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BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) commonly cause diarrhea in children living in developing countries and in travelers to those regions. ETEC are characterized by colonization factors (CFs) that mediate intestinal adherence. We assessed if bovine colostral IgG (bIgG) antibodies against a CF, CS17, or antibodies against CsbD, the minor tip subunit of CS17, would protect subjects against diarrhea following challenge with a CS17-expressing ETEC strain. METHODS: Adult subjects were randomized (1:1:1) to receive oral bIgG against CS17, CsbD, or placebo. Two days prior to challenge, subjects began dosing 3 times daily with the bIgG products (or placebo). On day 3, subjects ingested 5 × 109 cfu ETEC strain LSN03-016011/A in buffer. Subjects were assessed for diarrhea for 120 hours postchallenge. RESULTS: A total of 36 subjects began oral prophylaxis and 35 were challenged with ETEC. While 50.0% of the placebo recipients had watery diarrhea, none of the subjects receiving anti-CS17 had diarrhea (P = .01). In contrast, diarrhea rates between placebo and anti-CsbD recipients (41.7%) were comparable (P = 1.0). CONCLUSIONS: This is the first study to demonstrate anti-CS17 antibodies provide significant protection against ETEC expressing CS17. More research is needed to better understand why anti-CsbD was not comparably efficacious. Clinical Trials Registration. NCT00524004.
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Anticorpos Antibacterianos/imunologia , Colostro/imunologia , Diarreia/imunologia , Escherichia coli Enterotoxigênica/imunologia , Infecções por Escherichia coli/imunologia , Vacinas contra Escherichia coli/imunologia , Substâncias Protetoras/farmacologia , Adesinas Bacterianas/imunologia , Adulto , Animais , Toxinas Bacterianas/imunologia , Bovinos , Colostro/microbiologia , Diarreia/microbiologia , Método Duplo-Cego , Enterotoxinas/imunologia , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , MasculinoRESUMO
BACKGROUND: Provider-entered indications for antibiotics have been recommended as a tracking tool for antibiotic stewardship programs. The accuracy and utility of these indications are unknown. METHODS: Drug-specific lists of evidence-based indications were integrated into an electronic health system as an ordering hard-stop. We reviewed antibiotic orders with provider-entered indications to determine whether the chosen indication matched the documentation and whether antibiotic use was appropriate. RESULTS: One hundred fifty-five antibiotic orders were reviewed. Clinical documentation supported the entered indication in 80% of vancomycin orders, 78% of cefepime orders, and 74% of fluoroquinolone orders. The clinical appropriateness for vancomycin, cefepime, and fluoroquinolones were 94%, 100%, and 68%, respectively. When providers chose indications from the list as opposed to choosing "other" and entering free text, antibiotic orders were significantly more likely to be appropriate (odds ratio, 5.8; P = .001) but also less likely to match clinical documentation (odds ratio, 0.25; P = .0043). DISCUSSION: Provider-chosen indications are, overall, an accurate reflection of the true reason for antibiotic use at our institution. Providers frequently documented reasons for fluoroquinolone use that were not among the provided indications. CONCLUSION: Selecting an indication from an evidence-based list as opposed to free-text indications increases the odds that antibiotic agents will be used appropriately.
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Antibacterianos/uso terapêutico , Gestão de Antimicrobianos , Infecções Bacterianas/tratamento farmacológico , Padrões de Prática Médica , Adulto , Idoso , Sistemas de Apoio a Decisões Clínicas , Feminino , Humanos , Masculino , Sistemas de Registro de Ordens Médicas , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary. METHODS: Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events. RESULTS: Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum. CONCLUSION: Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints.
