Single-Dose Rifampicin Leprosy Chemoprophylaxis for Household Contacts in Kiribati: An Audit of a Combined Retrospective and Prospective Approach.

Kiribati is a Pacific Island nation with a widely dispersed population and one of the highest rates of leprosy worldwide. Single-dose rifampicin post-exposure prophylaxis (SDR-PEP) of leprosy contacts has reduced new case detection rates in controlled trials. In 2018, an SDR-PEP programme was introduced in Kiribati that included screening and chemoprophylaxis of household contacts of leprosy cases retrospectively (2010-2017) and prospectively (2018-2022). We conducted a retrospective audit to determine the comprehensiveness, timeliness and feasibility of the SDR-PEP programme. Overall, 13,641 household contacts were identified (9791 in the retrospective and 3850 in the prospective cohort). In the retrospective cohort, 1044 (11%) contacts were absent, 403 (4%) were ineligible for SDR, and 42 new cases were detected (0.4%) Overall, SDR coverage was 84.7%. In the prospective cohort, 164 (4%) contacts were absent, 251 (7%) were ineligible for SDR, and 23 new cases were diagnosed (0.6%). Overall, SDR coverage was 88.1%. Across both cohorts, there were 23 SDR refusals. The median time to SDR administration was 220 days (IQR 162-468) and 120 days (IQR 36-283) for the retrospective and prospective cohorts, respectively. SDR was readily accepted in both cohorts. The new case detection rate (0.5%) is consistent with that in other studies. Overall SDR coverage in both the retrospective and prospective phases met programmatic expectations.

SunGold Kiwifruit Consumption Restores Adequate to Optimal Vitamin C Status in People with a History of Severe Respiratory Infections.

Severe respiratory infections are characterised by depleted vitamin C and elevated inflammation and oxidative stress. The aim of this study was to recruit people with a history of severe respiratory infections to undergo a six-week intervention with SunGold kiwifruit to determine if this could restore adequate vitamin C status. Secondary outcomes included changes in inflammatory and oxidative stress biomarkers, self-reported fatigue and subjective mood, and the incidence, duration and severity of respiratory symptoms. The total cohort comprised 20 adults (65% female, age range 31-84 years). The participants had a low median fruit and vegetable intake of 2.3 servings/day and a correspondingly low vitamin C intake of 46 mg/day. Circulating vitamin C status was a median of 45 µmol/L and was in the hypovitaminosis range in 25% of the cohort. Following intervention with two SunGold kiwifruit/day (equivalent to ~300 mg vitamin C), there was an increase in plasma vitamin C concentrations to >60 µmol/L (p < 0.05). Approximately 20% of the participants were unable to reach adequate vitamin C status (≥50 µmol/L), possibly due to current smoking, which enhances vitamin C turnover, and a strong inverse correlation between body weight and vitamin C status (r = -0.734, p < 0.05). Following the intervention, there were indications towards decreases in the inflammatory biomarkers C-reactive protein and TNFα (p > 0.05), but no changes in oxidative stress biomarkers (F2isoprostanes, protein carbonyls). There were decreases in fatigue and depression (p < 0.05) and a lower number of individual respiratory symptoms reported during the kiwifruit intervention phase (8.5 vs. 10, p = 0.05). Overall, the consumption of two SunGold kiwifruit per day for six weeks was able to restore adequate to saturating vitamin C status in ~80% of the participants. Smokers and people with higher body weight may need larger doses and/or longer duration of supplementation. The contribution of vitamin C to reducing fatigue, depression, and number of respiratory symptoms warrants further investigation.

Low Vitamin C Concentrations in Patients with Community-Acquired Pneumonia Resolved with Pragmatic Administration of Intravenous and Oral Vitamin C.

