationships between skin infection, systemic liver infection, and presumptive death (a decrease in body temperature), we determined that liver infection is predicated on severe skin infection and that death requires significant liver infection. Although most strains caused severe skin infection, not every strain caused systemic infection and death. Strains with polymorphisms at multiple loci (rrn, vcg, housekeeping genes, and repetitive DNA) designated profile 2 were more likely to cause lethal systemic infection with more severe indicators of virulence than were profile 1 strains with different polymorphisms at these loci. However, some profile 1 strains were lethal and some profile 2 strains did not cause systemic infection. Therefore, current genotyping schemes cannot strictly predict the virulence of V. vulnificus strains and further investigation is needed to identify virulence genes as markers of virulence.

  • use of a marker plasmid to examine differential rates of growth and death between clinical and envIronmental strains of vibrio vulnificus in experimentally infected mice
    Molecular Microbiology, 2006
    Co-Authors: Angela M Starks, Patrick C Thiaville, Keri L Bourdage, Paul A Gulig
    Abstract:

    Vibrio vulnificus is Gram-negative bacterium that contaminates oysters, causing highly lethal sepsis after consumption of raw oysters and wound infection. We previously described two sets of V. vulnificus strains with different levels of virulence in subcutaneously inoculated Iron Dextran-treated mice. Both virulent, clinical strains and attenuated, envIronmental strains could be recovered in high numbers from skin lesions and livers; however, the attenuated envIronmental strains required significantly higher numbers of colony-forming units (cfu) in the inoculum to produce lethal infection. Using some of these strains and an additional clinical strain, we presently asked if the different abilities to cause infection between the clinical and envIronmental strains were due to differences in rates of growth or death of the bacteria in the mouse host. We therefore constructed a marker plasmid, pGTR902, that functions as a replicon only in the presence of arabinose, which is not present in significant levels in animal tissues. V. vulnificus strains containing pGTR902 were inoculated into Iron Dextran-treated and untreated mice. Measuring the proportion of bacteria that had maintained the marker plasmid recovered from mice enabled us to monitor the number of in vivo divisions, hence growth rate; whereas measuring the number of marker plasmid-containing bacteria recovered enabled the measurement of death of the vibrios in the mice. The numbers of bacterial divisions in vivo for all of the strains over a 12-15 h infection period were not significantly different in Iron Dextran-treated mice; however, the rate of death of one envIronmental strain was significantly higher compared with the clinical strains. Infection of non-Iron Dextran-treated mice with clinical strains demonstrated that the greatest effect of Iron Dextran-treatment was increased growth rate, while one clinical strain also experienced increased death in untreated mice. V. vulnificus inoculated into Iron Dextran-treated mice replicated extremely rapidly over the first 4 h of infection with doubling times of approximately 15-28 min. In contrast, one of the envIronmental strains exhibited a reduced early growth rate. These results demonstrate that differences in virulence among naturally occurring V. vulnificus can be explained by diverse abilities to replicate rapidly in or resist defences of the host. The marker plasmid pGTR902 should be useful for examining virulence of bacteria in terms of differentiating growth verses death in animal hosts for most Gram-negative bacteria.

  • phage therapy of local and systemic disease caused by vibrio vulnificus in Iron Dextran treated mice
    Infection and Immunity, 2002
    Co-Authors: Karen E Cerveny, Angelo Depaola, Donna H Duckworth, Paul A Gulig
    Abstract:

