A Model of How Antibiotics Work

Background: Neonatal sepsis, particularly early onset sepsis (EOS), remains a leading cause of neonatal morbidity and mortality. The standard treatment involves intravenous (IV) antibiotics; however, prolonged IV antibiotic use increases hospital stay, healthcare costs, and the risk of antimicrobial resistance. Transitioning from IV to oral antibiotics in stable neonates may be a viable alternative. Aim and objectives were to compare the clinical outcomes of neonates with EOS receiving a complete course of IV antibiotics versus those transitioning from IV to oral antibiotics following initial stabilization. Methods: A prospective observational study was conducted at the neonatal intensive care unit (NICU) of L.L.R.M Medical College, Meerut, from April 2023 to April 2024. Neonates diagnosed with EOS were categorized into two groups: group A (complete IV antibiotic course) and group B (IV-to-oral transition). Data on neonatal demographics, clinical parameters, duration of hospital stay, readmission rates, mortality, and weight gain were analysed. Statistical comparisons were performed using Chi-square and independent t-tests, with a p value <0.05 considered significant. Results: A total of 100 neonates were included (50 per group). The mean hospital stay was significantly shorter in group B (7.2±1.4 days) compared to group A (10.1±2.1 days; p<0.01). No significant difference in mortality was observed between the groups (group A: 4%, group B: 3%; p=0.68). Readmission rates were comparable (group A: 6%, group B: 5%; p=0.74). Weight gain was significantly higher in group B at follow-up (p=0.03). The incidence of hospital-acquired infections was lower in group B, suggesting potential benefits of early transition to oral therapy. Conclusions: Early transition from IV to oral antibiotics in stable neonates with EOS is a safe and effective strategy that reduces hospital stay without increasing mortality or readmission rates. This approach may contribute to antimicrobial stewardship by minimizing unnecessary IV antibiotic exposure. Further large-scale studies are needed to establish standardized protocols.

Acute sore throat is a common presentation in primary care settings. We aimed to improve our compliance with national antibiotic guidelines for sore throat symptoms to 90% in 3 months'...

Respiratory tract infections require early diagnosis and adequate treatment. With the antibiotic overuse and increment in antibiotic resistance there is an increased need to accurately distinguish between bacterial and viral infections. We investigated the diagnostic performance of calprotectin in respiratory tract infections and compared it with the performance of heparin binding protein (HBP) and procalcitonin (PCT). Biomarkers were analyzed in patients with viral respiratory infections and patients with bacterial pneumonia, mycoplasma pneumonia and streptococcal tonsillitis (n = 135). Results were compared with values obtained from 144 healthy controls. All biomarkers were elevated in bacterial and viral infections compared to healthy controls. Calprotectin was significantly increased in patients with bacterial infections; bacterial pneumonia, mycoplasma pneumonia and streptococcal tonsillitis compared with viral infections. PCT was significantly elevated in patients with bacterial pneumonia compared to viral infections but not in streptococcal tonsillitis or mycoplasma caused infections. HBP was not able to distinguish between bacterial and viral causes of infections. The overall clinical performance of calprotectin in the distinction between bacterial and viral respiratory infections, including mycoplasma was greater than performance of PCT and HBP. Rapid determination of calprotectin may improve the management of respiratory tract infections and allow more precise diagnosis and selective use of antibiotics.

