Amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis of potential high-risk groups

Background

Antibiotics are of limited overall clinical benefit for uncomplicated lower respiratory tract infection (LRTI) but there is uncertainty about their effectiveness for patients with features associated with higher levels of antibiotic prescribing.

Aim

To estimate the benefits and harms of antibiotics for acute LRTI among those producing coloured sputum, smokers, those with fever or prior comorbidities, and longer duration of prior illness.

Design and setting

Secondary analysis of a randomised controlled trial of antibiotic placebo for acute LRTI in primary care.

Method

Two thousand and sixty-one adults with acute LRTI, where pneumonia was not suspected clinically, were given amoxicillin or matching placebo. The duration of symptoms, rated moderately bad or worse (primary outcome), symptom severity on days 2–4 (0–6 scale), and the development of new or worsening symptoms were analysed in pre-specified subgroups of interest. Evidence of differential treatment effectiveness was assessed in prespecified subgroups by interaction terms.

Results

No subgroups were identified that were significantly more likely to benefit from antibiotics in terms of symptom duration or the development of new or worsening symptoms. Those with a history of significant comorbidities experienced a significantly greater reduction in symptom severity between days 2 and 4 (interaction term −0.28, P = 0.003; estimated effect of antibiotics among those with a past history −0.28 [95% confidence interval = −0.44 to −0.11], P = 0.001), equivalent to three people in 10 rating symptoms as a slight rather than a moderately bad problem. For subgroups not specified in advance antibiotics provided a modest reduction in symptom severity for non-smokers and for those with short prior illness duration (<7 days), and a modest reduction in symptom duration for those with short prior illness duration.

Conclusion

There is no clear evidence of clinically meaningful benefit from antibiotics in the studied high-risk groups of patients presenting in general practice with uncomplicated LRTIs where prescribing is highest. Any possible benefit must be balanced against the side-effects and longer-term effects on antibiotic resistance.     

Results of a phase I/II trial of recombinant human granulocyte- macrophage colony-stimulating factor in very low birthweight neonates: significant induction of circulatory neutrophils, monocytes, platelets, and bone marrow neutrophils

Neonates, especially those of very low birthweight (VLBW), have an increased risk of nosocomial infections secondary to deficiencies in development. We previously demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) production and mRNA expression from stimulated neonatal mononuclear cells are significantly less than that from adult cells. Recombinant murine GM-CSF administration to neonatal rats has resulted in neutrophilia, increased neutrophil production, and increased survival of pups during experimental Staphylococcus aureus sepsis. In the present study, we sought to determine the safety and biologic response of recombinant human (rhu) GM-CSF in VLBW neonates. Twenty VLBW neonates (500 to 1,500 g), aged < 72 hours, were randomized to receive either placebo (n = 5) or rhuGM-CSF at 5.0 micrograms/kg once per day (n = 5), 5.0 micrograms/kg twice per day (n = 5), or 10 micrograms/kg once per day (n = 5) given via 2-hour intravenous infusion for 7 days. Complete blood counts, differential, and platelet counts were obtained, and tibial bone marrow aspirate was performed on day 8. Neutrophil C3bi receptor expression was measured at 0 and 24 hours. GM-CSF levels were measured by a sandwich enzyme-linked immunosorbent assay at 2, 4, 6, 12, and 24 hours after the first dose of rhuGM-CSF. At all doses, rhuGM-CSF was well tolerated, and there was no evidence of grade III or IV toxicity. Within 48 hours of administration, there was a significant increase in the circulating absolute neutrophil count (ANC) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day, which continued for at least 24 hours after discontinuation of rhuGM-CSF. When the ANC was normalized for each patient's first ANC, there was a significant increase in the ANC on days 6 and 7 at each dose level. By day 7, all tested doses of rhuGM- CSF resulted in an increase in the absolute monocyte count (AMC) compared with placebo-treated neonates. In those receiving rhuGM-CSF 5.0 micrograms/kg twice per day, there was additionally a significant increase in the day 7 and 8 platelet count. Tibial bone marrow aspirates demonstrated a significant increase in the bone marrow neutrophil storage pool (BM NSP) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day. Neutrophil C3bi receptor expression was significantly increased 24 hours after the first dose of rhuGM-CSF at 5.0 micrograms/kg once per day. The elimination half-life (T1/2) of rhuGM-CSF was 1.4 +/- 0.8 to 3.9 +/- 2.8 hours.(ABSTRACT TRUNCATED AT 400 WORDS)     

Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Four patients with Philadelphia (Ph') positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.     

