ESPID 2024: Managing Children with Complex Infections Due to MDR Organisms: Treatment Strategies Based on Old, Repurposed Antibiotics
The session discusses treatment strategies utilizing old, repurposed antibiotics to manage complex infections in children caused by multidrug-resistant (MDR) organisms. It emphasizes the distinction between intrinsic and acquired resistance. As demonstrated by Pseudomonas spp, intrinsic resistance requires the use of alternative active agents because of its inherent insusceptibility to certain antibiotics, such as cefotaxime. On the other hand, acquired resistance may or may not be overcome with increased antimicrobial exposure. In vitro, susceptibility testing involving Minimum inhibitory concentration (MIC) determination helps categorize antibiotics as susceptible to standard dosing regimens or requiring increased exposure. This determination relies on predetermined values of pertinent pharmacokinetic/pharmacodynamic (PK/PD) indices such as fCmax over MIC, Area under the curve (fAUC) over MIC, or time above the MIC (fT>MIC). Resistance occurs when approved dosages fail to achieve the expected PK/PD indices. PK/PD target attainment depends on two parameters: MIC and drug exposure. Increasing MIC proportional to Cmax, AUC, or time above the MIC may yield similar PK/PD values. Adjusting the total daily dose increases Cmax or AUC while enhancing time above the MIC, which involves increasing daily doses or prolonging infusion time. Beta-lactams, for instance, benefit from short infusion durations (up to 60 minutes), prolonged infusions exceeding one hour (extended to 3-4 hours or continuous), or both. These approaches have been implemented to optimize treatment outcomes.
Extending the infusion of Meropenem can increase the time above the MIC, and another option to improve it is to increase the total dose. It is observed that better exposure is provided by giving 2gm than 1gm. A meta-analysis of the effect of prolonged infusion of beta-lactams for nosocomial pneumonia demonstrated a clear benefit on clinical cure and a borderline, not statistically significant benefit in reducing mortality. Another recent meta-analysis of studies involving adult patients with sepsis reveals a statistically significant decrease in all-cause mortality and an increase in clinical success in this population, with no significant difference in adverse events. The recent international consensus recommendations endorse extended infusion for beta-lactam agents. It is suggested that prolonged infusion be used for adults with severe illness or critically ill adults. However, there are insufficient data, pros or cons, to recommend or not recommend this approach for children without sufficient study evidence. The better tolerance of antibiotics in the pediatric population than in adults is to be considered. Vulnerable organs such as the kidney, liver, and GI tract have less chance of pre-existing damage or impairment in kids. Comorbidities are fewer, and there is usually no polypharmacy, implying no added toxicities or interactions. Age-related changes in drug metabolism and clearance are observed. A common example is a lower nephrotoxicity rate caused by colistin or aminoglycosides among pediatric patients compared to adults.
All this implies more room to increase antimicrobial exposure in pediatric patients. "Oldies but goodies" antibiotics to consider: Carbapenems, Ampicillin – sulbactam, Quinolones, Aminoglycosides, Colistin, Fosfomycin, Tigecycline, Minocycline, and Trimethoprim-sulfamethoxazole. Referring to the spectrum of activity of these antibiotics, all have activity against Enterobacterales, but for Pseudomonas, not all have activity. For Acinetobacter, most have some spectrum of activity. Considering gram-positive organisms in empiric regimens is important. Regarding the site of infection, not all antibiotics are appropriate for bacteraemia, CNS infections, and UTIs, especially tetracyclines, which do not achieve satisfactory concentrations for these sites.