Community-acquired pneumonia (CAP) is characterized by elevated markers of inflammation and oxidative stress and depleted circulating concentrations of the antioxidant nutrient vitamin C. A feasibility trial of intravenous and oral vitamin C supplementation, matched to the timing of intravenous and oral antibiotic formulations, was carried out and changes in vitamin C status were monitored to determine whether saturating status could be achieved throughout the administration period. Patients with moderate and severe CAP (CURB-65 ≥ 2; n = 75) who were receiving intravenous antimicrobial therapy were randomized to placebo (n = 39) or intravenous vitamin C (2.5 g per 8 h; n = 36) before moving to oral vitamin C (1 g three times daily) when prescribed oral antimicrobials. Blood samples were collected at baseline and then daily whilst in the hospital. Vitamin C concentrations were determined by high-performance liquid chromatography. The inflammatory and infection biomarkers C-reactive protein and procalcitonin were elevated at baseline (158 (61, 277) mg/L and 414 (155, 1708) ng/L, respectively), and vitamin C concentrations were depleted (15 (7, 25) µmol/L). There was an inverse association between vitamin C and C-reactive protein concentrations (r = -0.312, p = 0.01). Within one day of intervention initiation, plasma vitamin C concentrations in the vitamin C group reached median concentrations of 227 (109, 422) µmol/L, and circulating concentrations remained at ≥150 µmol/L for the duration of the intervention, whilst median vitamin C concentrations in the placebo group remained low (≤35 µmol/L). There was a trend toward decreased duration of hospital stay (p = 0.07) and time to clinical stability (p = 0.08) in the vitamin C group. In conclusion, patients with moderate to severe CAP have inadequate plasma vitamin C concentrations for the duration of their hospital stay. The administration of intravenous or oral vitamin C, titrated to match the antimicrobial formulation, provided saturating plasma vitamin C concentrations whilst in the hospital. There were trends toward shorter duration of hospital stay and time to clinical stability. Thus, larger trials assessing the impact of intravenous and oral vitamin C intervention on CAP clinical outcomes are indicated.

Adjunctive intravenous then oral vitamin C for moderate and severe community-acquired pneumonia in hospitalized adults: feasibility of randomized controlled trial.

Patients hospitalised with community acquired pneumonia (CAP) have low peripheral blood vitamin C concentrations and limited antioxidant capacity. The feasibility of a trial of vitamin C supplementation to improve patient outcomes was assessed. Participants with moderate and severe CAP (CURB-65 ≥ 2) on intravenous antimicrobial treatment were randomised to either intravenous vitamin C (2.5 g 8 hourly) or placebo before switching to oral intervention (1 g tds) for 7 days when they were prescribed oral antimicrobial therapy. Of 344 patients screened 75 (22%) were randomised and analysed. The median age was 76 years, and 43 (57%) were male. In each group, one serious adverse event that was potentially intervention related occurred, and one subject discontinued treatment. Vitamin C concentrations were 226 µmol/L in the vitamin C group and 19 µmol/L in the placebo group (p < 0.001) after 3 intravneous doses. There were no signficant differences between the vitamin C and placebo groups for death within 28 days (0 vs. 2; p = 0.49), median length of stay (69 vs. 121 h; p = 0.07), time to clinical stability (22 vs. 49 h; p = 0.08), or readmission within 30 days (1 vs. 4; p = 0.22). The vitamin C doses given were safe, well tolerated and saturating. A randomised controlled trial to assess the efficacy of vitamin C in patients with CAP would require 932 participants (CURB-65 ≥ 2) to observe a difference in mortality and 200 participants to observe a difference with a composite endpoint such as mortality plus discharge after 7 days in hospital. These studies are feasible in a multicentre setting.

The inhibitory effect of copper, zinc, and manganese on Legionella longbeachae and other Legionella spp. in vitro.