Dear Respected Editor, Diphtheria, caused by Corynebacterium diphtheria, affects the throat and nasopharynx. Transmission occurs through airborne respiratory droplets, secretions, or direct contact. Toxigenic strains produce diphtheria toxin (DT) that causes local inflammation and necrosis of the pharynx, forming a characteristic gray and leathery pseudo membrane. Symptoms are fever, a sore throat, a swollen neck, and dysphagia. It can even lead to serious complications like pseudomembranous pharyngitis, myocarditis, and arrhythmias. Before the development of the toxoid vaccine for diphtheria, millions of people perished from the severe respiratory distress produced by the disease. [1] In the days before vaccinations, diphtheria was the leading cause of death in children [2] In 1980, Pakistan reported 14,328 cases of diphtheria with an incidence rate of 177.7. [3] Strong public health efforts reduced cases of diphtheria from thousands to hundreds within 15 years. Pakistan’s launch of the Expanded Programme of Immunization (EPI) in 1978 significantly reduced diphtheria cases. From thousands in 1980, reported cases dropped to just 93 during 1995-2000 and a mere 9 during 2014-2015 [3]. Southeast Asia has borne the brunt of global diphtheria cases in the past decade, with Pakistan reporting the highest number (821 cases in 2018) [1, 3]. The disease recently resurfaced, tragically causing 45 deaths among children and teenagers in 2022 [1]. In November 2022, flood-affected areas in Sindh, Punjab, and Khyber Pakhtunkhwa further reported around 70 suspected cases [1]. A concerning 50% increase in diphtheria cases in 2023 prompted the NIH to issue an outbreak advisory, urging vigilance and strong preventive measures by both the public and officials [4]. The significant population growth in Pakistan, exacerbated by a lack of family planning, wealth inequality and COVID-19 outbreak affecting the immunization coverage has led to the spread of diphtheria in recent years. [5] Thus, to combat the rising diphtheria infection in Pakistan, we would like to make some recommendations: High quality, accessible vaccines: Ensure high-quality vaccine availability in rural and urban areas, with 10-year booster shots for sustained immunity [1, 3]. Large-scale vaccination: Implement WHO/UNICEF-recommended strategies for large-scale vaccination coverage in Pakistan [1, 3]. Rural awareness campaigns: Address vaccine hesitancy through targeted awareness programs in rural areas, highlighting benefits and dispelling misconceptions [1, 3]. Increased healthcare funding: Allocate increased budget for healthcare (NHSRC) to support vaccine production, storage, and distribution [4]. Strict antibiotic adherence: Implement daily patient checklist to ensure complete antibiotic courses, preventing recurrence [4].

We explored the relationship between the preparedness of master of public health (MPH) graduates in public health law and ethics and their completion of courses in these areas. We reviewed accredited public health schools and programs to assess the supply of required and elective courses in law and ethics. In addition, we conducted an Internet-based scenario survey of MPH graduates. Survey results were analyzed, and relationships between scenario responses and completion of law and ethics courses were assessed. Of the 93 programs and schools reviewed, 14% required a course in ethics and 16% required a course in law. The majority (range = 55%-76%) of the survey respondents indicated being "prepared" or "very prepared" for each of the 9 public health scenarios. There were no significant relationships between scenario responses and completion of an ethics course. Responses to 2 scenarios (one involving food code violations and one involving a prison population) were significantly related to participants' completion of a course in law. Few public health schools and programs require graduate courses in ethics and law. Most MPH graduates report being prepared to address public health challenges. Additional research is necessary to improve techniques for measuring preparedness.

BackgroundAcute febrile illness is a frequent cause of hospitalization in the tropics and often presents with respiratory symptoms, even when caused by nonrespiratory pathogens. Previously, host-based gene expression signatures accurately identified acute respiratory infections as being bacterial or viral in a U.S. cohort. We determined signature performance in a Sri Lankan cohort with acute febrile respiratory illness (AFRI).MethodsWe enrolled patients with AFRI in Sri Lanka from July 2012 to May 2013 and collected nasopharygeal swabs, acute/ convalescent sera, and blood in PAXgene RNA tubes. Bacterial (Orientia tsutsugamushi, Leptospira spp.) and viral (influenza A/B, dengue) infections were confirmed using polymerase chain reaction, virus isolation, enzyme immunoassay, and/or microscopic agglutination testing. We extracted total RNA and performed host RNA sequencing (Illumina). We aligned reads to hg38 reference genome using Bowtie2, quantified at isoform level using Express version 1.5.1, and normalized using trimmed-mean normalization. The original model estimated three classes and separate signatures predicted bacterial infections, viral infections, and non-infectious illnesses. Regularized regression was used to predict bacterial and viral infections based on prior signatures. Accuracy was estimated using leave-one-out cross-validation.ResultsAmong 43 patients with viral infections (14 dengue, 29 influenza) and 16 patients with bacterial infections (six Leptospira spp., 10 O. tsutsumagushi), median age was 37 years (IQR 23–51) and 49% were male. Of five respiratory symptoms (cough, sore throat, rhinitis/ congestion, shortness of breath, and pain with breathing), median (IQR) number of symptoms was 2 (1–2) for influenza, 2 (1–2) for dengue, 2 (2–3) for Leptospira spp., and 1.5 (1–2) for O. tsutsumagushi. We observed high predictive accuracy in discriminating bacterial and viral infections: AUROC 0.91 for the bacterial and AUROC 0.81 for the viral model. At enrollment, 65% of viral and 50% of bacterial AFRI patients received antibiotics.ConclusionHost gene expression classifiers performed well in a Sri Lankan population with AFRI, even with nonrespiratory pathogens that may not be readily identified. Host-based diagnostics may play a critical role in improving diagnostic ability and antibiotic use globally.Disclosures E. L. Tsalik, Host Response, Inc.: Founder, Equity. G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth <$100). C. W. Woods, Host Response, Inc.: Founder, Equity.