Dosing recommendations and issues for Ampicillin-sulbactam in Acinetobacter baumannii infections were discussed. The Infectious Diseases Society of America (IDSA) recommendation for adult patients included a high daily sulbactam dose ranging from 6-9 grams. It could have been administered every 4 hours through extended diffusion every 8 hours, as a continuous infusion, or as multiple short infusions throughout the day. Regarding colistin, it was noted to be a problematic drug due to its pharmacokinetics. Colistin was administered as the inactive prodrug colistimethate sodium (CMS), hydrolyzed in vivo and ex vivo to colistin. Different quantification methods for colistin included colistin-based activity (CBA), 2.66 mg of colistimethate sodium, or international units of colistimethate sodium, and understanding their equivalence was important. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute Minimum Inhibitory Concentration (CLSI MIC) susceptibility breakpoints for gram negatives for colistin had been set to 2 mg/L. The PK/PD efficacy index for colistin free drug AUC of MIC (area under the curve of the concentration-time profile) was proposed to be used for assessing the efficacy of colistin therapy. Preclinical and clinical data indicated that achieving a target steady-state concentration of around 2 mg/L balanced efficacy with nephrotoxicity. The early pharmacokinetic studies of colistin were based on microbiological assays that overestimated colistin concentrations due to ex-vivo conversion of CMS to colistin. In recent years, several pharmacokinetic studies using high-performance liquid chromatography or mass spectrometry methods provided more valid results for determining colistin levels.
The EMA/FDA's current CMS pediatric dosage recommendations for children with normal renal function were up to IU/kg/d (2.5-5 mg/kg/d of CBA) in 2-4 divided doses. In previous years, limited pediatric PK data from case reports and small series had shown that using these dosages, colistin levels in plasma frequently fell below 2 mg/L, the breakpoint for susceptibility. A population PK study was conducted for colistin in critically ill pediatric patients, with higher than recommended doses administered to patients aged 3 months to ~ 14 years. Dosages ranged from 200,000 IU/kg/d of CMS, with most receiving 300,000 IU/kg/d of CMS (9.9 mg CBA/kg/d) and one patient receiving 350,000 IU/kg/d of CMS. There were no issues with efficacy or toxicity. The median steady-state colistin concentration (CSS) was 2.92 mg/L. Ten patients achieved a CSS,avg level > 2 mg/L, and five patients exceeded 4 mg/L. Modelling data indicated that if patients had received the upper EMA-approved dosage (150,000 IU/kg/d of CMS or 5 mg CBA/kg/d), the expected concentration would be 1.50 (0.58-6.42) mg/L, suggesting sub-therapeutic levels, particularly for children with borderline susceptibility infections. An analysis of the relationship between colistin concentrations and creatinine clearance showed that the apparent clearance of colistin was influenced by creatinine clearance, correlating closely with the amount of colistin base activity required to achieve a 1 mg/L increase in plasma colistin and also correlating with the presence or absence of Systemic inflammatory response syndrome (SIRS).
Bacterial cell wall synthesis was inhibited by fosfomycin. Until recently, the EUCAST MIC susceptibility breakpoint for Enterobacterales was 32 mg/L. However, since January 2024, it has changed from 32 mg/L to 8 mg/L. Additionally, until a few years ago, the PK/PD index for the clinical efficacy of fosfomycin was believed to be the time above the MIC, similar to beta-lactams. Based on that understanding, an old study incorporated PK data from various studies to determine the dosages required to achieve time above the MIC of 32 mg/L for different ages and dosing regimens. The study indicated that with dosing regimens of 100 to 200 mg/kg BID or 100 mg/kg TID for children aged 1-12 years, the required time above the MIC of 40-50% was barely achieved, if at all. However, using regimens of 100 mg/kg every 4 hours met this requirement for most patients.
Another study on the PK/PD indices using dose fractionation in a neutropenic murine thigh infection model demonstrated that AUC/MIC was best correlated with in-vivo efficacy against Enterobacterales and Pseudomonas. For Colistin IV formulation, EMA dosing recommendations indicated that infants and children aged 1-12 years required a dose of up to 400 mg/kg/day.