Legionella longbeachae is an important cause of Legionnaires' disease in Australasia and is associated with exposure to potting soils. Our aim was to identify ways to reduce the load of L. longbeachae in potting soils. Inductively-coupled plasma optical emission spectrometry (ICP-OES) of an all-purpose potting mix showed copper (Cu) concentrations (mg/kg) range from 15.8 to 23.6. Zinc (Zn) and manganese (Mn) were significantly higher than Cu ranging from 88.6-106 to 171-203, respectively. Minimal inhibitory and bactericidal concentrations of 10 salts used in the horticultural industry were determined for Legionella species in buffered yeast extract (BYE) broth. For L. longbeachae (n = 9) the median (range) minimum inhibitory concentration (MIC) (mg/L) of copper sulfate was 31.25 (15.6-31.25), zinc sulfate 31.25 (7.81-31.25), and manganese sulfate 31.25 (7.81-62.5). The MIC and minimum bactericidal concentration (MBC) were within one dilution of each other. Susceptibility to Cu and Zn salts increased as the concentration of pyrophosphate iron in the media decreased. The MIC values for these three metals against Legionella pneumophila (n = 3) and Legionella micdadei (n = 4) were similar. Combinations of Cu, Zn, and Mn were additive. Legionella longbeachae has similar susceptibility to Cu and other metal ions in comparison to L. pneumophila.

Effectiveness of population-wide screening and mass drug administration for leprosy control in Kiribati: the COMBINE protocol.

INTRODUCTION: Progress towards leprosy elimination is threatened by increasing incidence in 'hot-spot' areas where more effective control strategies are urgently required. In these areas, active case finding and leprosy prevention limited to known contacts is insufficient for control. Population-wide active case-finding together with universal prevention through mass drug administration (MDA) has been shown to be effective in 'hot-spot' areas, but is logistically challenging and expensive. Combining leprosy screening and MDA with other population-wide screening activities such as for tuberculosis may increase programme efficiency. There has been limited evaluation of the feasibility and effectiveness of combined screening and MDA interventions. The COMBINE study aims to bridge this knowledge gap. METHODS AND ANALYSIS: This implementation study will assess the feasibility and effectiveness of active leprosy case-finding and treatment, combined with MDA using either single-dose rifampicin or rifamycin-containing tuberculosis preventive or curative treatment, for reducing leprosy incidence in Kiribati. The leprosy programme will run over 2022-2025 in concert with population-wide tuberculosis screening-and-treatment in South Tarawa. The primary research question is to what extent the intervention reduces the annual leprosy new case detection rate (NCDR) in adults and children compared with routine screening and postexposure prophylaxis (PEP) among close contacts (baseline leprosy control activities). Comparisons will be made with (1) the preintervention NCDR separably among adults and children in South Tarawa (before-after study) and (2) the corresponding NCDRs in the rest of the country. Additionally, the postintervention prevalence of leprosy obtained from a survey of a 'hot-spot' sub-population will be compared with prevalence documented during the intervention. The intervention will be implemented in collaboration with the Kiribati National Leprosy Programme. ETHICS AND DISSEMINATION: Approval has been obtained from the Kiribati Ministry of Health and Medical Services (MHMS), the University of Otago (H22/111) and the University of Sydney (2021/127) Human Research Ethics Committees. Findings will be shared with the MHMS, local communities and internationally through publication.

Safety and clinical outcomes of outpatient parenteral antibiotic therapy for infective endocarditis in Christchurch, New Zealand: A retrospective cohort study.

OBJECTIVES: We examined the safety and clinical outcomes of outpatient parenteral antibiotic therapy (OPAT) for patients with infective endocarditis (IE) in Christchurch, New Zealand. METHODS: Demographic and clinical data were collected from all adult patients treated for IE over 5 years. Outcomes were stratified by receipt of at least partial OPAT vs entirely hospital-based parenteral therapy. RESULTS: There were 172 episodes of IE between 2014 and 2018. OPAT was administered in 115 cases (67%) for a median of 27 days after a median of 12 days of inpatient treatment. In the OPAT cohort, viridans group streptococci were the commonest causative pathogens (35%) followed by Staphylococcus aureus (25%) and Enterococcus faecalis (11%). There were six (5%) antibiotic-related adverse events and 26 (23%) readmissions in the OPAT treatment group. Mortality in OPAT patients was 6% (7/115) at 6 months and 10% (11/114) at 1 year and for patients receiving wholly inpatient parenteral therapy was 56% (31/56) and 58% (33/56), respectively. Three patients (3%) in the OPAT group had a relapse of IE during the 1-year follow-up period. CONCLUSION: OPAT can be used safely in patients with IE, even in selected cases with complicated or difficult-to-treat infections.