Prevention of recurrent ear, nose, and throat infections in young children with ribomunyl®: Double-blind, placebo-controlled study

BackgroundAlthough a short course (7 days) of antibiotics has been demonstrated to be noninferior to a conventional course (14 days) in terms of mortality and infectious complications for patients with a Gram-negative bacterial bloodstream infection (GNB), it is unknown whether a shorter treatment duration can provide a better overall clinical outcome.MethodsWe applied a bloodstream infection-specific desirability of outcome ranking (DOOR) analysis to the results of a previously completed, randomized controlled trial comparing short versus conventional course antibiotic therapy for hospitalized patients with uncomplicated GNB. We determined the probability that a randomly selected participant in the short course group would have a more desirable overall outcome than a participant in the conventional duration group. We performed (1) partial credit analyses allowing for calculated and variable weighting of DOOR ranks and (2) subgroup analyses to elucidate which patients may benefit the most from short durations of therapy.ResultsFor the 604 patients included in the original study (306 short course, 298 conventional course), the probability of having a more desirable outcome with a short course of antibiotics compared with a conventional course was 51.1% (95% confidence interval, 46.7% to 55.4%), indicating no significant difference. Partial credit analyses indicated that the DOOR results were similar across different patient preferences. Prespecified subgroup analyses using DOOR did not reveal significant differences between short and conventional courses of therapy.ConclusionsBoth short and conventional durations of antibiotic therapy provide comparable clinical outcomes when using DOOR to consider benefits and risks of treatment options for GNB.

SARS-CoV-2 re-infection, vaccination and neutralizing antibodies

Typhoid fever remains a major health problem in developing countries: According to the World Health Organisation, there are 21 Million cases worldwide and 222,000 typhoid-related deaths occurring annually [1]. Mobile monitoring systems have been proposed for observing patient's physiological signals; these hardware and software solutions are broadly categorised as Healthcare Sensor Networks (HSNs). Since no two patients are alike with regards to biometric parameters and access to healthcare professionals can be difficult because of geography or scarcity of resources, monitoring must be observed in situ. Various serological and culture diagnostic tests for enteric fever exist, including the Widal test [44], TUBEX [45], ELISA [46] and the Gold Standard Blood Culture test [32]. The limitations of these existing conventional tests include lack of speed, sensitivity, and specificity, ambiguity in the classification of symptoms, diagnosis by inexperienced healthcare workers and the fact that they are predominantly clinic-based tests. Critical to typhoid care is outpatient support after the completion of courses of antibiotics, and the two to three-week reoccurrence period is crucial in aftercare. Our research is designed for patients during this period. In this paper, we propose a mobile-based monitoring methodology, which uses vital signs monitoring apparatus, which is configured to recognise the characteristics of typhoid recurrence. Key to our design is the implementation of sensors for body temperature monitoring and physiological testing through galvanic skin response (GSR), electrocardiographic testing (ECG) and electromyography (EMG). The paper introduces an invaluable tool for (i) software programmers and algorithm designers working with biometric HSNs and (ii) practitioners working in public health monitoring and disease prevention.

