Case 1 by Dr Julie Toubiana

The session discusses a case of a one-month-old boy presenting with fever, chills, and unusual crying, with no evident source of infection. Initial workup revealed high inflammatory parameters, with a positive urine exam indicating a probable febrile urinary tract infection (UTI). Participants were asked to choose empiric treatment, with the majority opting for Cefotaxime and hospitalization. French guidelines recommend hospitalization for infants <3 Months old, with IV third-generation cephalosporin or amikacin as empiric therapy. Outpatient treatment is considered for older children with certain criteria. The decision in this case was to start oral cefixime based on a French trial comparing oral versus IV and then oral treatment for acute pyelonephritis in children. Despite some limitations, including underpowered results, no difference was found in renal scarring between the two groups. The culture revealed Citrobacter freundii and E. Cloacae, both sensitive to third-generation cephalosporins and most non-beta lactam alternatives. The term SDD describes susceptible increased exposure, as per UCAS.

The speaker then focused on antibiotic treatment decisions for a patient with Citrobacter freundii and E. Cloacae infections, which produce AmpC-beta lactamase. Initially, third-generation cephalosporins were considered viable options due to their sensitivity to these pathogens. However, caution was advised as there is a high frequency of mutant strains resistant to these cephalosporins. In severe infections, avoiding third-generation cephalosporins was recommended to prevent the selection of resistant mutants. In the case of a UTI without complications or underlying uropathy, continuing with Cefepime was suggested. However, a subsequent consultation revealed bilateral renal duplication with nephritis, indicating a more complex scenario. Treatment with Ceftriaxone and amikacin was initiated due to the presence of Vesicoureteral reflux on a duplicated system. Upon further analysis, the second UTI was caused by E. Cloacae, which showed resistance to cefixime but remained susceptible to increased exposure to Cefepime and amikacin, raising the question of whether to switch antibiotic therapy. A poll revealed a preference for Meropenem, with Cefepime and amikacin as close alternatives. Concerns were raised regarding aminoglycosides due to ototoxicity risk, but their advantage of once-daily administration and potential for outpatient management was acknowledged. Given the increasing prevalence of resistant infections, carefully considering antibiotic choices is crucial. Genetic testing for ototoxicity risk may aid in decision-making. Despite reservations, some participants expressed willingness to consider gentamicin or amikacin for their advantages. The patient was initially treated with amikacin, then cotrimoxazole, and the patient experienced multiple infections with resistant bacteria. Despite recommendations for surgery to address an underlying uropathy, surgeons were hesitant due to the patient's age. However, after 15 days, the patient experienced multiple episodes of UTIs caused by different bacterial strains (E. Cloacae and Klebsiella variicola), some of which showed resistance to commonly used antibiotics like Sulfamethoxazole and trimethoprim (SMX-TMT). The patient was treated with amikacin and later with penicillinase and third-generation cephalosporin. Treatment involved changing antibiotics based on susceptibility testing, concerned with escalating resistance. The session also discussed the dilemma of whether to continue prophylaxis, recommend surgery for underlying uropathy, or switch to a different prophylactic regimen. While many suggest surgery, the reluctance of surgeons poses a challenge. Two recent meta-analyses (2015 and 2017) identified a reduced risk of UTIs with prophylaxis but also noted an increased risk of resistant organisms and no reduction in renal scarring rates. Accurately diagnosing kidney infections (pyelonephritis) was emphasized as a crucial standard due to its implications for renal function. In a newer study, the PREDICT trial (published in 2023 in the New England Journal of Medicine) focused on patients with underlying uropathy of varying severity. This trial reported a significant reduction in recurrent UTIs within two years of starting prophylaxis compared to untreated patients. However, similar to the meta-analyses, the trial noted a higher rate of resistant organisms among those receiving prophylaxis and no change in renal scarring rates. 

