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1.
Clin Infect Dis ; 74(8): 1476-1479, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-34410348

RESUMO

Completion of a 5-day course of remdesivir was associated with approximately 17-fold increased odds of survival among a sample of 54 nursing home residents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the course of an outbreak from October to December 2020. Remdesivir was well tolerated; administration was logistically feasible in a pre-hospital environment.


Assuntos
Tratamento Farmacológico da COVID-19 , Administração Hospitalar , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Surtos de Doenças , Humanos , SARS-CoV-2 , Instituições de Cuidados Especializados de Enfermagem
2.
J Infect Dis ; 223(2): 319-325, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32697310

RESUMO

BACKGROUND: Inhalational anthrax is rare and clinical experience limited. Expert guidelines recommend treatment with combination antibiotics including protein synthesis-inhibitors to decrease toxin production and increase survival, although evidence is lacking. METHODS: Rhesus macaques exposed to an aerosol of Bacillus anthracis spores were treated with ciprofloxacin, clindamycin, or ciprofloxacin + clindamycin after becoming bacteremic. Circulating anthrax lethal factor and protective antigen were quantitated pretreatment and 1.5 and 12 hours after beginning antibiotics. RESULTS: In the clindamycin group, 8 of 11 (73%) survived demonstrating its efficacy for the first time in inhalational anthrax, compared to 9 of 9 (100%) with ciprofloxacin, and 8 of 11 (73%) with ciprofloxacin + clindamycin. These differences were not statistically significant. There were no significant differences between groups in lethal factor or protective antigen levels from pretreatment to 12 hours after starting antibiotics. Animals that died after clindamycin had a greater incidence of meningitis compared to those given ciprofloxacin or ciprofloxacin + clindamycin, but numbers of animals were very low and no definitive conclusion could be reached. CONCLUSION: Treatment of inhalational anthrax with clindamycin was as effective as ciprofloxacin in the nonhuman primate. Addition of clindamycin to ciprofloxacin did not enhance reduction of circulating toxin levels.


Assuntos
Antraz/sangue , Antraz/prevenção & controle , Antígenos de Bactérias/sangue , Bacillus anthracis/efeitos dos fármacos , Bacillus anthracis/fisiologia , Toxinas Bacterianas/sangue , Ciprofloxacina/uso terapêutico , Clindamicina/uso terapêutico , Infecções Respiratórias/sangue , Infecções Respiratórias/prevenção & controle , Animais , Antraz/microbiologia , Antraz/mortalidade , Antibacterianos/uso terapêutico , Biomarcadores , Ciprofloxacina/farmacologia , Clindamicina/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Macaca mulatta , Prognóstico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Resultado do Tratamento
3.
Curr Opin Infect Dis ; 31(3): 257-262, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29570493

RESUMO

PURPOSE OF REVIEW: Inhalational anthrax is a rare disease and Bacillus anthracis is a likely pathogen to be used in a biological attack. The lack of clinical experience with anthrax has led experts to develop treatment guidelines. These guidelines recommend anthrax antitoxin to be used in conjunction with antibiotics for the treatment of patients with systemic anthrax infection, yet there is still a lack of human or animal data to support this recommendation. RECENT FINDINGS: The U.S. Food and Drug Administration-approved anthrax antitoxins in 2012, 2015, and 2016. These products have been stockpiled for use in a public health emergency. Although efficacy is high when given early, their efficacy diminishes quickly when given after the development of bacteremia. Animal studies showing a significant incremental benefit of antitoxin therapy when combined with antibiotic therapy were not required by the U.S. Food and Drug Administration for product approval. SUMMARY: There is no conclusive evidence demonstrating that anthrax antitoxin therapy, when combined with a therapeutic course of antibiotics provides a survival benefit in inhalational anthrax. Additional research is needed in improved anthrax-antitoxin therapies, novel small molecule toxin inhibitors that act intracellularly, and studies of supportive care such as hemodynamic and ventilatory support, to improve the survival for inhalational anthrax patients and help mitigate the threat caused by the misuse of B. anthracis.