Tigecycline, an AUC/MIC agent, had its clinical efficacy tied to this ratio. For adults, the SmPC recommended a dosage of 50 mg every 12 hours with a 100 mg loading dose. However, the IDSA 2023 guidelines for treating antimicrobial-resistant gram-negative recommended a doubled dosage of 100 mg every 12 hours with a 200 mg loading dose. One PK study of tigecycline included children aged 8 to 11 years, which evaluated the AUC and showed that the A dosage of 1.2 mg/kg q12h appears to provide drug exposure similar to adults treated with 50 mg q12h. However, higher doses in accordance with. So, the recommended dosage of tigecycline for children, according to SmPC, is from 8- 12 years of 2 mg/kg 12 hourly with a maximum of 50 mg 12 hourly with no loading dose for adolescents the same. However, higher doses, according to those recommended by IDSA for adults with MDR gram-negative infections, have been used in certain patient series or recommended by some experts. These doses are 2 mg/kg 12-hourly, without a 4 mg/kg loading dose. Pharmacokinetic issues in sepsis patients were discussed, highlighting hemodynamic alterations such as increased cardiac output, leaky capillaries, and altered drug binding, leading to increased drug clearance and volume of distribution. These changes affected drugs excreted by the kidneys, often resulting in low plasma concentrations. Studies showed lower levels of beta-lactam agents correlating with creatinine clearance, particularly for Cefepime/Ceftazidime and Piperacillin, and to a lesser extent for Meropenem. Recent position papers suggested the use of therapeutic drug monitoring (TDM) for aminoglycosides and beta-lactams in critically ill sepsis patients to ensure appropriate drug levels are achieved.
Combination therapy was warranted for critically ill patients with signs of infection and unidentified organisms to ensure broad coverage. Clinical benefits were observed for targeted treatments, especially when no in-vitro-active agents were available. Several synergistic interactions were described in both in-vitro and in-vivo studies, though clinical evidence often remained weak or contradictory. A recent in-vitro study of Fosfomycin plus Meropenem in a hollow fibre infection model demonstrated significant synergy for Pseudomonas aeruginosa, enhancing bacterial killing and resistance suppression. Additionally, multiple studies on combining daptomycin and colistin showed synergy in the Galleria mellonella model of Acinetobacter baumannii. Time-kill assays indicated that daptomycin inhibited regrowth after colistin administration and improved animal survival. Despite these findings, the IDSA did not recommend combination therapy for infections caused by carbapenem-resistant Enterobacteriaceae (CRE).
The session discussed the OVERCOME (Colistin Monotherapy versus Combination Therapy) trial that compared Colistin monotherapy and combination therapy for Carbapenem-Resistant Organisms (CRO) in adults. It was observed that for carbapenem-resistant Enterobacterales and Pseudomonas, the combination therapy showed improved survival rates, with mortality decreasing from 32% to 17% and from 42% to 25%. However, these results were not statistically significant as the study was not powered for this purpose.
Similar findings were reported in the AIDA trial, where Enterobacterales and Pseudomonas exhibited somewhat better survival rates with colistin and meropenem combination therapy, although these findings were also not statistically significant. The IDSA recommended combination therapy for Carbapenem-resistant Acinetobacter baumannii (CRAB) using at least two agents. Suggested components included high-dose ampicillin-sulbactam, tetracyclines (minocycline, tigecycline), Polymyxin B, and Cefiderocol. The combination of meropenem and colistin alone was not recommended, and there was insufficient data to support the use of fosfomycin or rifampin in combination therapy. The findings from the study focused on treating a series of adult patients with highly resistant acetobacter baumannii bacteraemia revealed that colistin and tigecycline were resisted by nearly all patients who resisted Meropenem. A combination of colistin, daptomycin, Meropenem, and tigecycline was administered to all patients. Clinical and microbiological responses were observed in 15 out of 16 patients.
Another study emphasized the importance of combination therapy for fungal infections, highlighting the inadequacy of evidence-based medicine when clinical management is paramount. It suggested that decisions should also be guided by management reasoning. The study suggested clever empirical regimens, indicating that patients colonized or previously infected with many different definitions for multidrug-resistant, extensively drug-resistant (MDR-XDR) gram-negative bacteria could develop signs of infection, necessitating broad coverage. Instead of administering vancomycin (and potentially exacerbating nephrotoxicity with polymyxins/aminoglycosides), teicoplanin, or linezolid, agents like fosfomycin, cotrimoxazole, or tigecycline could be considered, combining possible activity against Gram (-) with satisfactory activity against Gram (+). In conclusion, older but effective drugs were available. Additionally, new super drugs were being explored, along with more studies on TDM, host immune response, and management reasoning, indicating a multifaceted approach to combat gram-negative bacteria.
European Society for Paediatric Infectious Diseases (ESPID) 2024, 20th May- 24th May 2024, Copenhagen