Symptom persistence and recovery among COVID-19 survivors during a limited outbreak in Canterbury, New Zealand: a prospective cohort study.

BACKGROUND: In Canterbury, near complete identification of coronavirus disease 2019 (COVID-19) cases during a limited outbreak provides unique insights into sequelae. AIMS: The current study aimed to measure symptom persistence, time to return to normal activity, generalised anxiety and health-related quality of life (HrQoL) among COVID-19 survivors compared with uninfected participants. METHODS: The authors conducted a prospective cohort study of people tested for COVID-19 by reverse transcriptase polymerase chain reaction of nasopharyngeal swabs from 1 March to 30 June 2020. They enrolled participants who tested positive and negative at a 1:2 ratio, and administered community-acquired pneumonia, 7-item generalised anxiety disorder (GAD-7) and HrQoL (RAND-36) questionnaires. RESULTS: The authors recruited 145 participants, 48 with COVID-19 and 97 without COVID-19. The mean time from COVID-19 testing to completing the health questionnaire was 306 days. The mean age of patients was 46.7 years, and 70% were women. Four (8%) COVID-19-positive and eight (8%) COVID-19-negative participants required hospitalisation. Fatigue (30/48 [63%] vs 13/97 [13%]; P < 0.001), dyspnoea (13/48 [27%] vs 6/97 [6%]; P < 0.001) and chest pain (10/48 [21%] vs 1/97 [1%]; P < 0.001) were persistent in those with COVID-19. Fewer COVID-19-positive participants returned to normal activity levels (35/48 [73%] vs 94/97 97%; P < 0.001), with longer times taken (median 21 vs 14 days; P = 0.007). The GAD-7 and RAND-36 scores of both groups were similar across all anxiety and HrQoL subscales. CONCLUSIONS: Persistent symptoms and longer recovery times were found in COVID-19 survivors, but not impaired generalised anxiety levels or HrQoL compared with COVID-19-uninfected participants.

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients.

BACKGROUND: The proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations. PATIENTS AND METHODS: Unbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT≥1MIC, 50%fT≥2MIC). RESULTS: There were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT≥2MIC and 95 (95%) patients met the target of 50%fT≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0-8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8-28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations. CONCLUSIONS: Standard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.

Supplementation with Oral Vitamin C Prior to and during Myeloablative Chemotherapy and Autologous Haematopoietic Stem Cell Transplantation: A Pilot Study.

Chemotherapy-related side effects are common in patients undergoing myeloablative chemotherapy and haematopoietic stem cell transplantation. Some, such as oral mucositis, are believed to be due to enhanced oxidative stress and inflammation. Vitamin C, a potent antioxidant with anti-inflammatory properties, becomes severely depleted following myeloablative chemotherapy. The aim of our study was to assess the feasibility and efficacy of oral vitamin C supplementation to restore and maintain adequate vitamin C concentrations in patients undergoing myeloablative chemotherapy and stem cell transplantation. We carried out a pilot randomized controlled trial in 20 patients with myeloma and lymphoma. Placebo or vitamin C tablets (1 g twice daily) were initiated one week prior to transplantation and continued for 4 weeks post-transplantation. Blood samples were collected weekly for analysis of plasma vitamin C concentrations using high-performance liquid chromatography. The patients' symptoms and quality of life parameters were monitored using the World Health Organization oral toxicity scale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). Pre-supplementation with oral vitamin C doubled vitamin C concentrations relative to placebo by day 0 (median 61 vs. 31 µmol/L), with 60% of those in the vitamin C group achieving concentrations ≥ 50 µmol/L, compared with only 10% in the placebo group. Following chemotherapy and transplantation, significance between the vitamin C and placebo groups was lost by day 7, with only 30% of the patients in the vitamin C group having plasma concentrations ≥ 50 µmol/L. This was partly due to intolerance of the oral intervention due to nausea/vomiting and diarrhoea (40% of the participants in each group). Oral mucositis was also observed in 40% of the participants at day 7 or 14. Overall, our study showed that whilst short-term oral vitamin C pre-supplementation was able to restore adequate vitamin C status by day 0, ongoing supplementation could not maintain adequate vitamin C concentrations following chemotherapy and transplantation. Thus, intravenous vitamin C should be trialled as this bypasses the gastrointestinal system, negating intolerance issues and improving bioavailability of the vitamin.

A Novel Monoclonal Antibody 1D2 That Broadly Inhibits Clinically Important Aspergillus Species.

Aspergillus fumigatus is a ubiquitous airborne fungus, is the predominant cause (>90%) of invasive aspergillosis (IA) in immunosuppressed patients and has a high mortality. New approaches to prevention and treatment are needed because of the poor efficacy, toxicity and side effects of the current anti-Aspergillus drugs on patients. Thus, we aim to explore a new avenue to combat Aspergillus infection by using a novel monoclonal antibody (mAb) 1D2 against a glycoprotein on the cell wall of Aspergillus. The ability of this mAb to inhibit attachment, germination, and growth of Aspergillus conidia and hyphae in vitro were examined. A dose-dependent growth inhibition of Aspergillus conidia in the presence of mAb 1D2 was found. The mAb 1D2 inhibited attachment of Aspergillus conidia to an untreated slide surface and fibronectin-treated surface compared to an unrelated mAb 6B10. When conidia were exposed to 1D2 concomitantly with inoculation into culture media, the mAb prevented the swelling and germination of conidia. This inhibitory ability of 1D2 was less apparent if it was added two hours after inoculation. Damage to hyphae was also observed when 1D2 was added to Aspergillus hyphae that had been incubated in media overnight. These in vitro results indicate that mAb 1D2 broadly inhibits clinically important Aspergillus species and has a promising therapeutic effect both as prophylaxis to inhibit an Aspergillus infection as well as a treatment.

Hydrogen Sulfide and Substance P Levels in Patients with Escherichia coli and Klebsiella pneumoniae Bacteraemia.

Hydrogen sulfide (H2S) and substance P (SP) are known from animal models and in vitro studies as proinflammatory mediators. In this study, peripheral blood concentrations of H2S and SP were measured in patients with Escherichia coli or Klebsiella pneumoniae bacteraemia. Fifty patients were recruited from general wards at Christchurch Hospital, during 2020-2021. Samples from age- and sex-matched healthy subjects previously recruited as controls for studies of cardiovascular disease were used as controls. The concentrations of H2S were higher than controls on day 0, day 1, and day 2, and SP was higher than controls on all 4 days. The concentrations of H2S were highest on day 0, whereas SP concentrations were higher on day 2 than other days. Interleukin-6 and C-reactive protein were significantly higher on day 0 and day 1, respectively. The concentrations of H2S and SP did not differ between 15 non-septic (SIRS 0-1) and the 35 septic subjects (SIRS ≥ 2). Substance P concentrations were higher in subjects with abdominal infection than urinary tract infections on day 0 (p = 0.0002) and day 1 (p = 0.0091). In conclusion, the peak H2S concentrations precede the SP peak in patients with Gram-negative bacteraemia, but this response varies with the site of infection.

Monoclonal Antibodies and Invasive Aspergillosis: Diagnostic and Therapeutic Perspectives.

Invasive aspergillosis (IA) is a life-threatening fungal disease that causes high morbidity and mortality in immunosuppressed patients. Early and accurate diagnosis and treatment of IA remain challenging. Given the broad range of non-specific clinical symptoms and the shortcomings of current diagnostic techniques, most patients are either diagnosed as "possible" or "probable" cases but not "proven". Moreover, because of the lack of sensitive and specific tests, many high-risk patients receive an empirical therapy or a prolonged treatment of high-priced antifungal agents, leading to unnecessary adverse effects and a high risk of drug resistance. More precise diagnostic techniques alongside a targeted antifungal treatment are fundamental requirements for reducing the morbidity and mortality of IA. Monoclonal antibodies (mAbs) with high specificity in targeting the corresponding antigen(s) may have the potential to improve diagnostic tests and form the basis for novel IA treatments. This review summarizes the up-to-date application of mAb-based approaches in assisting IA diagnosis and therapy.

Clinical characteristics and outcome of infective endocarditis due to Abiotrophia and Granulicatella compared to Viridans group streptococci.

OBJECTIVE: To describe the clinical characteristics and outcome of Abiotrophia and Granulicatella infective endocarditis and compare them with Viridans group streptococci infective endocarditis. METHODS: All patients in the International Collaboration on Endocarditis (ICE) - prospective cohort study (PCS) and the ICE-PLUS cohort were included (n = 8112). Data from patients with definitive or possible IE due to Abiotrophia species, Granulicatella species and Viridans group streptococci was analyzed. A propensity score (PS) analysis comparing the ABI/GRA-IE and VGS-IE groups according to a 1:2 ratio was performed. RESULTS: Forty-eight (0.64%) cases of ABI/GRA-IE and 1,292 (17.2%) VGS-IE were included in the analysis. The median age of patients with ABI/GRA-IE was lower than VGS-IE (48.1 years vs. 57.9 years; p = 0.001). Clinical features and the rate of in-hospital surgery was similar between ABI/GRA-IE and VGS-IE (52.1% vs. 45.4%; p = 0.366). Unadjusted in-hospital death was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 8.8%; p = 0.003), and cumulative six-month mortality was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 11.9%; p<0.001). After PS analysis, in-hospital mortality was similar in both groups, but six-month mortality was lower in the ABI/GRA IE group (2.1% vs. 10.4%; p = 0.029). CONCLUSIONS: Patients with ABI/GRA-IE were younger, had similar clinical features and rates of surgery and better prognosis than VGS-IE.

Population-wide active case finding and prevention for tuberculosis and leprosy elimination in Kiribati: the PEARL study protocol.

INTRODUCTION: Population-wide interventions offer a pathway to tuberculosis (TB) and leprosy elimination, but 'real-world' implementation in a high-burden setting using a combined approach has not been demonstrated. This implementation study aims to demonstrate the feasibility and evaluate the effect of population-wide screening, treatment and prevention on TB and leprosy incidence rates, as well as TB transmission. METHODS AND ANALYSIS: A non-randomised 'screen-and-treat' intervention conducted in the Pacific atoll of South Tarawa, Kiribati. Households are enumerated and all residents ≥3 years, as well as children <3 years with recent household exposure to TB or leprosy, invited for screening. Participants are screened using tuberculin skin testing, signs and symptoms of TB or leprosy, digital chest X-ray with computer-aided detection and sputum testing (Xpert MTB/RIF Ultra). Those diagnosed with disease are referred to the National TB and Leprosy Programme for management. Participants with TB infection are offered TB preventive treatment and those without TB disease or infection, or leprosy, are offered leprosy prophylaxis. The primary study outcome is the difference in the annual TB case notification rate before and after the intervention; a similar outcome is included for leprosy. The effect on TB transmission will be measured by comparing the estimated annual risk of TB infection in primary school children before and after the intervention, as a co-primary outcome used for power calculations. Comparison of TB and leprosy case notification rates in South Tarawa (the intervention group) and the rest of Kiribati (the control group) before, during and after the intervention is a secondary outcome. ETHICS AND DISSEMINATION: Approval was obtained from the University of Sydney Human Research Ethics Committee (project no. 2021/127) and the Kiribati Ministry of Health and Medical Services (MHMS). Findings will be shared with the MHMS and local communities, published in peer-reviewed journals and presented at international conferences.