Assuntos
Antraz/terapia , Antibacterianos/administração & dosagem , Antitoxinas/administração & dosagem , Toxinas Bacterianas/antagonistas & inibidores , Terapia Combinada/métodos , Fatores Imunológicos/administração & dosagem , Exposição por Inalação , Animais , Antígenos de Bactérias , Modelos Animais de Doenças , Humanos , Resultado do Tratamento
4.
PLoS One ; 12(3): e0174106, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28328947

RESUMO

Francisella tularensis, a gram-negative facultative intracellular bacterial pathogen, is the causative agent of tularemia and able to infect many mammalian species, including humans. Because of its ability to cause a lethal infection, low infectious dose, and aerosolizable nature, F. tularensis subspecies tularensis is considered a potential biowarfare agent. Due to its in vitro efficacy, ciprofloxacin is one of the antibiotics recommended for post-exposure prophylaxis of tularemia. In order to identify therapeutics that will be efficacious against infections caused by drug resistant select-agents and to better understand the threat, we sought to characterize an existing ciprofloxacin resistant (CipR) mutant in the Schu S4 strain of F. tularensis by determining its phenotypic characteristics and sequencing the chromosome to identify additional genetic alterations that may have occurred during the selection process. In addition to the previously described genetic alterations, the sequence of the CipR mutant strain revealed several additional mutations. Of particular interest was a frameshift mutation within kdsD which encodes for an enzyme necessary for the production of 3-Deoxy-D-manno-Octulosonic Acid (KDO), an integral component of the lipopolysaccharide (LPS). A kdsD mutant was constructed in the Schu S4 strain. Although it was not resistant to ciprofloxacin, the kdsD mutant shared many phenotypic characteristics with the CipR mutant, including growth defects under different conditions, sensitivity to hydrophobic agents, altered LPS profiles, and attenuation in multiple models of murine tularemia. This study demonstrates that the KdsD enzyme is essential for Francisella virulence and may be an attractive therapeutic target for developing novel medical countermeasures.


Assuntos
Proteínas de Bactérias/genética , Farmacorresistência Bacteriana/genética , Francisella tularensis/genética , Mutação/genética , Açúcares Ácidos/metabolismo , Tularemia/microbiologia , Animais , Ciprofloxacina/farmacologia , Francisella tularensis/efeitos dos fármacos , Francisella tularensis/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Profilaxia Pós-Exposição/métodos , Virulência/genética
5.
Clin Infect Dis ; 34(1): E14-5, 2002 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11731967

RESUMO

Opportunistic infections during primary infection with human immunodeficiency virus type 1 have occasionally been reported in the medical literature, and those caused by cytomegalovirus have tended to be severe and prolonged. We describe a 40-year-old man who had acute retroviral syndrome complicated by a severe cytomegalovirus-induced esophageal ulceration, which was successfully treated with total parenteral nutrition and ganciclovir in addition to highly active antiretroviral therapy.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/virologia , Infecções por Citomegalovirus/etiologia , Doenças do Esôfago/virologia , Infecções por HIV/complicações , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Doença Aguda , Adulto , Terapia Antirretroviral de Alta Atividade , Infecções por Citomegalovirus/tratamento farmacológico , Doenças do Esôfago/tratamento farmacológico , Doenças do Esôfago/etiologia , Feminino , Infecções por HIV/tratamento farmacológico , Humanos
6.
Am J Infect Control ; 32(5): 262-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15292889

RESUMO

BACKGROUND: The influence of hospital design on nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA) is unknown. Our hospital's relocation to a new building with radically different ward design allowed us to study this question. Our old hospital facility had open bay wards and intensive care units, and few poorly located sinks for handwashing (bed:sink ratio 4:1). Our new hospital facility had optimized hand-washing geography and distribution of ward beds into mostly single or double rooms (bed:sink ratio 1.3:1). METHODS: We compared the prevalence of MRSA in the 2 institutions by obtaining nasal swabs from all patients on 8 selected wards and intensive care units at 2 time points both before and after the move. In addition, passive surveillance rates of MRSA for all hospitalized patients for 2 years both before and after the move were compared. Hand hygiene practices, although unrelated to the study periods, were directly observed. RESULTS: Eight of 123 patients cultured before the move were MRSA positive, compared to 5 of 138 patients cultured after the move (P=NS). MRSA prevalence determined by passive surveillance of all hospitalized patients before and after the move was also unchanged. An insignificant increase in the frequency of hand-hygiene performance following the move (20% to 23%) was observed. CONCLUSION: Radical facility design changes, which would be permissive of optimal infection control practices, were not sufficient, by themselves, to reduce the nosocomial spread of MRSA in our institution.