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Disenteria Bacilar/imunologia , Shigella/imunologia , Análise por Conglomerados , Disenteria Bacilar/diagnóstico , Disenteria Bacilar/microbiologia , Disenteria Bacilar/prevenção & controle , Humanos , Razão de Chances , Curva ROC , Índice de Gravidade de Doença , Vacinas contra Shigella/administração & dosagem , Vacinas contra Shigella/imunologia , Avaliação de Sintomas , Vacinação/métodosRESUMO
BACKGROUND: European trials using procalcitonin (PCT)-guided antibiotic therapy for patients with lower respiratory tract infections (LRTIs) have demonstrated significant reductions in antibiotic use without increasing adverse outcomes. Few studies have examined PCT for LRTIs in the United States. METHODS: In this study, we evaluated whether a PCT algorithm would reduce antibiotic exposure in patients with LRTI in a US hospital. We conducted a controlled pre-post trial comparing an intervention group of PCT-guided antibiotic therapy to a control group of usual care. Consecutive patients admitted to medicine services and receiving antibiotics for LRTI were enrolled in the intervention. Providers were encouraged to discontinue antibiotics according to a PCT algorithm. Control patients were similar patients admitted before the intervention. RESULTS: The primary endpoint was median antibiotic duration. Overall adverse outcomes at 30 days comprised death, transfer to an intensive care unit, antibiotic side effects, Clostridium difficile infection, disease-specific complications, and post-discharge antibiotic prescription for LRTI. One hundred seventy-four intervention patients and 200 controls were enrolled. Providers complied with the PCT algorithm in 75% of encounters. Procalcitonin-guided therapy reduced median antibiotic duration for pneumonia from 7 days to 6 (P = .045) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from 4 days to 3 (P = .01). There was no difference in the rate of adverse outcomes in the PCT and control groups. CONCLUSIONS: A PCT-guided algorithm safely reduced the duration of antibiotics for treating LRTI. Utilization of a PCT algorithm may aid antibiotic stewardship efforts.This clinical trial was a single-center, controlled, pre-post study of PCT-guided antibiotic therapy for LRTI. The intervention (incorporation of PCT-guided algorithms) started on April 1, 2017: the preintervention (control group) comprised patients admitted from November 1, 2016 to April 16, 2017, and the postintervention group comprised patients admitted from April 17, 2017 to November 29, 2017 (Supplementary Figure 1). The study comprised patients admitted to the internal medicine services to a medical ward, the Medical Intensive Care Unit (MICU), the Cardiac Intensive Care Unit (CICU), or the Progressive Care Unit (PCU) "step down unit". The registration data for the trails are in the ClinicalTrials.gov database, number NCT0310910.
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Clostridium difficile causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase and has potent activity against C. difficile and aerobic Gram-positive bacteria but little activity against Gram-negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects each received CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC-MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active-treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. The absorbed drug was glucuronidated at reactive amino groups on the molecule, which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for C. difficile infections. (This study has been registered at ClinicalTrials.gov under identifier NCT01551004.).
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Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Benzopiranos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/tratamento farmacológico , Metionina tRNA Ligase/antagonistas & inibidores , Tiofenos/farmacologia , Adulto , Benzopiranos/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/prevenção & controle , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Placebos/uso terapêutico , Tiofenos/uso terapêutico , Adulto JovemRESUMO
Background: Tip-localized adhesive proteins of bacterial fimbriae from diverse pathogens confer protection in animal models, but efficacy in humans has not been reported. Enterotoxigenic Escherichia coli (ETEC) commonly elaborate colonization factors comprising a minor tip adhesin and major stalk-forming subunit. We assessed the efficacy of antiadhesin bovine colostral IgG (bIgG) antibodies against ETEC challenge in volunteers. Methods: Adults were randomly assigned (1:1:1) to take oral hyperimmune bIgG raised against CFA/I minor pilin subunit (CfaE) tip adhesin or colonization factor I (CFA/I) fimbraie (positive control) or placebo. Two days before challenge, volunteers began a thrice-daily, 7-day course of investigational product administered in sodium bicarbonate 15 minutes after each meal. On day 3, subjects drank 1 × 109 colony-forming units of colonization factor I (CFA/I)-ETEC strain H10407 with buffer. The primary efficacy endpoint was diarrhea within 120 hours of challenge. Results: After enrollment and randomization, 31 volunteers received product, underwent ETEC challenge, and were included in the per protocol efficacy analysis. Nine of 11 placebos developed diarrhea, 7 experiencing moderate to severe disease. Protective efficacy of 63% (P = .03) and 88% (P = .002) was observed in the antiadhesin bIgG and positive control groups, respectively. Conclusions: Oral administration of anti-CFA/I minor pilin subunit (CfaE) antibodies conferred significant protection against ETEC, providing the first clinical evidence that fimbrial tip adhesins function as protective antigens.