    Although research regarding the therapeutic use of bacteriophages has gone on without interruption since 1926 in Eastern Europe, this field of study has been, until very recently, somewhat neglected in the West (for reviews, see references 10 and 39). Within the past two decades, however, there has been a renewed interest in phage therapy due primarily to the increasing incidence of antibiotic-resistant bacteria and the lack of development of new types of antibiotics to control infections caused by these antibiotic-resistant organisms. The efficacy of phages in treating bacterial disease has been demonstrated by using animal models for Escherichia coli (21, 31-34), Salmonella enterica serovar Typhimurium (2), and Pseudomonas aeruginosa (35, 36). Phages have also been used successfully to prevent bacterial disease in fish (26) and to control pathogens of tomatoes (12). Although it is unlikely that phages will ever replace antibiotics, they may be of some use when no effective antibiotics are available or in conjunction with antibiotics for better treatment of disease. To examine the potential usefulness of phages, either alone or in conjunction with antibiotics, phages will have to be studied in a variety of animal models against bacteria with different mechanisms of virulence. To contribute to this understanding of where and how phage therapy may be appropriate, we have begun studying the therapeutic effect of phages against V. vulnificus. V. vulnificus is an opportunistic pathogen of humans that causes septicemia after ingestion of contaminated oysters and necrotizing fasciitis after contamination of wounds (reviewed in references 19 and 38). Septicemia occurs primarily in people with high levels of Iron saturation caused by genetic mutation, such as primary hemochromatosis, or by liver damage (cirrhosis). Immunosuppressed individuals and people with diabetes are also at risk (4, 6, 18, 43). Septicemia is characterized by fever, chills, and bullous skin lesions on the lower extremities and has a mortality rate of greater than 50% (14). Wound infection leads to necrotizing fasciitis, which is characterized by extensive tissue damage down to, but not usually including, the musculature and can necessitate surgical intervention for debridement or amputation. Wound infection can occur in the absence of predisposing conditions but progresses more frequently to septicemia and has a higher mortality rate in predisposed people. V. vulnificus is a halophilic, gram-negative, curved rod that thrives in tropical and temperate estuarine envIronments throughout the world. The bacteria are found in filter-feeding shellfish, primarily oysters. Estimates of the prevalence of V. vulnificus in oysters from the Gulf of Mexico during the summer months have been as high as nearly 100% (23). Bacteriophages for V. vulnificus also are frequently found in oysters and estuarine waters (8, 9, 27). V. vulnificus is highly genetically diverse, and single oysters can contain over 100 different strains (5). Despite the diversity of strains present in oysters, one study demonstrated that only single strains of V. vulnificus were recovered from the blood of patients who had lethal infections and who had consumed oysters contaminated with numerous strains (15), suggesting that not all strains possess equal potential for human disease. Little is known about the virulence mechanisms of V. vulnificus. The primary virulence factor is the polysaccharide capsule, which prevents phagocytosis and activation of complement (1, 30, 41, 42, 45, 46), classifying V. vulnificus as an extracellular pathogen. The ability to acquire Iron from the host via siderophore production is also an essential virulence attribute (20). The production of a prepilin peptidase of a type 2 secretion system, which exerts pleiotropic effects on numerous secreted proteins, is required for full virulence in mice (24). Two other putative virulence factors, hemolysin and metalloprotease, have failed to be confirmed as virulence factors by genetic analysis (11, 16, 29, 44), despite the fact that injection of the purified proteins into laboratory animals induces several symptoms of V. vulnificus infection (13, 17, 22, 25). An Iron-Dextran-treated mouse model of V. vulnificus disease was previously used to compare the virulence of three clinical isolates with that of three envIronmental strains isolated from oysters or seawater (37). It appeared that the envIronmental strains either grew more slowly in or were killed more effectively by the host. The availability of a useful animal model to examine virulence, the existence of bacteriophages for V. vulnificus, and the extracellular nature of the disease process led us to use V. vulnificus as a model for testing the effectiveness of phage therapy for human disease. We show here that phage treatment of Iron-Dextran-treated mice infected subcutaneously (s.c.) with V. vulnificus can prevent both local and systemic disease. (These results were presented in preliminary form at the 100th General Meeting of the American Society for Microbiology in Los Angeles, Calif. [K. E. Cerveny, T. J. Doyle, G. M. Escudero, D. H. Duckworth, and P. A. Gulig, Abstr. 100th Gen. Meet. Am. Soc. Microbiol., abstr. D230, p. 279, 2000] and the 13th Annual International Phage Biology Meeting in Montreal, Quebec, Canada [K. Cerveny, T. J. Doyle, A. DePaola, P. Gulig, and D. Duckworth, Abstr. Millennial Phage Biol. Meet., 2000]).

