Heidi S. M. Ammerlaan

Bio: Heidi S. M. Ammerlaan is an academic researcher from University Medical Center Utrecht. The author has contributed to research in topics: Medicine & Vaccination. The author has an hindex of 12, co-authored 19 publications receiving 927 citations. Previous affiliations of Heidi S. M. Ammerlaan include Eindhoven University of Technology.

Eradication of Methicillin-Resistant Staphylococcus aureus Carriage: A Systematic Review

Abstract: A systematic review was performed to determine the effectiveness of different approaches for eradicating methicillin-resistant Staphylococcus aureus carriage. Twenty-three clinical trials were selected that evaluated oral antibiotics (7 trials), topically applied antibiotics (12 trials), or both (4 trials). Because of clinical heterogeneity, quantitative analysis of all studies was deemed to be inappropriate, and exploratory subgroup analyses were performed for studies with similar study populations, methods, and targeted bacteria. The estimated pooled relative risk of treatment failure 1 week after short-term nasal mupirocin treatment, compared with placebo, was 0.10 (range, 0.07–0.14). There was low heterogeneity between study outcomes, and effects were similar for patients and healthy subjects, as well as in studies that included only methicillin-susceptible S. aureus carriers or both methicillin-susceptible S. aureus and methicillin-resistant S. aureus carriers. The development of drug resistance during treatment was reported in 1% and 9% of patients receiving mupirocin and oral antibiotics, respectively. Short-term nasal application of mupirocin is the most effective treatment for eradicating methicillin-resistant S. aureus carriage, with an estimated success of rate of 90% 1 week after treatment and ∼60% after a longer follow-up period. Colonization is an important step in the pathogenesis of Staphylococcus aureus infection and is instrumental in the nosocomial epidemiology of these bacteria. Approximately 20% of the general population is persistently colonized with S. aureus, most frequently in the anterior nares, although other body sites, such as the perineum and throat, may also be colonized. Another 30% of the general population is intermittently colonized, and the remaining 50% appear not to be susceptible, for unknown reasons, to S. aureus carriage [1]. Methicillin-resistant S. aureus (MRSA) has become endemic in health care institutions worldwide, with up to 70% of invasive S. aureus infections having resistance [2–5], and most patients who develop drug-resistant S. aureus infection will have been colonized prior to infection. The half-life of MRSA carriage has been reported to be as long as 40 months in individuals who do not receive treatment [6].

Effects of confounders and intermediates on the association of bacteraemia caused by extended-spectrum β-lactamase-producing Enterobacteriaceae and patient outcome: a meta-analysis

Abstract: Background and objectives: Bacteraemia caused by Enterobacteriaceae (EB) producing extended-spectrum b-lactamase (ESBL+) has been associated with higher mortality compared with non-ESBL-producing (ESBL2) EB bacteraemia in observational studies. We conducted a systematic review and meta-analysis of these studies to assess how adjusting for confounding in multivariate analyses affects the pooled estimate, and whether multivariate analyses that include intermediates in the causal pathway of outcome (sepsis severity and inadequate empirical therapy) have lower estimates of attributable mortality. Data sources: PubMed search on 23 November 2010 followed by manually searching reference lists of included studies. Study eligibility criteria: Cohort studies published in English with separate mortality rates for ESBL+ and ESBL2 EB bacteraemia. Synthesis methods: Random-effects pooling of unadjusted and adjusted ORs followed by subgroup analyses to explore effects of adjustment procedures on adjusted ORs. Results: The pooled OR for the unadjusted mortality associated with ESBL production was 2.35 (95% CI 1.90– 2.91, I 2 ¼ 42%, 32 studies). The pooled adjusted OR was 1.52 (95% CI 1.15– 2.01, I 2 ¼ 32%, 15 studies). Adjustment for more intermediates was associated with decreasing ORs. The pooled OR for the analyses adjusting for inadequate empirical therapy was 1.37 (95% CI 1.04 –1.82). Conclusions: ESBL production in EB bacteraemia is associated with a higher mortality compared with bacteraemia with ESBL2 EB, although the estimate of this association is affected by adjustment procedures. Adjustment for inadequate empirical therapy leads to a reduction in ORs, indicating that higher mortality is likely to be mediated through this phenomenon.

Convalescent Plasma for COVID-19. A randomized clinical trial

Abstract: Background After recovery from COVID-19, most patients have anti-SARS-CoV-2 neutralizing antibodies. Their convalescent plasma could be an inexpensive and widely available treatment for COVID-19. Methods The Convalescent-plasma-for-COVID (ConCOVID) study was a randomized trial comparing convalescent plasma with standard of care therapy in patients hospitalized for COVID-19 in the Netherlands. Patients were randomized 1:1 and received 300ml of plasma with anti-SARS-CoV-2 neutralizing antibody titers of at least 1:80. The primary endpoint was day-60 mortality and key secondary endpoints were hospital stay and WHO 8-point disease severity scale improvement on day 15. Results The trial was halted prematurely after 86 patients were enrolled. Although symptomatic for only 10 days (IQR 6-15) at the time of inclusion, 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline. A SARS-CoV-2 plaque reduction neutralization test showed neutralizing antibodies in 44 of the 56 (79%) patients tested with median titers comparable to the 115 donors (1:160 vs 1:160, p=0.40). These observations caused concerns about the potential benefit of convalescent plasma in the study population and after discussion with the data safety monitoring board, the study was discontinued. No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care. Conclusion Most COVID-19 patients already have high neutralizing antibody titers at hospital admission. Screening for antibodies and prioritizing convalescent plasma to risk groups with recent symptom onset will be key to identify patients that may benefit from convalescent plasma. Clinicaltrials.gov: NCT04342182

Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection.