Assuntos
Infecção Hospitalar/epidemiologia , Infecção Hospitalar/transmissão , Arquitetura Hospitalar , Resistência a Meticilina , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/transmissão , Staphylococcus aureus/isolamento & purificação , Análise de Variância , Distribuição de Qui-Quadrado , Humanos , Controle de Infecções/organização & administração , Prevalência , Estudos Prospectivos , Estatísticas não Paramétricas , Texas/epidemiologia
7.
Virulence ; 3(6): 504-9, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23076278

RESUMO

Many bacterial species use secreted quorum-sensing autoinducer molecules to regulate cell density- and growth phase-dependent gene expression, including virulence factor production, as sufficient environmental autoinducer concentrations are achieved. Bacillus anthracis, the causative agent of anthrax, contains a functional autoinducer (AI-2) system, which appears to regulate virulence gene expression. To determine if the AI-2 system is necessary for disease, we constructed a LuxS AI-2 synthase-deficient mutant in the virulent Ames strain of B. anthracis. We found that growth of the LuxS-deficient mutant was inhibited and sporulation was delayed when compared with the parental strain. However, spores of the Ames luxS mutant remained fully virulent in both mice and guinea pigs.


Assuntos
Antraz/genética , Bacillus anthracis/patogenicidade , Proteínas de Bactérias/metabolismo , Liases de Carbono-Enxofre/metabolismo , Homosserina/análogos & derivados , Lactonas/metabolismo , Percepção de Quorum , Animais , Antraz/imunologia , Antraz/patologia , Bacillus anthracis/genética , Bacillus anthracis/crescimento & desenvolvimento , Proteínas de Bactérias/genética , Liases de Carbono-Enxofre/genética , Regulação Bacteriana da Expressão Gênica , Cobaias , Homosserina/genética , Homosserina/metabolismo , Camundongos , Percepção de Quorum/genética , Esporos Bacterianos/patogenicidade , Virulência/genética , Fatores de Virulência/genética
8.
Vaccine ; 30(5): 846-52, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22172509

RESUMO

Bacillus anthracis, the causative agent of anthrax, is recognized as one of the most serious bioterrorism threats. The current human vaccines are based on the protective antigen component of the anthrax toxins. Concern about possible vaccine resistant strains and reliance on a single antigen has prompted the search for additional immunogens. Bacterial capsules, as surface-expressed virulence factors, are well-established components of several licensed vaccines. In a previous study we showed that an anthrax vaccine consisting of the B. anthracis poly-γ-D-glutamic acid capsule covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B protected mice against parenteral B. anthracis challenge. Here we tested this vaccine in rabbits and monkeys against an aerosol spore challenge. The vaccine induced anti-capsule antibody responses in both species, measured by ELISA and a macrophage opsono-adherence assay. While rabbits were not protected against a high aerosol challenge dose, significant protection was observed in monkeys receiving the capsule conjugate vaccine. The results confirm that the capsule is a protective immunogen against anthrax, being the first non-toxin antigen shown to be efficacious in monkeys and suggest that addition of capsule may broaden and enhance the protection afforded by protective antigen-based vaccines.


Assuntos
Vacinas contra Antraz/imunologia , Antraz/prevenção & controle , Cápsulas Bacterianas/imunologia , Proteínas da Membrana Bacteriana Externa/química , Animais , Antraz/imunologia , Vacinas contra Antraz/administração & dosagem , Anticorpos Antibacterianos/sangue , Cápsulas Bacterianas/química , Proteínas da Membrana Bacteriana Externa/isolamento & purificação , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Macaca mulatta , Macrófagos/imunologia , Masculino , Neisseria meningitidis/química , Proteínas Opsonizantes/sangue , Fagocitose , Coelhos , Análise de Sobrevida , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia
9.
J Infect Dis ; 199(3): 336-41, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19099484

RESUMO

BACKGROUND: Postexposure prophylaxis of inhalational anthrax requires prolonged antibiotic therapy or antibiotics and vaccination. The duration of treatment for established anthrax is controversial, because retained spores may germinate and cause disease after antibiotics are discontinued. Using rhesus macaques, we determined whether a short course of antibiotic treatment, as opposed to prophylaxis, could effectively treat inhalational anthrax and prevent disease caused by the germination of spores after discontinuation of antibiotics. METHODS: Two groups of 10 rhesus macaques were exposed to an aerosol dose of Bacillus anthracis spores. Animals in group 1 received ciprofloxacin prophylaxis beginning 1-2 h after exposure. Those in group 2 began receiving ciprofloxacin after becoming bacteremic, and treatment was continued for 10 days. When each group 2 animal completed 10 days of therapy, the prophylactic antibiotic was discontinued in the paired group 1 animal. RESULTS: In group 1 (prophylaxis), no deaths occurred during antibiotic treatment, but only 2 (20%) of 10 animals survived after antibiotics were discontinued. In contrast, in group 2 (treatment), 3 deaths occurred during antibiotic treatment, but all 7 animals (100%) alive after 10 days of therapy survived when antibiotics were discontinued. CONCLUSIONS: In the treatment of inhalational anthrax, the prolonged course of antibiotics required to achieve prophylaxis may not be necessary to prevent anthrax that results from the germination of retained spores after the discontinuation of antibiotics.