Upon returning from Tunisia, the patient exhibited fever and hemodynamic instability. Laboratory tests detected elevated inflammatory markers and a positive urine culture for gram-negative rods, specifically Klebsiella pneumoniae. Empiric treatment with Ceftriaxone and Amikacin commenced, and the antimicrobial stewardship (AMS) team was consulted due to resistance shown in the urine culture, including carbapenems. Further testing revealed carbapenemase resistance genes OXA 48 and NDM. Treatment options for multidrug-resistant bacterial infections include extended infusion Meropenem, colistine, Cefiderocol, Ceftazidime-avibactam, Aztreonam, Ceftolozane-tazobactam, and Tigecycline, based on empirical evidence and considering resistance mechanisms like carbapenemases such as OXA 48 and NDM. Aztreonam with Ceftazidime-avibactam or Cefiderocol often showed susceptibility in many cases. Challenges with colistine arise from its toxicity and emerging resistance. Cefiderocol's limited pediatric data is mainly observational, with no official recommendations yet. Efforts to establish dosing recommendations based on pharmacokinetics/pharmacodynamics (PKPD) data are ongoing despite challenges, particularly with NDM Enterobacteriales, where resistance issues reach 40%. Therefore, alternative treatments like Tigecyclin are recommended in European guidelines. However, Tigecyclin's efficacy is limited due to poor PKPD diffusion and a lack of pediatric studies. Instead, the combination of Avibactam plus Aztreonam is proposed. Avibactam, a potent inhibitor, could enhance Aztreonam's effectiveness against NDM and OXA 48 carbapenemases. The session also addresses susceptibility rates. While susceptibility tests initially classified both molecules as resistant, the combination demonstrates up to 95% susceptibility in NDM carbapenemase cases. However, it's crucial to note that some bacteria, such as E.coli, may resist Cefiderocol and the Avibactam plus Aztreonam combination. Additionally, travel to regions like Tunisia, where carbapenem-resistant Klebsiella pneumoniae rates are high (20-30%), could pose a risk factor for difficult-to-treat infections. Furthermore, studies indicate the cross-border spread of such bacteria from Africa to Europe, emphasizing the global challenge of antibiotic resistance. Despite awaiting antibiotic susceptibility testing, Ceftazidime/avibactam+aztreonam was initially selected, but colistine was added as a therapy due to poor antibiogram results. However, due to concerns about toxicity and the patient's condition improving, colistine was discontinued, and Ceftazidime/avibactam+aztreonam was continued, leading to a successful outcome. In subsequent episodes of gram-negative UTI, the speaker discusses various antibiotic options, including 3rd generation cephalosporin + amikacin, Meropenem with optimal PK-PD dosage, prophylaxis with fosfomycin 1g/week, and Ceftazidime-avibactam + aztreonam. Based on the case outcome, Ceftazidime-avibactam + Aztreonam was favoured, with a shift away from empiric therapy unless the patient showed signs of sepsis.

In combating carbapenem-resistant infections, Proper identification and assessment of infection severity are crucial but challenging due to imperfect urine specimens, contamination risks, and variable categorization practices. Risk factors, including travel abroad, epidemiology and host factors like uropathy and recurrent antibiotic therapy, contribute to escalating resistance. Limited data on PKPD of new drugs in paediatrics complicates treatment optimization. While carbapenem use is common, its efficacy remains inadequate. Optimal treatment often involves challenging choices due to the toxicity or low efficacy of alternative drugs like colistine. Alternative therapies like colistine face issues with toxicity and effectiveness. The speaker emphasizes the necessity of Antimicrobial Stewardship (AMS) expertise, uniting clinicians, microbiologists, and pharmacists alongside rapid microbiological testing to guide treatment decisions and minimize combined therapy use. Access to new drugs remains a concern due to cost, highlighting the need for equitable distribution. Additionally, monitoring plasma concentration levels of new drugs is proposed to enhance understanding of PKPD profiles. 

