Antimicrob Agents Chemother Research Articles

Rothia mucilaginosa Pneumonia in an Immunocompromised Patient

Abstract Rothia mucilaginosa is a gram-positive coccus recognized as an opportunistic pathogen capable of causing pneumonia in immunocompromised patients (Antimicrob Agents Chemother. 1995;39:268–270). The organism is often resistant to fluoroquinolones and trimethoprim/sulfamethoxazole, agents routinely used as anti-infective prophylaxis in immunocompromised individuals (Inf Dis Clin Pract. 2020;28:361–365; Infect Dis Now. 2021;51:228–235). Plasma next-generation sequencing (NGS) is increasing in clinical use to aid in diagnosis of infections in immunocompromised patients (Infect Dis (Lond). 2015;47:125–1299). A patient with advanced multiple myeloma was admitted with pneumonia. Plasma NGS initially suggested R. mucilaginosa, which was confirmed by cultures of bronchoalveolar lavage (BAL) fluid. Treatment with eravacycline led to clinical and radiographic resolution of pneumonia.

Case Commentary: Extending our therapeutic range against multidrug-resistant Candida.

Deep-seated Candida spp. infections may necessitate extended durations of antifungal therapy. Increasing resistance to first-line antifungals threatens the most common options for long-term treatment. In this issue, Ponta et al. (Antimicrob Agents Chemother 68:e00750-24, 2024, https://doi.org/10.1128/aac.00750-24) present cases in which they used rezafungin, a novel long-acting echinocandin antifungal, for extended durations. While excellent clinical evidence supports the short-term safety of rezafungin, these cases demonstrate that rezafungin may additionally have a role in long-term suppressive therapy for antifungal-resistant Candida spp. infections.

Case Commentary: Dual β-lactam as part of regimen to treat Mycobacterium abscessus lung disease.

Individuals with compromised lung function and immunity are susceptible to developing chronic Mycobacterium abscessus infection. Current treatment recommendations typically involve using one β-lactam antibiotic in combination with non-β-lactam antibiotics. However, a recent case study (B. Becken, K. M. Dousa, J. L. Johnson, S. M. Holland, and R. A. Bonomo, Antimicrob Agents Chemother 68:e00319-24, 2024, https://doi.org/10.1128/aac.00319-24) demonstrated successful treatment of chronic M. abscessus lung disease in a child using two β-lactam antibiotics simultaneously. This commentary reviews the emerging evidence and outstanding questions regarding dual β-lactam therapy for M. abscessus infections.

Imaging in a rare case of cerebral phaeohyphomycosis caused by Cladophialophora bantiana in a renal transplant patient: a case report and the literature review

BackgroundCerebral phaeohyphomycosis is a rare and potentially life-threatening fungal infection caused by dematiaceous fungi (Levin TP et al. in J Clin Microbiol 42(9):4374–4378, 2004). It may occur in both immunocompetent and immunodeficient individuals, with a relatively higher incidence in the former (Revankar SG et al. in J Trop Med Hyg 38(1):206–222, 2004). A search of the Pubmed and Google Scholar databases revealed seven cases of cerebral phaeohyphomycosis in renal transplant patients caused by Cladophialophora bantiana (C. bantiana).Case presentationA 35-year-old male patient who had undergone a renal transplant presented with fever, imbalance while walking, and focal seizures involving the right lower limb. Magnetic Resonance Imaging (MRI) of the brain showed two lesions in the cerebral hemispheres. Craniotomy with excision of the lesion was done. The Periodic Acid Schiff (PAS) stain and the tissue culture on the Sabouraud dextrose agar suggested C. bantiana. The broad-spectrum antifungal drugs were started. However, the patient deteriorated in the subsequent follow-ups and eventually died of the disease.ConclusionsWe present a detailed report on the imaging characteristics of a rare fungal brain abscess caused by C. bantiana, which is the first case of its kind (refer to Table 1). In immunodeficient cases, intracranial pathologies can encompass a wide range of conditions, from infections to neoplasms, which often exhibit significant imaging overlap. In such a setting, the remote possibility of phaeohyphomycosis is easy to miss clinically and imaging-wise. MRI can narrow down the differential diagnosis and raise suspicion. In every suspicious case, it is of the utmost importance to correlate with the histopathology and the culture reports to initiate the prompt targeted therapy and avoid a fatal outcome. Complete excision of the abscess and antifungal agents like Voriconazole and Posaconazole are the mainstay of management in these patients.

1954. Dynamic PET facilitated Modeling and Novel Antibiotic Regimens for Tuberculous Meningitis due to Multidrug-Resistant Strains

1954. Dynamic PET facilitated Modeling and Novel Antibiotic Regimens for Tuberculous Meningitis due to Multidrug-Resistant Strains

Case Commentary: The hidden side of oxacillin resistance in Staphylococcus aureus.

Acquisition of PBP2a (encoded by the mec gene) is the key resistance mechanism to β-lactams in Staphylococcus aureus. The mec gene can be easily detected by PCR assays; however, these tools will miss mec-independent oxacillin resistance. This phenotype is mediated by mutations in cell wall metabolism genes that can be acquired during persistent infections under prolonged antibiotic exposure. The complex case presented by Hess et al. (Antimicrob Agents Chemother 67:e00437-23, 2023, https://doi.org/10.1128/aac.00437-23) highlights the diagnostic and therapeutic challenges in the management of mec-independent oxacillin resistance.

Case Commentary: Unlocking the Potential of Bacteriophage to Prevent Recurrent Urinary Tract Infections after Kidney Transplantation.

Recurrent urinary tract infections (UTIs) are common in kidney transplant recipients, and novel prevention approaches are needed. The case presented by Le et al. (Antimicrob Agents Chemother, in press) describes a patient with recurrent UTIs due to extended-spectrum β-lactamase-producing Klebsiella pneumoniae who was successfully treated with bacteriophage therapy. This commentary highlights the potential for bacteriophage therapy to prevent recurrent UTIs, as well as outstanding questions that require further investigation.

606. Efficacy and Safety of Ceftazidime-Avibactam Comparative Dosage Regimens in Patients with Kidney Injury: A Retrospective Cohort Study

Abstract Background Limited data are available for Ceftazidime-avibactam (CAZ AVI) dosing in patients with chronic kidney diseases. High rate of treatment failure was found among patients with chronic kidney diseases for which renally adjusted doses has been used(1). In our institution, higher than labeled adjusted dosing regimens (HLAD) has been used for the treatment of severe infections. Doses were driven from ceftazidime adjusted dosing regimens in CKD patients. Therefore, we aimed to compare the efficacy and safety between labeled and HLAD regimens of CAZ-AVI in CKD patients. Methods A retrospective cohort study conducted between June 2018 and December 2020 in a tertiary hospital in Saudi Arabia, Jeddah. Patients ≥ 14 years old who received at least 48 hours of CAZ-AVI and have chronic kidney disease or on dialysis were included. The primary outcome was to assess the clinical cure of the HLAD group compared to labeled adjusted doses (LAD) group and defined as complete or partial resolution of fever and leukocytosis at the end of CAZ-AVI course. The secondary outcome was 30-day-mortality secondary to infections and recurrent of infections. Fisher's exact, chi-square test and contingency table analysis were used as appropriate. Results A total of 75 patients were included, 40 patients (46.7%) received HLAD. Fifty percent of the patients were on hemodialysis during CAZ-AVI course (n=38, 50%). The majority of our patients were in ICU (n=48, 64%). Clinical cure was relatively the same among the two groups with no statistical difference (57% with higher dose and 66%, 0.095 (-0.31-0.12), P=0.39). The number of 30-day mortality secondary to infection was higher (n=48, 64%) among the HLAD group compared to LAD group (74.2% and 55% respectively). Recurrence of infection were low in this study, which can be explained by the high rates of mortality, however, it was higher among patients who received LAD. Conclusion The efficacy and safety of both regimens of CAZ-AVI dosing were comparable and was not statistically significant in renally impaired patients. Larger studies are needed, however, to answer the study question on the use of higher than labeled adjusted dosing. Reference: Shields RK, Nguyen MH, Chen L, Press EG, Kreiswirth BN, Clancy CJ. Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance. Antimicrob Agents Chemother. 2018;62(5) Disclosures All Authors: No reported disclosures.

IN VITRO TO IN VIVO: COMBATING MULTIDRUG-RESISTANT ENTEROBACTERIACAE IN THE AGE OF COVID-19

IN VITRO TO IN VIVO: COMBATING MULTIDRUG-RESISTANT ENTEROBACTERIACAE IN THE AGE OF COVID-19

Characterization of the microbial resistome in a prospective trial of CBM588 in metastatic renal cell carcinoma (mRCC) offers mechanism for interplay between antibiotic (abx) use and immune checkpoint inhibitor (ICI) activity.

4510 Background: The negative association between ICI response and abx therapy is well defined (Derosa et al Cancer Discov 2021). Paradoxically, a retrospective assessment of the live bacterial product (LBP) CBM588 in patients (pts) with advanced lung cancer showed improved outcome with ICIs when the combination of CBM588 and abx (as compared to CBM588 alone) was employed (Tomita et al Cancer Immunol Res 2020). We postulated that the microbial resistome (genes encoding antimicrobial resistance) could shift in a manner with CBM588 therapy that facilitated ICI response. Methods: Pts with newly diagnosed mRCC with clear cell and/or sarcomatoid histology and intermediate/high risk disease per IMDC criteria were randomized to nivolumab/ipilimumab (nivo/ipi) or nivo/ipi/CBM588 in a 1:2 ratio. Stool samples were collected at baseline and week 12. Whole-metagenome sequencing was performed to analyze stool microbiome composition. Abx resistance genes (RGs) were inferred using publicly available database (McArthur et al. Antimicrob Agents Chemother 2013), and groups of abx RGs for various classes of abx were characterized. Wilcoxon signed-rank test was used for comparison of abx RG abundance between baseline and week 12 in each treatment arm and in responders (R) and non-responders (NR). Results: The study enrolled 30 pts, with the final analysis including 29 eligible pts (median age: 66 years, M:F 21:8, nivo/ipi: 19 pts, nivo/ipi/CBM588:10 pts). Objective response was 20% and 58% in nivo/ipi and nivo/ipi/CBM588 arms, respectively. The overall abundance of abx RGs remained unchanged between baseline and week 12 in pts receiving nivo/ipi alone. In contrast, a decrease in abx RGs was observed in pts receiving nivo/ipi with CBM588 arm from baseline to week 12 (p = 0.042 in Rs; p = 0.078 in NRs). More specifically, nivo/ipi/CBM588 treatment led to a significant reduction in fosfomycin RGs and nitroimidazole (e.g., metronidazole) RGs in both pts with R (p = 0.019 and 0.042, respectively) and NR (p = 0.031 and p = 0.031, respectively). A multitude of other clinically relevant abx RGs were downregulated in pts receiving CBM588, including those mediating resistance to glycopeptide (e.g., vancomycin) and lincosamide (e.g., clindamycin) abx. Conclusions: In the first interrogation of the resistome in mRCC, we demonstrate that CBM588 decreases abx RGs associated with multiple commonly used classes of abx. Abx clear commensals and increase pathogenic (abx resistant) bacteria in the gut. Based on our data, we formulate the hypothesis that combining abx with CBM588 may decrease potentially pathobionts and favor butyrogenic species, thereby improving CPI response. Clinical studies using CBM588 with abx priming may be warranted. Clinical trial information: NCT03829111.

Antiplatelet Therapy in Staphylococcus aureus Bacteremia: No Time Like the Past?

In this invited commentary, we reflect on the accompanying study by A. R. Caffrey, H. J. Appaneal, K. L. LaPlante, V. V. Lopes, et al. (Antimicrob Agents Chemother 66:e02117-21, 2022, https://doi.org/10.1128/aac.02117-21), which analyzed the impact of clopidogrel use on clinical outcomes in Staphylococcus aureus bacteremia.

Expression of Concern for Shin et al., "blaNDM-5-Bearing IncFII-Type Plasmids of Klebsiella pneumoniae Sequence Type 147 Transmitted by Cross-Border Transfer of a Patient".

The American Society for Microbiology (ASM) and Antimicrobial Agents and Chemotherapy (AAC) are issuing this Expression of Concern regarding the following publication: Shin J, Baek JY, Cho SY, Huh HJ, Lee NY, Song J-H, Chung DR, Ko KS. 2016. blaNDM-5-bearing IncFII-type plasmids of Klebsiella pneumoniae sequence type 147 transmitted by cross-border transfer of a patient. Antimicrob Agents Chemother 60:1932–1934. https://doi.org/10.1128/AAC.02722-15.

Risk of Healthcare-Associated Clostridioides difficile Infection During Pandemic Preparation: A Retrospective Cohort Study.

Risk of Healthcare-Associated Clostridioides difficile Infection During Pandemic Preparation: A Retrospective Cohort Study.

Establishing Population Pharmacokinetic Model for Pyrazinamide in Pulmonary Tuberculosis Patients

In this study, a reasonable population pharmacokinetic model with influencing covariates for pyrazinamide was established based on the data of 129 pulmonary tuberculosis patients in 3 hospitals: Hanoi Lung Hospital, K74 Hospital, and Central Lung Hospital. Blood samples were obtained on the 10-14th day after initiation of treatment. Time-concentration data were incorporated into the software MONOLIX 2019R2 for model building by non-linear mixed effect modeling method. The final population pharmacokinetic model is a one-compartment model, first-order absorption with lag time (Ka = 3.99 h-1, Tlag = 0.445 h), linear elimination, volume of distribution V = 27.5 L, and clearance rate Cl = 2.65 L/h. Janmahasatian’s Fat-free mass was found to be influential to the inter-individual variability of volume of distribution and rate of clearance.
 Keywords
 Population pharmacokinetic, pyrazinamide, pulmonary tuberculosis, fat-free mass.
 References
 [1] World Health Organization, Global Tuberculosis Report 2020, https://www.who.int/publications-detail-redirect/9789240013131 (accessed on: May 7th, 2021).[2] C. Lienhardt, P. Nahid, M. L. Rich et al., Target Regimen Profiles for Treatment of Tuberculosis: A WHO Document. European Respiratory Journal, Vol. 49, No. 1, 2017, https://doi.org/10.1128/AAC.00490-17.[3] E. F. Egelund, A. Alsultan, C. A. Peloquin, Optimizing the Clinical Pharmacology of Tuberculosis Medications, Clin Pharmacol Ther, Vol. 98, No. 4, 2015 pp. 387-393, https://doi.org/10.1128/AAC.03931-1-4.[4] M. A. Steele, R. M. D. Prez, The Role of Pyrazinamide in Tuberculosis Chemotherapy. Chest, Vol. 94, No. 4, pp. 845-850, 1988, https://doi.org/10.1378/chest.94.4.845.[5] L. T. Luyen, T. M. Hung, L. T. Huyen et al., Simultaneous Determination of Pyrazinamide, Rifampicin, Ethambutol, Isoniazid and Acetyl Isoniazid in Human Plasma by LC-MS/MS Method. Journal of Applied Pharceutical Science, Vol. 8, No. 9, 2018 pp. 061-073, https://doi.org/10.7324/JAPS.2018.8910.[6] R. M. Savic, D. M. Jonker, T. Kerbusch et al., Implementation of A Transit Compartment Model for Describing Drug Absorption in Pharmacokinetic Studies, J Pharmacokinet Pharmacodyn, Vol. 34, No. 5, 2007, pp. 711-726, https://doi.org/ 10.1038/psp.2012.4.[7] S, Janmahasatian, S. B. Duffull, S. Ash et al., Quantification of Lean Bodyweight, Clin Pharmacokinet, Vol. 44, No. 10, 2005, pp. 1051-1065, https://doi.org/10.1016/S0099-5428(08)60173-2.[8] M. T. Chirehwa, H. McIlleron, R. Rustomjee et al., Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis, Antimicrobial Agents and Chemotherapy, Vol. 61, No. 8, 2017, https://doi.org/10.1128/AAC.00490-17.[9] M. T. Abdelwahab, R. Leisegang, K. E. Dooley et al., Population Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Pregnant South African Women with Tuberculosis and HIV. Antimicrob Agents Chemother, Vol. 64, No. 3, 2020, https://doi.org/10.1128/AAC.01978-19.[10] P. Denti, K. Jeremiah, E. Chigutsa et al., Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania. PLoS One, Vol. 10, No. 10, 2015, https://doi.org/10.1371/journal.pone.0141002.[11] P. Mugabo, M. Mulubwa, Population Pharmacokinetic Modelling of Pyrazinamide and Pyrazinoic Acid in Patients with Multi-Drug Resistant Tuberculosis. Eur J Drug Metab Pharmacokinet, Vol. 44, No. 4, 2019, pp. 519-530, https://doi.org/ 10.1007/s13318-018-00540-w.[12] A. Alsultan, R. Savic, K.E. Dooley et al., Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis. Antimicrobial Agents and Chemotherapy, Vol. 61, No. 6, 2017, https://doi.org/10.1128/AAC.02625-16.[13] H. McIlleron, M. Willemse, H. S. Schaaf et al., Pyrazinamide Plasma Concentrations in Young Children with Tuberculosis, Pediatr Infect Dis J, Vol. 30, No. 3, 2011, pp. 262-265, https://doi.org/10.1097/inf.0b013e3181fbefe1.[14] B. J. Anderson, N. H. G. Holford, Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics, Annu Rev Pharmacol Toxicol, Vol. 48, 2008, pp. 303-332, https://doi.org/10.1146/annurev.pharmtox.48.113006.094708.[15] Ministry of Health, Guideline of Diagnosis, Treatment and of Tuberculosis, 2018 (in Vietnamese).

Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States

Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States

Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results?

Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results?

The Antibiotic Efflux Protein TolC Is a Highly Evolvable Target under Colicin E1 or TLS Phage Selection.

Bacteriophages and bacterial toxins are promising antibacterial agents to treat infections caused by multidrug-resistant (MDR) bacteria. In fact, bacteriophages have recently been successfully used to treat life-threatening infections caused by MDR bacteria (Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, et al. 2017. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother. 61(10); Chan BK, Turner PE, Kim S, Mojibian HR, Elefteriades JA, Narayan D. 2018. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health. 2018(1):60–66; Petrovic Fabijan A, Lin RCY, Ho J, