Distinct clinical endpoints of Staphylococcus aureus bacteraemia complicate assessment of outcome.

BACKGROUND: We aimed to test the hypothesis that development of metastatic infection represents a distinct clinical endpoint from death due to SAB. METHODS: We conducted a retrospective observational study of adults with SAB between 20/12/2019 and 23/08/2022 (n=464). Simple logistic regression, odds ratios, and z-scores were used to compare host, clinical and microbiologic features. RESULTS: Co-occurrence of attributable mortality and metastatic infection was infrequent. Charlson Comorbidity Index and age were strongly associated with attributable mortality, but not metastatic infection. We compared patients with fatal SAB (without clinically-apparent metastatic complications, 14·4% of cohort), metastatic SAB (without attributable mortality, 22·2%), neither complication (56·7%), and overlapping fatal/metastatic SAB (6·7%). Compared to SAB without complications, fatal SAB was specifically associated with older age and multi-morbidity. Metastatic SAB was specifically associated with community acquisition, persistent fever, persistent bacteraemia, and recurrence. Endocarditis was over-represented in the fatal/metastatic SAB overlap group, which shared patient characteristics with fatal SAB. In contrast to other (predominantly musculoskeletal) metastatic complications, endocarditis was associated with increased mortality, with death occurring in older multi-morbid patients later after SAB onset. CONCLUSIONS: Patients with SAB experience distinct clinical endpoints: (i) early death, associated with multi-morbidity and age; (ii) metastatic (predominantly musculoskeletal) SAB; (iii) endocarditis, associated with late death occurring in older people with multi-morbidity, and (iv) bacteraemia without complications. These distinctions could be important for selecting appropriate outcomes in clinical trials: different interventions might be required to reduce mortality vs. improve clinical response in patients with metastatic SAB.

Clinical sub-phenotypes of Staphylococcus aureus bacteraemia.

BACKGROUND: Staphylococcus aureus bacteraemia (SAB) is a clinically heterogeneous disease. The ability to identify sub-groups of patients with shared traits (sub-phenotypes) is an unmet need that could allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically-relevant sub-phenotypes can be reproducibly identified amongst patients with SAB. METHODS: We studied three cohorts of hospitalised adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n=458), the UK ARREST randomised trial (n=758), and the Spanish SAFO randomised trial (n=214). Latent class analysis was used to identify sub-phenotypes using routinely-collected clinical data, without considering outcomes. Mortality and microbiologic outcomes were then compared between sub-phenotypes. RESULTS: Included patients had predominantly methicillin-susceptible SAB (1366/1430,95.5%). We identified five distinct, reproducible clinical sub-phenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the sub-phenotypes. 84-day mortality was highest in sub-phenotype A, and lowest in B and E. Microbiologic outcomes were worse in sub-phenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased 84-day mortality in sub-phenotype B and improved microbiologic outcomes in sub-phenotype C. CONCLUSIONS: We have identified reproducible and clinically-relevant sub-phenotypes within SAB, and provide proof-of-principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these sub-phenotypes could contribute to a personalised medicine approach to SAB.

Helminth induced monocytosis conveys protection from respiratory syncytial virus infection in mice.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infants is a major cause of viral bronchiolitis and hospitalisation. We have previously shown in a murine model that ongoing infection with the gut helminth Heligmosomoides polygyrus protects against RSV infection through type I interferon (IFN-I) dependent reduction of viral load. Yet, the cellular basis for this protection has remained elusive. Given that recruitment of mononuclear phagocytes to the lung is critical for early RSV infection control, we assessed their role in this coinfection model. METHODS: Mice were infected by oral gavage with H. polygyrus. Myeloid immune cell populations were assessed by flow cytometry in lung, blood and bone marrow throughout infection and after secondary infection with RSV. Monocyte numbers were depleted by anti-CCR2 antibody or increased by intravenous transfer of enriched monocytes. RESULTS: H. polygyrus infection induces bone marrow monopoiesis, increasing circulatory monocytes and lung mononuclear phagocytes in a IFN-I signalling dependent manner. This expansion causes enhanced lung mononuclear phagocyte counts early in RSV infection that may contribute to the reduction of RSV load. Depletion or supplementation of circulatory monocytes prior to RSV infection confirms that these are both necessary and sufficient for helminth induced antiviral protection. CONCLUSIONS: H. polygyrus infection induces systemic monocytosis contributing to elevated mononuclear phagocyte numbers in the lung. These cells are central to an anti-viral effect that reduces the peak viral load in RSV infection. Treatments to promote or modulate these cells may provide novel paths to control RSV infection in high risk individuals.

DETOMIDINE AND BUTORPHANOL FOR STANDING SEDATION IN A RANGE OF ZOO-KEPT UNGULATE SPECIES.

General anesthesia poses risks for larger zoo species, like cardiorespiratory depression, myopathy, and hyperthermia. In ruminants, ruminal bloat and regurgitation of rumen contents with potential aspiration pneumonia are added risks. Thus, the use of sedation to perform minor procedures is justified in zoo animals. A combination of detomidine and butorphanol has been routinely used in domestic animals. This drug combination, administered by remote intramuscular injection, can also be applied for standing sedation in a range of zoo animals, allowing a number of minor procedures. The combination was successfully administered in five species of nondomesticated equids (Przewalski horse [ Equus ferus przewalskii; n = 1], onager [ Equus hemionus onager; n = 4], kiang [ Equus kiang ; n = 3], Grevy's zebra [ Equus grevyi ; n = 4], and Somali wild ass [ Equus africanus somaliensis; n = 7]), with a mean dose range of 0.10-0.17 mg/kg detomidine and 0.07-0.13 mg/kg butorphanol; the white ( Ceratotherium simum simum; n = 12) and greater one-horned rhinoceros ( Rhinoceros unicornis ; n = 4), with a mean dose of 0.015 mg/kg of both detomidine and butorphanol; and Asiatic elephant bulls ( Elephas maximus ; n = 2), with a mean dose of 0.018 mg/kg of both detomidine and butorphanol. In addition, the combination was successfully used for standing sedation in six species of artiodactylids: giraffe ( Giraffa camelopardalis reticulata; n = 3), western bongo ( Tragelaphus eurycerus eurycerus; n = 2), wisent ( Bison bonasus ; n = 5), yak ( Bos grunniens ; n = 1), water buffalo ( Bubalus bubalis ; n = 4) and Bactrian camel ( Camelus bactrianus ; n = 5). The mean dose range for artiodactylid species except bongo was 0.04-0.06 mg/kg detomidine and 0.03-0.06 mg/kg butorphanol. The dose in bongo, 0.15-0.20 mg/kg detomidine and 0.13-0.15 mg/kg butorphanol, was considerably higher. Times to first effect, approach, and recovery after antidote were short. The use of detomidine and butorphanol has been demonstrated to be a reliable, safe alternative to general anesthesia for a number of large ungulate species.

THE MANAGEMENT OF AN ORAL ANAPLASTIC SARCOMA IN A PYGMY HIPPOPOTAMUS (CHOEROPSIS LIBERIENSIS) USING INTRALESIONAL CHEMOTHERAPY.

An adult female captive pygmy hippopotamus (Choeropsis liberiensis) was diagnosed with an oral anaplastic sarcoma. The tumor was surgically debulked and intralesional chemotherapy with mitomycin C (0.4 mg/cm3 of tumor) and cisplatin (1 mg/cm3 of tumor) was administered. Chemotherapeutic treatment proved difficult due to the risks of repeated anesthetics and unknown drug efficacies. Marked proliferation of the mass was observed during estrus, and chemotherapy was repeated as an experimental treatment to slow tumor progression in order for the animal to remain in the species breeding program. Tumor proliferation was detected during the first trimester of pregnancy; however, in the lactation period, the mass became quiescent. No adverse reactions to chemotherapeutic drugs were observed and the animal continues to be monitored for tumor progression. This is the first report of an anaplastic sarcoma and of chemotherapy use in a pygmy hippopotamus and it highlights logistical considerations for treating neoplasia in this species.

Evaluation of medetomidine-ketamine and dexmedetomidine-ketamine in Chinese water deer (Hydropotes inermis).

OBJECTIVE: To investigate physiological and sedative/immobilization effects of medetomidine or dexmedetomidine combined with ketamine in free-ranging Chinese water deer (CWD). STUDY DESIGN: Prospective clinical trial. ANIMALS: 10 free-ranging adult Chinese water deer (11.0±2.6 kg). METHODS: Animals were darted intramuscularly with 0.08±0.004 mg kg(-1) medetomidine and 3.2±0.2 mg kg(-1) ketamine (MK) or 0.04±0.01 mg kg(-1) dexmedetomidine and 2.9±0.1 mg kg(-1) ketamine (DMK). If the animal was still laterally recumbent after 60 minutes of immobilization, atipamezole was administered intravenously (MK: 0.4±0.02 mg kg(-1), DMK: 0.2±0.03 mg kg(-1)). Heart rate (HR) respiratory rate (f(R)) and temperature were recorded at 5-minute intervals. Arterial blood was taken 15 and 45 minutes after initial injection. Statistical analysis was performed using Student's t-test or ANOVA. p<0.05 was considered significant. RESULTS: Animals became recumbent rapidly in both groups. Most had involuntary ear twitches, but there was no response to external stimuli. There were no statistical differences in mean HR (MK: 75±14 beats minute(-1); DMK: 85±21 beats minute(-1)), f(R) (MK: 51±35 breaths minute(-1); DMK; 36±9 breaths minute(-1)), temperature (MK: 38.1±0.7 °C; DMK: 38.4±0.5 °C), blood gas values (MK: PaO(2) 63±6 mmHg, PaCO(2) 49.6±2.6 mmHg, HCO(3)(-) 30.8±4.5 mmol L(-1); DMK: PaO(2) 77±35 mmHg, PaCO(2) 45.9±11.5 mmHg, HCO(3)(-) 31.0±4.5 mmol L(-1)) and biochemical values between groups but temperature decreased in both groups. All animals needed antagonism of immobilization after 60 minutes. Recovery was quick and uneventful. There were no adverse effects after recovery. CONCLUSION AND CLINICAL RELEVANCE: Both anaesthetic protocols provided satisfactory immobilisation. There was no clear preference for either protocol and both appear suitable for CWD.