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Anticorpos Antibacterianos/uso terapêutico , Colostro/imunologia , Diarreia/tratamento farmacológico , Escherichia coli Enterotoxigênica , Infecções por Escherichia coli/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Adesinas Bacterianas/imunologia , Administração Oral , Adulto , Animais , Antígenos de Bactérias/imunologia , Bovinos , Contagem de Colônia Microbiana , Diarreia/microbiologia , Método Duplo-Cego , Feminino , Proteínas de Fímbrias/imunologia , Fímbrias Bacterianas/genética , Fímbrias Bacterianas/metabolismo , Humanos , Masculino , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Experimental human challenge models have played a major role in enhancing our understanding of infectious diseases. Primary outcomes have typically utilized overly simplistic outcomes that fail to entirely account for complex illness syndromes. We sought to characterize clinical outcomes associated with experimental infection with enterotoxigenic Escherichia coli (ETEC) and to develop a disease score. METHODS: Data were obtained from prior controlled human ETEC infection studies. Correlation and univariate regression across sign and symptom severity was performed. A multiple correspondence analysis was conducted. A 3-parameter disease score with construct validity was developed in an iterative fashion, compared to standard outcome definitions and applied to prior vaccine challenge trials. RESULTS: Data on 264 subjects receiving seven ETEC strains at doses from 1x105 to 1x1010 cfu were used to construct a standardized dataset. The strongest observed correlation was between vomiting and nausea (r = 0.65); however, stool output was poorly correlated with subjective activity-impacting outcomes. Multiple correspondence analyses showed covariability in multiple signs and symptoms, with severity being the strongest factor corresponding across outcomes. The developed disease score performed well compared to standard outcome definitions and differentiated disease in vaccinated and unvaccinated subjects. CONCLUSION: Frequency and volumetric definitions of diarrhea severity poorly characterize ETEC disease. These data support a disease severity score accounting for stool output and other clinical signs and symptoms. Such a score could serve as the basis for better field trial outcomes and gives an additional outcome measure to help select future vaccines that warrant expanded testing in pivotal pre-licensure trials.
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Diarreia/fisiopatologia , Escherichia coli Enterotoxigênica/patogenicidade , Infecções por Escherichia coli/fisiopatologia , Vacinas contra Escherichia coli/uso terapêutico , Adulto , Diarreia/microbiologia , Infecções por Escherichia coli/microbiologia , Feminino , Febre/microbiologia , Febre/fisiopatologia , Cefaleia/microbiologia , Cefaleia/fisiopatologia , Humanos , Masculino , Náusea/microbiologia , Náusea/fisiopatologia , Índice de Gravidade de Doença , Vômito/microbiologia , Vômito/fisiopatologiaRESUMO
BACKGROUND: Overuse of antibiotics to treat urinary tract infections (UTIs) is common in hospitalized patients and may begin in the emergency department (ED). METHODS: For a 4-week period we reviewed medical records of all patients admitted to the hospital who initiated treatment for a UTI in the ED. RESULTS: According to study criteria, initiation of antibiotics was inappropriate for 55 of 94 patients (59% [95% confidence interval {CI}, 48%-69%]), and continuation after admission was inappropriate for 54 of 80 patients (68% [95% CI, 57%-78%]). CONCLUSION: Failure to reevaluate the need for antibiotics initiated in the ED to treat UTIs may lead to overuse of antibiotics in hospitalized patients.
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Antibacterianos/uso terapêutico , Serviço Hospitalar de Emergência , Prescrição Inadequada/estatística & dados numéricos , Infecções Urinárias/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Since the advent of anti-retroviral therapy, patients with HIV are living longer, and in the year 2015, over half of those infected with the virus will be older than age 50. Moreover, as the general aging population continues to grow, more elderly individuals will become newly infected with HIV. Older patients with HIV contribute to high numbers of initial and rehospitalizations, have longer lengths of hospital day stays, and are at increased risk of death compared to younger patients with HIV and those without HIV. Age-related comorbidities can be exaggerated in HIV-positive patients on and off therapy. Furthermore, signs and symptoms of HIV and AIDS may mimic features seen in the normal aging process of older adults. Internists caring for patients in inpatient settings will be expected to care for and diagnose increasing numbers of older patients with HIV. This will be critical for improving quality of patient care, reducing morbidity and mortality, and managing newly diagnosed patients earlier in the disease course while reducing spread of the virus. Internists should be central leaders in the development of targeted and non-targeted HIV screening efforts in inpatient general medicine wards.