Bacterial infections are the cause of significant mortality and morbidity in children. Infections of surgical importance may affect virtually any organ or tissue in the body. These may be community and hospital acquired. Among the community-acquired infections, the major groups are skin and soft tissue infections, bone infections, and infections of specific organs. Hospital-acquired infections may further be classified as infections of surgical wounds, infections in wards, and infections in immunocompromised and critically ill patients. Bacterial infections are more common at extreme of ages, and thus small babies less than 2 months are highly susceptible to acquire bacterial infection. Other conditions like malnutrition, immune-deficiency states, and prolonged illnesses make the children more susceptible to acquire infections. Skin and soft tissue infections are better described according to the depth of tissue involved. Common soft tissue infections in children are impetigo, scalded skin syndrome, folliculitis, furuncle or boil, carbuncle, erysipelas, necrotizing fasciitis, clostridial myonecrosis (gas gangrene), non-clostridial myonecrosis, synergistic gangrenes, lymphadenitis, and abscesses. Besides these ear and throat infections and infections of specific system like urinary tract infections and bone infections, respiratory tract infections may be important in the management of pediatric surgical patients. Tuberculosis is again emerging as a major health hazard in some countries. The end result of bacterial infection may be simple cellulitis to abscess formation and generalized sepsis. Due to excessive and improper use of antibiotics, drug resistance has become a major issue and is responsible for serious bacterial infections and related complications in some children.

Chickenpox is generally considered to be a benign self limiting illness in children. Indeed, mild secondary bacterial infection of the skin, of little clinical importance, is the most common complication of varicella virus infection.1 2 There has been a recent increase in reports of serious bacterial infections, however, both during or after chickenpox. We reviewed the case notes of 13 children (mean age 30 months; seven boys, six girls) who presented to our unit over 12 months (1994-5) with bacterial sepsis associated with chickenpox. We also included one case (case 1) who died of group A streptococcal septicaemia at another hospital. Occult bacterial infection with group A streptococcus or Staphylococcus aureus may complicate chickenpox and cause potentially lethal disease An 11 month old girl was admitted with fever, poor feeding, and diarrhoea on the fourth day after the onset of chickenpox. She had a fever of 40°C and a haemorrhagic pustular rash. There was periorbital oedema and conjunctival injection with oral erythema and a 1 cm diameter black necrotic lesion around a vesicle on the dorsum of her left hand. There was no neurological or cardiovascular compromise at presentation. Twenty four hours later she became shocked with a capillary refill time of four seconds, peripheral core temperature difference of 8°C, blood pressure of 75/40 mm Hg, and a pulse of 150 beats/min. She developed increasing oedema and required supplementary oxygen. Despite resuscitation with colloid and a course of antibiotics she continued to deteriorate and was intubated and mechanically ventilated. Inotropic support and large volumes of colloid were required to correct the shock. Initial laboratory investigations indicated a haemoglobin concentration of 103 g/l, a white cell count of 7.2 × 109/l, and a platelet count of 119 x109/l with normal clotting. There was hyponatraemia with a …

Antibiotics are the major tool for treating bacterial infections. Rising antibiotic resistance, however, calls for a better use of antibiotics. While classical recommendations favor long and aggressive treatments, more recent clinical trials advocate for moderate regimens. In this debate, two axes of ‘aggression’ have typically been conflated: treatment intensity (dose) and treatment duration. The third dimension of treatment timing along each individual’s infection course has rarely been addressed. By using a generic mathematical model of bacterial infection controlled by immune response, we examine how the relative effectiveness of antibiotic treatment varies with its timing, duration and antibiotic kill rate. We show that short or long treatments may both be beneficial depending on treatment onset, the target criterion for success and on antibiotic efficacy. This results from the dynamic trade-off between immune response build-up and resistance risk in acute, self-limiting infections, and uncertainty relating symptoms to infection variables. We show that in our model early optimal treatments tend to be ‘short and strong’, while late optimal treatments tend to be ‘mild and long’. This suggests a shift in the aggression axis depending on the timing of treatment. We find that any specific optimal treatment schedule may perform more poorly if evaluated by other criteria, or under different host-specific conditions. Our results suggest that major advances in antibiotic stewardship must come from a deeper empirical understanding of bacterial infection processes in individual hosts. To guide rational therapy, mathematical models need to be constrained by data, including a better quantification of personal disease trajectory in humans. Lay summary: Bacterial infections are becoming more difficult to treat worldwide because bacteria are becoming resistant to the antibiotics used. Addressing this problem requires a better understanding of how treatment along with other host factors impact antibiotic resistance. Until recently, most theoretical research has focused on the importance of antibiotic dosing on antibiotic resistance, however, duration and timing of treatment remain less explored. Here, we use a mathematical model of a generic bacterial infection to study three aspects of treatment: treatment dose/efficacy (defined by the antibiotic kill rate), duration, and timing, and their impact on several infection endpoints. We show that short and long treatment success strongly depends on when treatment begins (defined by the symptom threshold), the target criterion to optimize, and on antibiotic efficacy. We find that if administered early in an infection, “strong and short” therapy performs better, while if treatment begins at higher bacterial densities, a “mild and long” course of antibiotics is favored. In the model host immune defenses are key in preventing relapses, controlling antibiotic resistant bacteria and increasing the effectiveness of moderate intervention. In order to improve rational treatments of human infections, we call for a better quantification of individual disease trajectories in bacteria-immunity space.