Case 2 by Dr Sanjay Patel

A 3-year-old boy presents with a one-week history of cough, fatigue, and reduced oral intake. Despite being treated with a week of antibiotics (amoxicillin) by his primary care physician the week before, he appeared very ill upon arrival at the hospital. He is floppy, less responsive, slightly hypoxic, tachycardic, and tachypneic. His fever was higher at home (37.8°C) than in the hospital. A capillary gas test shows a base excess of -6.5. The child was born prematurely but required only brief CPAP after birth. He has a history of asthma but no signs of underlying immune deficiency or recurrent infections. He had not taken antibiotics before the recent course and is up to date on his immunizations. Chest X-ray reveals shadowing on the right side with an obscured right hemidiaphragm, suggesting fluid accumulation. Blood tests show elevated CRP levels (329 mg/L) and abnormal kidney and liver function. Further, the session delves into the importance of understanding local epidemiology to guide empirical treatment choices and avoid cognitive biases. The discussion touches on the balance between narrow-spectrum and broad-spectrum antibiotics, highlighting the challenges of antimicrobial stewardship. While narrow-spectrum antibiotics like amoxicillin are often preferred, broader-spectrum options like Ceftriaxone may be necessary in certain cases, especially for severely ill patients. The convenience of antibiotics like Ceftriaxone (once-a-day dosing) is suggested against the need for IV access, which is particularly challenging in pediatric cases. There's a trend towards empirical use of azithromycin for conditions like cellulitis, while clindamycin is less preferred. The use of vancomycin is questioned due to low penicillin resistance in certain countries. In regions with higher resistance, Ceftriaxone remains a viable option over vancomycin. A session highlighted a concerning increase in mycoplasma detection, particularly in children, which poses a complex challenge in understanding its clinical significance. The rise in mycoplasma detection coincides with an increased emphasis on diagnostic testing, raising questions about diagnostic stewardship. Despite the surge in diagnoses, there remains uncertainty about the appropriate management, as many practitioners opt for treatment upon detection. This trend prompts consideration for potentially reducing diagnostic testing while grappling with the implications of overtesting. Mycoplasma infections are notably prevalent in Europe and the UK, with a significant portion affecting children. However, the implications of these findings on clinical management remain uncertain amidst the current emphasis on testing for various respiratory pathogens such as RSV, influenza, and COVID-19. Ceftriaxone and po azithromycin were initiated, and supplemental oxygen (45%) was administered as the child was hemodynamically unstable and had received fluid (40ml/kg). Initially, improvement was observed. However, subsequent rapid deterioration was noted, with the child becoming more hemodynamically unstable, cold, flue-like, hypotensive, anuric, and increasingly acidotic. Organ support was required, which was provided in an intensive care unit. Double inotropes were administered, and despite the absence of diagnostic results, Ceftriaxone + Clindamycin and IVIg were initiated. The presentation did not focus on the management of group A toxic shock syndrome, as this was not a classic case. The challenges faced in managing severely unwell children, including the complexity of antimicrobial and adjuvant therapy, were highlighted. Additionally, a normal echo was obtained. The chest drain was observed to be placed according to X-ray findings. Reduction in the size of the effusion was noted despite the presence of fluid at the apex, horizontal fissure, and patchy consolidation with air bronchograms in the lower lobes bilaterally, with a more pronounced manifestation on the right side. A diagnosis of severe right-sided pneumonia with sepsis was made. However, the challenge often encountered was that the blood cultures, pleural fluid cultures, and endotracheal secretions yielded negative results on culture testing. a positive result was obtained for pneumococcal antigen testing when performed on this child, prompting further consideration regarding diagnosing pneumococcal pneumonia. The speaker highlighted the findings on the urinary pneumococcal antigen's poor specificity in children, which is attributed to the high rates of S. pneumoniae colonization. Pneumococcal carriage rates in children, possibly up to 60% even after PCV immunization, were noted due to colonization rates. In a study involving children aged 36-83 months (n=197), Streptococcus pneumoniae was cultured in 53.3% of healthy children, with the highest rate (59.3%) observed in those aged 48-59 months. The presence of pneumococcal antigen in urine decreased with age, ranging from 39.0% in 36-47 months to 17.9% in 72-83 months. It was highlighted that organism culturing from pleural fluid in children with bacterial empyema is challenging, typically yielding low positive rates, often less than 50% and sometimes below 40%. The utilization of PCR technology was emphasized as a valuable addition to diagnostics, with studies indicating an increase in positive detection rates to 81%. The importance of CT values in interpreting PCR results was underscored, with a case example demonstrating the significance of a low CT value indicating a high bacterial load. In the presented case, the diagnosis of pneumococcal disease was confirmed by PCR with a CT value of 17, leading to the cessation of clindamycin treatment. 