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Accurately assessing mucosal immune responses to candidate vaccines remains a technical challenge. ELISPOT is widely used as a surrogate of mucosal immune response by directly enumerating circulating antibody secreting cells (ASCs), while antibody in lymphocyte supernatant (ALS) titers the total amount of antibody secreted by ASC ex vivo using ELISA. ALS is more practical than ELISPOT because the ASC supernatant is frozen for ELISA that can be conducted at any time, with any antigen, and in any laboratory. We compared IgA and IgG responses to serotype-specific Shigella LPS using ELISPOT and ALS in subjects following vaccination or infection with Shigella. ALS results correlated well with ELISPOT results, and the ALS method was both sensitive and specific for the detection of antibody responses against Shigella LPS. Based on these observations, the ALS assay is a practical and flexible alternative to ELISPOT for measuring mucosal IgA responses to Shigella LPS antigen.
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Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Técnicas de Laboratório Clínico/métodos , Imunidade nas Mucosas , Linfócitos/imunologia , Shigella/imunologia , Humanos , Técnicas Imunoenzimáticas/métodos , Imunoglobulina A/análise , Imunoglobulina G/análiseRESUMO
Human challenges with enterotoxigenic Escherichia coli (ETEC) have broadened our understanding of this important enteropathogen. We report findings from the first challenge studies using ETEC-expressing colonization factor fimbria CS17 and CS19. LSN03-016011/A (LT, CS17) elicited a dose-dependent effect, with the upper dose (6 × 10(9) organisms) causing diarrhea in 88% of recipients. WS0115A (LTSTp, CS19) also showed a dose response, with a 44% diarrhea rate at 9 × 10(9) organisms. Both strains elicited homologous antifimbrial and anti-LT antibody seroconversion. These studies establish the relative pathogenicity of ETEC expressing newer class 5 fimbriae and suggest suitability of the LT|CS17-ETEC challenge model for interventional trials.
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Adesinas Bacterianas/biossíntese , Escherichia coli Enterotoxigênica/patogenicidade , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Proteínas de Escherichia coli/biossíntese , Fatores de Virulência/biossíntese , Adesinas Bacterianas/imunologia , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Toxinas Bacterianas/imunologia , Diarreia/microbiologia , Diarreia/patologia , Escherichia coli Enterotoxigênica/crescimento & desenvolvimento , Enterotoxinas/imunologia , Proteínas de Escherichia coli/imunologia , Feminino , Experimentação Humana , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Virulência/imunologia , Adulto JovemRESUMO
Volunteer challenge with enterotoxigenic Escherichia coli (ETEC) has been used for four decades to elucidate the pathogenesis and immune responses and assess efficacy of various interventions. We performed a systematic review of these studies and a meta-analysis of individual patient-level data (IPD) from a subset of studies using standard methodology. We identified 27 studies of 11 ETEC strains administered to 443 naive subjects at doses from 1×10(6) to 1×10(10) colony forming units (cfu). Diarrhea attack rates varied by strain, dose and enterotoxin. Similar rates were seen at doses of 5×10(8) to 1×10(10)cfu with the three most commonly used strains B7A, E24377A, H10407. In IPD analysis, the highest diarrhea attack rates were seen with strains B7A, H10407 and E24377A. The H10407 induced significantly higher stool output than the other strains. Additionally, the rate of output was different across strains. The risk of diarrhea, abdominal cramps, nausea and headaches differed significantly by ETEC strain. An increased risk of nausea, abdominal cramps and headaches was seen for females. Baseline anti-LT IgG titers appeared to be associated with a decrease risk of diarrhea outcomes, a trend not seen with anti-LT IgA or seen consistently with anti-colonization factor antibodies. Neither early antibiotic treatment nor diarrhea duration significantly affected the frequency or magnitude of serologic responses. These studies have served as an invaluable tool in understanding disease course, pathogenicity, innate immune responses and an early assessment of product efficacy. When designing and planning experimental ETEC infection studies in this age of increased ethical scrutiny and growing appreciation of post-infectious sequelae, better understanding of available data is essential.