  • phage therapy of local and systemic disease caused by vibrio vulnificus in Iron Dextran treated mice
    Infection and Immunity, 2002
    Co-Authors: Karen E Cerveny, Angelo Depaola, Donna H Duckworth, Paul A Gulig
    Abstract:

    Vibrio vulnificus is a gram-negative bacterium that contaminates filter-feeding shellfish such as oysters. After ingestion of contaminated oysters, predisposed people may experience highly lethal septicemia. Contamination of wounds with the bacteria can result in devastating necrotizing fasciitis, which can progress to septicemia. The extremely rapid progression of these diseases can render antibiotic treatment ineffective, and death is a frequent outcome. In this study, we examined the potential use of bacteriophages as therapeutic agents against V. vulnificus in an Iron-Dextran-treated mouse model of V. vulnificus infection. Mice were injected subcutaneously with 10 times the lethal dose of V. vulnificus and injected intravenously, either simultaneously or at various times after infection, with phages. Treatment of mice with phages could prevent death; systemic disease, as measured by CFU per gram of liver and body temperature; and local disease, as measured by CFU per gram of lesion material and histopathologic analysis. Two different phages were effective against three different V. vulnificus strains with various degrees of virulence, while a third phage that required the presence of seawater to lyse bacteria in vitro was ineffective at treating mice. Optimum protection required that the phages be administered within 3 h of bacterial inoculation at doses as high as 10(8) PFU. One of the protective phages had a half-life in blood of over 2 h. These results demonstrate that bacteriophages have therapeutic potential for both localized and systemic infections caused by V. vulnificus in animals. This model should be useful in answering basic questions regarding phage therapy.

  • pathogenesis of infection by clinical and envIronmental strains of vibrio vulnificus in Iron Dextran treated mice
    Infection and Immunity, 2000
    Co-Authors: Angela M Starks, Trenton R Schoeb, M L Tamplin, Salina Parveen, Thomas J Doyle, Philip E Bomeisl, Gloria M Escudero, Paul A Gulig
    Abstract:

    Vibrio vulnificus is an opportunistic pathogen that contaminates oysters harvested from the Gulf of Mexico. In humans with compromising conditions, especially excess levels of Iron in plasma and tissues, consumption of contaminated seafood or exposure of wounds to contaminated water can lead to systemic infection and disfiguring skin infection with extremely high mortality. V. vulnificus-associated diseases are noted for the rapid replication of the bacteria in host tissues, with extensive tissue damage. In this study we examined the virulence attributes of three virulent clinical strains and three attenuated oyster or seawater isolates in mouse models of systemic disease. All six V. vulnificus strains caused identical skin lesions in subcutaneously (s.c.) inoculated Iron Dextran-treated mice in terms of numbers of recovered CFU and histopathology; however, the inocula required for identical frequency and magnitude of infection were at least 350-fold higher for the envIronmental strains. At lethal doses, all strains caused s. c. skin lesions with extensive edema, necrosis of proximate host cells, vasodilation, and as many as 10(8) CFU/g, especially in perivascular regions. These data suggest that the differences between these clinical and envIronmental strains may be related to growth in the host or susceptibility to host defenses. In non-Iron Dextran-treated mice, strains required 10(5)-fold-higher inocula to cause an identical disease process as with Iron Dextran treatment. These results demonstrate that s.c. inoculation of Iron Dextran-treated mice is a useful model for studying systemic disease caused by V. vulnificus.