Certain bacterial pathogens are able to evade the host immune system and persist within the human host. The consequences of persistent bacterial infections potentially include increased morbidity and mortality from the infection itself as well as an increased risk of dissemination of disease. Eradication of persistent infections is difficult, often requiring prolonged or repeated courses of antibiotics. During persistent infections, a population or subpopulation of bacteria exists that is refractory to traditional antibiotics, possibly in a non-replicating or metabolically altered state. This review highlights the clinical significance of persistent infections and discusses different in vitro models used to investigate the altered physiology of bacteria during persistent infections. We specifically focus on recent work establishing increased protection against oxidative stress as a key element of the altered physiologic state across different in vitro models and pathogens.

BackgroundNeonatal sepsis is a global public health problem. There is no consensus regarding the optimum duration of antibiotics for culture-proven neonatal sepsis. Published randomized controlled trials (RCTs) comparing shorter versus longer courses of antibiotics provide low-quality evidence with serious risk of bias. We hypothesized that among neonates with uncomplicated culture-proven sepsis, antibiotic duration of 7 days is not inferior to 14 days.MethodsThis is a multi-centric, parallel-group, stratified, block-randomized, active-controlled, non-inferiority trial with outcome assessment blinded. Stratification is by center and birth weight. Neonates weighing ≥1000 g at birth, with blood-culture-proven sepsis (barring Staphylococcus aureus and fungi), without conditions warranting > 14 days antibiotics, and who clinically remit, are enrolled in the RCT on day 7 of administration of sensitive antibiotics. They are randomly allocated to no further antibiotics (intervention arm: total 7 days) or 7 more days of the same antibiotics (control arm: total 14 days). Allocation is concealed by opaque, sealed envelopes. The primary outcome is “definite or probable relapse” within 21 days after antibiotic completion. Secondary outcomes include definite and probable relapses at various timepoints until day 35 post-randomization, secondary infections, and adverse events. The neonatologist adjudicating probable relapses and lab personnel are blinded. Three hundred fifty subjects will be recruited in each arm, assuming a non-inferiority margin of 7%, one-sided alpha error 5%, and power of 90%. Analysis will be per protocol and by intention-to-treat. An independent Data Safety Monitoring Board monitors adverse events and will perform one interim analysis when 50% of expected primary outcomes have occurred or 50% of subjects have completed follow-up, whichever is earlier. O’Brien-Fleming criteria will be used to stop for mid-term benefit and Pocock’s to stop for mid-term harm. A priori subgroup analyses are planned by birth weight categories, gram-stain status of pathogens, and radiological pneumonia.DiscussionThis trial will provide evidence to guide practice regarding optimum duration of antibiotics for culture-proven neonatal bacterial sepsis. If a 7-day regime is proved to be non-inferior to a 14-day regime, it is likely to reduce hospital stay, costs, adverse effects of drugs, and nosocomial infections.Trial registrationClinical Trials Registry India CTRI/2017/09/009743. Registered on 13 September 2017.