Evaluation of medetomidine-alfaxalone and medetomidine-ketamine in semi-free ranging Bennett's wallabies (Macropus rufogriseus).

Twenty-six adult semi-free-ranging Bennett's wallabies were anesthetized. Animals in group MA received medetomidine 0.1 mg/kg and alfaxalone 4 mg/kg i.m. in a 5-ml dart, whereas those in group MK received medetomidine 0.1 mg/kg and ketamine 5 mg/kg i.m. in a 3-ml dart. Dosages were based on estimated body weights. The wallabies were allowed to recover spontaneously or, if still nonresponsive at the end of the procedure, were given atipamezole 0.5 mg/kg (half the dose via i.m. and the other half via i.v.). Heart rate and respiratory rate were monitored at 5-min intervals, temperature at 10-min intervals, and two arterial blood samples were taken for blood gas analysis. Statistical analysis was performed by using analysis of variance (P < 0.05). The use of 5-ml darts in group MA compared with 3-ml darts in group MK could potentially increase the risk of iatrogenic trauma and should be considered. Induction and maintenance of anesthesia were satisfactory in both groups. There were no significant differences between the groups in mean time to first effect, recumbency, and approach, or to time to sternal recumbency and standing after reversal with atipamezole. Although bradycardia was present in both groups, no statistical differences were calculated for respiratory rate and heart rate, whereas the mean cloacal temperature was significantly lower in group MA (P = 0.01). Mixed acid-base disturbances occurred in both groups. All but one animal in group MK needed atipamezole at the end of the procedure. No adverse effects were observed after recovery.

Comparison of three anaesthetic protocols in Bennett's wallabies (Macropus rufogriseus).

OBJECTIVE: Investigate physiological and sedative/anaesthetic effects of xylazine, medetomidine or dexmedetomidine combined with ketamine in free-ranging Bennett's wallabies. STUDY DESIGN: Prospective clinical trial. ANIMALS: Twenty-six adult free-ranging Bennett's wallabies. METHODS: Animals were darted intramuscularly with one of three treatments: xylazine and ketamine, 2.0 and 15.0 mg kg(-1), respectively (XK): medetomidine and ketamine 0.1 and 5.0 mg kg(-1) (MK) and dexmedetomidine and ketamine 0.05 and 5.0 mg kg(-1) (DMK). Body weights were estimated. If the animal was still laterally recumbent after 45 minutes of anaesthesia, then an alpha-2 adrenoceptor antagonist, atipamezole, was administered (XK: 0.4 mg kg(-1), MK: 5 mg kg(-1), DMK: 2.5 mg kg(-1)). Heart rate (HR) and respiratory rate (f(R)) were recorded at 5-minute intervals and temperature at 10-minute intervals. Venous blood was taken 30 minutes after initial injection. Statistical analysis utilized anova. p < 0.05 was considered significant. RESULTS: Animals became recumbent rapidly in all groups. XK animals had muscle twitches, responded to external stimuli, and three animals required additional dosing; this was not observed in the MK and DMK groups. HR (mean +/- SD beats minute(-1)) in XK (81 +/- 4) was significantly higher than MK (74 +/- 2) and DMK (67 +/- 4). There were no differences in f(R), temperature, blood-gas and biochemical values between groups. More animals in MK (9/10) and DMK (5/6) needed antagonism of anaesthesia compared with XK (1/10). There were no adverse effects after anaesthesia. CONCLUSION AND CLINICAL RELEVANCE: Cardio-respiratory effects were similar in all groups. There were fewer muscle twitches and reactions to external stimuli in MK and DMK. Duration of anaesthesia was shorter in XK; most animals in MK and DMK needed atipamezole to assist recovery. All three treatments provided satisfactory sedation/anaesthesia and are suitable for use in Bennett's wallabies.