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  • sodium ferric gluconate complex in sucrose safer intravenous Iron therapy than Iron Dextrans
    American Journal of Kidney Diseases, 1999
    Co-Authors: Gerald Faich, Jur Strobos
    Abstract:

    Use of recombinant human erythropoietin in patients with end-stage renal disease has highlighted Iron deficiency as the major cause of resistant anemia. The current mainstay of intravenous (i.v.) Iron replacement therapy, Iron Dextran, has been shown in prior studies to have a risk of serious life-threatening anaphylaxis of just under 1 per 100 patients exposed. The current study assessed the safety profile of an alternative i.v. Iron, sodium ferric gluconate complex in sucrose (Ferrlecit), as compared with Iron Dextrans. Sodium ferric gluconate complex in sucrose, a unique chemical preparation, has been in use since 1959, principally in Europe, at a rate of approximately 2.7 million i.v. doses per year (1992 to 1996) in Germany and Italy alone. For Iron Dextran, usage in the United States was comparable--principally renal hemodialysis--and estimated from market sources at 3.0 million doses per year (1995). From 1976 to 1996, there were 74 allergic adverse events reported for sodium ferric gluconate complex in sucrose to the World Health Organization (WHO), German Health Bureau, and the manufacturer (all combined). For the years 1992 to 1996, sodium ferric gluconate complex in sucrose had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for Iron Dextran in the United States in 1995. Case fatalities for sodium ferric gluconate complex in sucrose and Iron Dextran within these reports were then compared. For sodium ferric gluconate complex in sucrose, there were no reports of deaths over the entire period (1976 to 1996). However, for Iron Dextrans, there were 31 fatalities among 196 allergy/anaphylaxis cases reported in the United States between 1976 and 1996, yielding a case-fatality rate of 15.8%. These data show that sodium ferric gluconate complex in sucrose, when compared with Iron Dextrans in comparably sized patient usage populations with similar total rates of reporting of allergic events, has a significantly lower reported mortality rate (P < 0.001). Thus, the data justify usage of sodium ferric gluconate complex in sucrose as the safer Iron replacement therapeutic agent.

  • sodium ferric gluconate complex in sucrose safer intravenous Iron therapy than Iron Dextrans
    American Journal of Kidney Diseases, 1999
    Co-Authors: Gerald Faich, Jur Strobos
    Abstract:

    Abstract Use of recombinant human erythropoietin in patients with end-stage renal disease has highlighted Iron deficiency as the major cause of resistant anemia. The current mainstay of intravenous (IV) Iron replacement therapy, Iron Dextran, has been shown in prior studies to have a risk of serious life-threatening anaphylaxis of just under 1 per 100 patients exposed. The current study assessed the safety profile of an alternative IV Iron, sodium ferric gluconate complex in sucrose (Ferrlecit), as compared with Iron Dextrans. Sodium ferric gluconate complex in sucrose, a unique chemical preparation, has been in use since 1959, principally in Europe, at a rate of approximately 2.7 million IV doses per year (1992 to 1996) in Germany and Italy alone. For Iron Dextran, usage in the United States was comparable—principally renal hemodialysis—and estimated from market sources at 3.0 million doses per year (1995). From 1976 to 1996, there were 74 allergic adverse events reported for sodium ferric gluconate complex in sucrose to the World Health Organization (WHO), German Health Bureau, and the manufacturer (all combined). For the years 1992 to 1996, sodium ferric gluconate complex in sucrose had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for Iron Dextran in the United States in 1995. Case fatalities for sodium ferric gluconate complex in sucrose and Iron Dextran within these reports were then compared. For sodium ferric gluconate complex in sucrose, there were no reports of deaths over the entire period (1976 to 1996). However, for Iron Dextrans, there were 31 fatalities among 196 allergy/anaphylaxis cases reported in the United States between 1976 and 1996, yielding a case-fatality rate of 15.8%. These data show that sodium ferric gluconate complex in sucrose, when compared with Iron Dextrans in comparably sized patient usage populations with similar total rates of reporting of allergic events, has a significantly lower reported mortality rate ( P