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Ensaios Clínicos como Assunto , Escherichia coli Enterotoxigênica/patogenicidade , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/fisiopatologia , Experimentação Humana , Adulto , Anticorpos Antibacterianos/sangue , Diarreia/imunologia , Diarreia/microbiologia , Diarreia/fisiopatologia , Escherichia coli Enterotoxigênica/classificação , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Virulência , Adulto JovemAssuntos
Hepatomegalia/parasitologia , Hipertensão Portal/parasitologia , Schistosoma/isolamento & purificação , Esquistossomose/complicações , Esquistossomose/diagnóstico , Esplenomegalia/parasitologia , Adulto , Animais , Anti-Helmínticos/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Humanos , Hipertensão Portal/diagnóstico , Imunoglobulina G/sangue , Imageamento por Ressonância Magnética , Masculino , Praziquantel/administração & dosagem , Propranolol/administração & dosagem , Schistosoma/imunologia , Tomografia Computadorizada por Raios X , Ultrassonografia DopplerRESUMO
The incidence rates of travelers' diarrhea (TD) have remained high for the last 50 years. More recently, there have been increasing recommendations for self-initiated therapy and use of prophylactic drugs for TD. We last examined the in vitro susceptibilities of commonly used antibiotics against TD pathogens in 1997. We now examine 456 enteropathogens isolated from adult travelers to Mexico, India, and Guatemala with diarrhea acquired between 2006 and 2008 to determine changes in susceptibility against 10 different antimicrobials by the agar dilution method. Traditional antibiotics, such as ampicillin, trimethoprim-sulfamethoxazole, and doxycycline, continue to show high levels of resistance. Current first-line antibiotic agents, including fluoroquinolones and azithromycin, showed significantly higher MICs than in our earlier study, and MIC(90) levels were above the Clinical and Laboratory Standards Institute cutoffs for resistance. There were significant geographical differences in resistance patterns when Central America was compared with India. Entertoxigenic Escherichia coli (ETEC) isolates showed increased resistance to ciprofloxacin (P = 0.023) and levofloxacin (P = 0.0078) in India compared with Central America. Enteroaggregative E. coli (EAEC) isolates from Central America showed increased resistance to nearly all of the antibiotics tested. Compared to MICs of isolates 10 years prior, there were 4- to 10-fold increases in MIC(90) values for ceftriaxone, ciprofloxacin, levofloxacin, and azithromycin for both ETEC and EAEC. There were no significant changes in rifaximin MICs. Rising MICs over time imply the need for continuous surveillance of susceptibility patterns worldwide and geographically specific recommendations in TD therapy.
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Antibacterianos/farmacologia , Diarreia/microbiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Viagem , Adolescente , Adulto , Azitromicina/farmacologia , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana , Escherichia coli Enterotoxigênica/efeitos dos fármacos , Escherichia coli Enterotoxigênica/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/microbiologia , Guatemala , Humanos , Índia , México , Testes de Sensibilidade Microbiana , Rifamicinas/farmacologia , RifaximinaRESUMO
Antibiotic-associated diarrhoea (AAD) is a common cause of morbidity and mortality. Older individuals in long-term care facilities are particularly vulnerable due to multisystem illnesses and the prevailing conditions for nosocomial infections. Lactoferrin, an antimicrobial protein in human breastmilk, was tested to determine whether it would prevent or reduce AAD, including Clostridium difficile in tube-fed long-term care patients. Thirty patients were enrolled in a randomized double-blind study, testing eight weeks of human recombinant lactoferrin compared to placebo for the prevention of antibiotic-associated diarrhoea in long-term care patients. Fewer patients in the lactoferrin group experienced diarrhoea compared to controls (p = 0.023). Based on the findings, it is concluded that human lactoferrin may reduce post-antibiotic diarrhoea.