Abstract: In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.

Adequacy of Antimicrobial Treatment and Outcome of Staphylococcus aureus Bacteremia in 9 Western European Countries

Abstract: BACKGROUND: Little is known about the incidence of inadequate treatment of severe Staphylococcus aureus infection in Europe. We aimed to evaluate the adequacy of antibiotic therapy for S. aureus bacteremia (SAB), to identify determinants of inadequate treatment, and to determine the effect of inadequate treatment on patient outcome in a representative selection of hospitals in 9 Western European countries. METHODS: In this retrospective cohort study, all adult patients with SAB (due to methicillin-susceptible S. aureus [MSSA] or methicillin-resistant S. aureus [MRSA]) who were admitted to 60 randomly selected hospitals from 1 November 2007 through 31 December 2007 were included. Adequate antimicrobial therapy was defined as intravenous administration of at least 1 antibiotic to which the isolate showed in vitro susceptibility that was initiated within 2 days after onset of SAB. RESULTS: A total of 334 SAB episodes (257 due to MSSA and 77 due to MRSA) were included. Ninety-four patients (28%) received inadequate empirical therapy (21% in the MSSA group and 52% in the MRSA group). Both length of stay before SAB onset and methicillin-resistant infection were associated with inadequate therapy, with adjusted odds ratios (ORs) of 1.01 (95% confidence interval [CI], 1.00-1.03) and 3.7 (95% CI, 2.2-6.4), respectively. Age (OR, 1.06; 95% CI, 1.03-1.10), Charlson comorbidity score (OR, 2.1; 95% CI, 1.2-3.6), severe sepsis or septic shock (OR, 2.7; 95% CI, 1.5-4.8), and intensive care unit stay at onset of SAB (OR, 2.9; 95% CI, 1.5-5.6) but not inadequate treatment (OR, 0.7; 95% CI, 0.4-1.3) were associated with increased 30-day mortality. CONCLUSION: Inadequate empirical antimicrobial therapy for SAB is common in Western Europe and is strongly associated with infection caused by MRSA. In this study, inadequate treatment was not associated with increased 30-day mortality rates.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.

Abstract: Background Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. Methods We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. Results A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200]. No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83 (95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. Conclusions No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).

Predictors of Mortality in Staphylococcus aureus Bacteremia

Abstract: Staphylococcus aureus bacteremia (SAB) is an important infection with an incidence rate ranging from 20 to 50 cases/100,000 population per year. Between 10% and 30% of these patients will die from SAB. Comparatively, this accounts for a greater number of deaths than for AIDS, tuberculosis, and viral hepatitis combined. Multiple factors influence outcomes for SAB patients. The most consistent predictor of mortality is age, with older patients being twice as likely to die. Except for the presence of comorbidities, the impacts of other host factors, including gender, ethnicity, socioeconomic status, and immune status, are unclear. Pathogen-host interactions, especially the presence of shock and the source of SAB, are strong predictors of outcomes. Although antibiotic resistance may be associated with increased mortality, questions remain as to whether this reflects pathogen-specific factors or poorer responses to antibiotic therapy, namely, vancomycin. Optimal management relies on starting appropriate antibiotics in a timely fashion, resulting in improved outcomes for certain patient subgroups. The roles of surgery and infectious disease consultations require further study. Although the rate of mortality from SAB is declining, it remains high. Future international collaborative studies are required to tease out the relative contributions of various factors to mortality, which would enable the optimization of SAB management and patient outcomes.

Methicillin-resistant Staphylococcus aureus.

Abstract: Since the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has emerged, disseminated globally and become a leading cause of bacterial infections in both health-care and community settings. However, there is marked geographical variation in MRSA burden owing to several factors, including differences in local infection control practices and pathogen-specific characteristics of the circulating clones. Different MRSA clones have resulted from the independent acquisition of staphylococcal cassette chromosome mec (SCCmec), which contains genes encoding proteins that render the bacterium resistant to most β-lactam antibiotics (such as methicillin), by several S. aureus clones. The success of MRSA is a consequence of the extensive arsenal of virulence factors produced by S. aureus combined with β-lactam resistance and, for most clones, resistance to other antibiotic classes. Clinical manifestations of MRSA range from asymptomatic colonization of the nasal mucosa to mild skin and soft tissue infections to fulminant invasive disease with high mortality. Although treatment options for MRSA are limited, several new antimicrobials are under development. An understanding of colonization dynamics, routes of transmission, risk factors for progression to infection and conditions that promote the emergence of resistance will enable optimization of strategies to effectively control MRSA. Vaccine candidates are also under development and could become an effective prevention measure.

Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).

Abstract: Objective To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India. Design Open label, parallel arm, phase II, multicentre, randomised controlled trial. Setting 39 public and private hospitals across India. Participants 464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm). Interventions Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study. Main outcome measure Composite of progression to severe disease (PaO2/FiO2 Results Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54). Conclusion Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19. Trial registration Clinical Trial Registry of India CTRI/2020/04/024775.