From the Cover: Complex history of the amphibian-killing chytrid fungus revealed with genome resequencing data

Understanding the evolutionary history of microbial pathogens is critical for mitigating the impacts of emerging infectious diseases on economically and ecologically important host species. We used a genome resequencing approach to resolve the evolutionary history of an important microbial pathogen, the chytrid Batrachochytrium dendrobatidis (Bd), which has been implicated in amphibian declines worldwide. We sequenced the genomes of 29 isolates of Bd from around the world, with an emphasis on North, Central, and South America because of the devastating effect that Bd has had on amphibian populations in the New World. We found a substantial amount of evolutionary complexity in Bd with deep phylogenetic diversity that predates observed global amphibian declines. By investigating the entire genome, we found that even the most recently evolved Bd clade (termed the global panzootic lineage) contained more genetic variation than previously reported. We also found dramatic differences among isolates and among genomic regions in chromosomal copy number and patterns of heterozygosity, suggesting complex and heterogeneous genome dynamics. Finally, we report evidence for selection acting on the Bd genome, supporting the hypothesis that protease genes are important in evolutionary transitions in this group. Bd is considered an emerging pathogen because of its recent effects on amphibians, but our data indicate that it has a complex evolutionary history that predates recent disease outbreaks. Therefore, it is important to consider the contemporary effects of Bd in a broader evolutionary context and identify specific mechanisms that may have led to shifts in virulence in this system.Emerging infectious diseases (EIDs) pose significant challenges for human health, agricultural crops, and economically and ecologically important populations in nature (1–4). The incidence of EIDs has been steadily rising over the last several decades (5, 6), and EIDs are of particular concern in an increasingly globalized world. For example, the majority of human EIDs is zoonoses that originate in wildlife (5) and subsequently, create a significant burden for global economies and public health (7, 8). Therefore, scientific efforts to understand and respond to EIDs are critical in diverse fields from biomedicine to conservation biology.Although EIDs result from a complex interplay of factors, many studies focus primarily on the emergence of novel microbial pathogens. There are, in fact, high-profile examples of EIDs caused by the rapid appearance of novel, hypervirulent, or host-switching strains (9–11), but EIDs are not always caused by rapid or recent evolution of the pathogen itself. Virulence itself is an emergent property of microbe–host–environment interactions (12). Thus, EIDs can result from shifts in any factor—or combination of factors—in the microbe–host–environment epidemiological triangle (13). Characterizing the evolutionary history of emerging pathogens is, thus, critical, allowing us to determine whether observed EIDs result from rapid, recent shifts in organisms with pathogenic potential.Chytridiomycosis is an EID responsible for declines in amphibian species around the world. The chytrid fungus Batrachochytrium dendrobatidis (Bd) was discovered and linked to amphibian declines in 1998 (14, 15). Chytridiomycosis is caused by Bd and kills amphibians by disrupting the integrity of their skin, a physiologically important organ that is involved in gas exchange, electrolyte balance, hydration, and protection from other pathogens (16, 17). Bd infects hundreds of species of amphibians, is found on all continents where amphibians occur, and is responsible for declines and extirpations in a diversity of amphibian hosts (18).Soon after Bd was discovered, researchers proposed two competing hypotheses for the emergence of chytridiomycosis. The emerging pathogen hypothesis posited that a novel disease agent caused chytridiomycosis, and the endemic pathogen hypothesis proposed that an environmental shift disrupted a previously benign microbe–host interaction (19). Over the years, spatiotemporal and genetic data have supported the emerging pathogen hypothesis (reviewed in refs. 20 and 21). Spatiotemporal data provided clear evidence that Bd arrived and spread through geographic regions where it was not present historically (22–24). Early genetic studies also found very little genetic differentiation in Bd with no geographic signal, consistent with a recent, rapid spread of a novel disease agent (25–27). Recently, genetic and genomic data have been used to describe a geographically widespread Bd lineage [termed the global panzootic lineage (GPL)] (28) and several putatively endemic Bd lineages (28–30). However, different studies have used different methods and focused sampling in different parts of the world, precluding integration across studies to determine the evolutionary history leading to the emergence of Bd as a global threat to amphibians.Here, we present whole-genome sequencing from a global panel of Bd isolates to show that Bd has a historically deeper and more complex evolutionary history than previously appreciated. We sequenced Bd genomes from around the world and also, a non-Bd chytrid outgroup that does not attack amphibians [Homolaphlyctis polyrhiza (Hp)] (31). Our focus was primarily on the evolutionary dynamics of Bd in the Americas, because many of the most devastating outbreaks have occurred in the New World. We address outstanding questions about the origins, genetic diversity, and genome structure of Bd that can be resolved using whole-genome data. We also integrate our genomic data with those data from a previous study with complementary geographic sampling (28). Our results reveal that the evolutionary history of Bd is complex, with multiple divergent lineages, heterogeneous patterns of genomic evolution, and no simple link between a single evolutionary event and observed amphibian declines.     

Microlaryngeal surgery on a day case basis

The aim of this study was to assess the clinical safety of performing microlaryngeal surgery (MLS) under general anaesthesia in selected patients in the ambulatory setting. Twenty-two adult patients were scheduled to have tissue specimens of the larynx taken by biopsy (54%), for vocal cord polypectomy (41%) or for vocal cord cyst excision (5%). Twenty-one ASA I and II patients (95%) were discharged home the same day of the procedure. Two of them presented with laryngospasm after extubation of the trachea. One ASA III patient (5%) had to be admitted overnight because of severe laryngospasm and bronchospasm, but was discharged the day after the operation. None of the patients had significant complications after leaving the recovery room (mean stay 85 min). There were no re-admissions to the hospital. Our data suggests that microlaryngeal surgery in selected patients can be safely performed on a day case basis.