Improvements have been noted in chest drain management. The child's condition improved, leading to the chest drain removal on day five due to cessation of drainage. Pneumococcal empyemas are relatively simple to manage, whereas group A strep empyemas pose greater challenges and often require extended hospital stays. Despite the removal of the chest drain, the chest X-ray still shows pneumonia and persistent right-sided changes. The patient remains on Cefriaxone but experiences recurrent fluid accumulation on the right side, necessitating the insertion of another chest drain two days later. Subsequent monitoring indicates a rise in CRP levels, suggesting ongoing inflammation. Microbiological analysis identifies Staph haemolyticus in the pleural fluid, raising concerns about nosocomial infection. Intensive care colleagues seek guidance on adjusting antibiotic therapy, considering options such as adding clindamycin for enhanced tissue penetration or broadening the spectrum of antibiotics to address potential nosocomial pathogens like Staph haemolyticus. Piperacillin/tazobactam and Linezolid were administered to the patient due to concerns about potential Ventilator-Associated Pneumonia (VAP). Discussions ensued regarding steroid use for managing the patient's condition, despite ongoing febrile episodes and rising CRP levels casting doubts on their efficacy. Surgical intervention was eventually deemed necessary, with cardiothoracic surgeons performing a thoracotomy and drainage procedure to address the infection's source. Antibiotic rationalization followed, leading to improvement with the placement of a chest drain. Linezolid was discontinued, and by day 21 in the ICU, significant improvement was observed, with the removal of the chest drain and notable changes on the right side. 

Various factors, including the timing of thoracotomy for source control and the initiation of antibiotic treatment, should inform the decision-making process. A duration of at least three weeks was deemed necessary due to the patient's three-week hospitalization. Extending antibiotic therapy and post-source control was discussed, with suggestions ranging from a two to four to six weeks duration from admission onset. Incorporating oral antibiotics into the regimen was considered, emphasizing that intravenous antibiotics are not inherently superior in efficacy if the drug reaches the infection site. While an early switch to oral antibiotics could benefit some healthcare providers, they may be reluctant due to the perceived advantages of intravenous administration. Continuation of antibiotic therapy for at least a few more weeks was emphasized, cautioning against premature cessation or transitioning to oral antibiotics, given the severity of the lung infection despite partial source control interventions such as lung abscess. The antibiotics were stopped about two weeks after his definitive source control, and unfortunately, 48 hours later, a relapse was experienced, with the return of fever. At that point, it was deemed necessary to restart the antibiotics. Additionally, air leaks were observed. Oral antibiotics were restarted, resulting in a decrease in CRP levels, although the fever persisted. A treatment duration of two to four to six weeks was reasonable for the patient. It is emphasized that prevention is preferable to cure, particularly in light of the historical burden of pneumococcal disease before the introduction of effective vaccines such as Prevnar 7 in 2006. The subsequent introduction of Prevnar 13 in 2010 further contributed to reducing invasive pneumococcal disease rates. However, the emergence of non-vaccine strains necessitated ongoing efforts to combat the disease. The onset of the COVID-19 pandemic in 2020 disrupted both epidemiology and vaccine development, with a notable increase in pneumococcal disease observed in children compared to pre-pandemic levels, contrasting with relatively stable adult rates. This trend has been observed globally, indicating a significant challenge in managing complex pneumococcal disease. 

An experience was shared regarding the observed increase in invasive pneumococcal disease, particularly in five-year-old children. It was noted that the prevalence of group A streptococcus has been high, while meningococcus cases have decreased due to effective vaccines. Invasive pneumococcal disease, previously minimal, has now become more prevalent. Data presented from 2020 to 2024 indicated a shift in disease patterns, with notable cases of central nervous system (CNS) infections causing serious complications, including fatalities. Certain strains persist despite effective vaccines like Prevnar 13, with serogroup 3 remaining less antigenic within the vaccine. Despite these advancements, serogroup 3 infections continue. The introduction of Prevenar 20, featuring additional serogroups, promises to reduce mortality and morbidity from invasive pneumococcal disease, especially in children. PCV20 rollout in Germany has begun, with other European countries considering it. Different scheduling approaches are observed, with some countries still using a 3 plus 1 regimen and others adopting a 1 plus 1 regimen. After three years of transitioning to the 1+1 schedule, no increase in vaccine failure has been noted, indicating potential cost-effectiveness. 

European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2024, 27th April–30th April 2024, Barcelona, Spain