Probenecid effects on cephalexin pharmacokinetics and pharmacodynamics in healthy volunteers.

OBJECTIVES: We evaluated the effects of probenecid on the Pharmaco Kinetics (PK) and pharmacodynamics (PD) of oral cephalexin in healthy volunteers. METHODS: Cephalexin 1000 mg was administered orally to 11 healthy volunteers following a standardized meal, with and without probenecid 500 mg orally, on two separate days one week apart. Total plasma concentrations of cephalexin and probenecid over a 12 h period were measured by liquid chromatography tandem mass spectrometry. Standard pharmacokinetic measures and contemporary PK/PD targets were compared. RESULTS: Probenecid increased the mean (95% CI) cephalexin area under the concentration-time curve (AUC0-∞) 1.73-fold (1.61-1.85, p < 0.0001), peak concentration 1.37-fold (1.16-1.58, p < 0.01), time to peak concentration 1.45-fold (1.1-1.8, p < 0.01), and half-life 1.33-fold (1.03-1.62, p < 0.05). The effects resulted in clinically meaningful increases in the probability of PK/PD target attainment (PTA). As an example, the PTA of total concentrations above the minimum inhibitory concentration required to inhibit methicillin-susceptible Staphylococcus aureus isolates (MIC ≤ 8 mg/L) for 70% of a 6 h dose interval approached 100% for cephalexin + probenecid while for cephalexin alone it was <15%. CONCLUSIONS: Probenecid prolonged and flattened the plasma concentration-time curve, enhancing the probability of attaining PK/PD targets. Co-administration of probenecid may expand the clinical benefits of oral cephalexin.

Population pharmacokinetics of free flucloxacillin in patients treated with oral flucloxacillin plus probenecid.

Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination. METHODS: We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly for proven or probable staphylococcal infections. Steady-state mid-dose-interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration). RESULTS: Flucloxacillin disposition was best described by a 1-compartment model with a lag time and first-order absorption. Free flucloxacillin clearance depended on probenecid, allometrically-scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid. CONCLUSION: The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6-hourly dosing to achieve PK/PD targets. The regimen was well-tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.

Legionellosis Caused by Non-Legionella pneumophila Species, with a Focus on Legionella longbeachae.

Although known as causes of community-acquired pneumonia and Pontiac fever, the global burden of infection caused by Legionella species other than Legionella pneumophila is under-recognised. Non-L. pneumophila legionellae have a worldwide distribution, although common testing strategies for legionellosis favour detection of L. pneumophila over other Legionella species, leading to an inherent diagnostic bias and under-detection of cases. When systematically tested for in Australia and New Zealand, L. longbeachae was shown to be a leading cause of community-acquired pneumonia. Exposure to potting soils and compost is a particular risk for infection from L. longbeachae, and L. longbeachae may be better adapted to soil and composting plant material than other Legionella species. It is possible that the high rate of L. longbeachae reported in Australia and New Zealand is related to the composition of commercial potting soils which, unlike European products, contain pine bark and sawdust. Genetic studies have demonstrated that the Legionella genomes are highly plastic, with areas of the chromosome showing high levels of recombination as well as horizontal gene transfer both within and between species via plasmids. This, combined with various secretion systems and extensive effector repertoires that enable the bacterium to hijack host cell functions and resources, is instrumental in shaping its pathogenesis, survival and growth. Prevention of legionellosis is hampered by surveillance systems that are compromised by ascertainment bias, which limits commitment to an effective public health response. Current prevention strategies in Australia and New Zealand are directed at individual gardeners who use potting soils and compost. This consists of advice to avoid aerosols generated by the use of potting soils and use masks and gloves, but there is little evidence that this is effective. There is a need to better understand the epidemiology of L. longbeachae and other Legionella species in order to develop effective treatment and preventative strategies globally.