Assuntos
Antraz/tratamento farmacológico , Antraz/mortalidade , Antibacterianos/administração & dosagem , Ciprofloxacina/administração & dosagem , Administração por Inalação , Aerossóis , Animais , Antibacterianos/uso terapêutico , Bioterrorismo , Ciprofloxacina/uso terapêutico , Modelos Animais de Doenças , Feminino , Macaca mulatta , Masculino , Distribuição Aleatória
10.
Antimicrob Agents Chemother ; 51(1): 215-22, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17074794

RESUMO

The poly-gamma-d-glutamic acid capsule confers antiphagocytic properties on Bacillus anthracis and is essential for virulence. In this study, we showed that CapD, a gamma-polyglutamic acid depolymerase encoded on the B. anthracis capsule plasmid, degraded purified capsule and removed the capsule from the surface of anthrax bacilli. Treatment with CapD induced macrophage phagocytosis of encapsulated B. anthracis and enabled human neutrophils to kill encapsulated organisms. A second glutamylase, PghP, a gamma-polyglutamic acid hydrolase encoded by Bacillus subtilis bacteriophage PhiNIT1, had minimal activity in degrading B. anthracis capsule, no effect on macrophage phagocytosis, and only minimal enhancement of neutrophil killing. Thus, the levels of both phagocytosis and killing corresponded to the degree of enzyme-mediated capsule degradation. The use of enzymes to degrade the capsule and enable phagocytic killing of B. anthracis offers a new approach to the therapy of anthrax.


Assuntos
Bacillus anthracis/metabolismo , Cápsulas Bacterianas/metabolismo , Ácido Poliglutâmico/metabolismo , gama-Glutamiltransferase/metabolismo , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Bacillus anthracis/efeitos dos fármacos , Bacillus anthracis/genética , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/farmacologia , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/farmacologia , Células Cultivadas , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Fagocitose/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , gama-Glutamil Hidrolase/metabolismo , gama-Glutamiltransferase/genética , gama-Glutamiltransferase/farmacologia
11.
Proc Natl Acad Sci U S A ; 103(20): 7813-6, 2006 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-16672361

RESUMO

Prevention of inhalational anthrax after Bacillus anthracis spore exposure requires a prolonged course of antibiotic prophylaxis. In response to the 2001 anthrax attack in the United States, approximately 10,000 people were offered 60 days of antibiotic prophylaxis to prevent inhalational anthrax, but adherence to this regimen was poor. We sought to determine whether a short course of antibiotic prophylaxis after exposure could protect non-human primates from a high-dose spore challenge if vaccination was combined with antibiotics. Two groups of 10 rhesus macaques were exposed to approximately 1,600 LD50 of spores by aerosol. Both groups were given ciprofloxacin by orogastric tube twice daily for 14 days, beginning 1-2 h after exposure. One group also received three doses of the licensed human anthrax vaccine (anthrax vaccine adsorbed) after exposure. In the ciprofloxacin-only group, four of nine monkeys (44%) survived the challenge. In contrast, all 10 monkeys that received 14 days of antibiotic plus anthrax vaccine adsorbed survived (P = 0.011). Thus postexposure vaccination enhanced the protection afforded by 14 days of antibiotic prophylaxis alone and completely protected animals against inhalational anthrax. These data provide evidence that postexposure vaccination can shorten the duration of antibiotic prophylaxis required to protect against inhalational anthrax and may impact public health management of a bioterrorism event.


Assuntos
Administração por Inalação , Antraz/prevenção & controle , Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Ciprofloxacina/uso terapêutico , Vacinação , Animais , Antraz/imunologia , Vacinas contra Antraz , Bacillus anthracis/metabolismo , Bioterrorismo , Sinergismo Farmacológico , Humanos , Macaca mulatta , Testes de Sensibilidade Microbiana , Distribuição Aleatória , Esporos Bacterianos , Taxa de Sobrevida , Fatores de Tempo
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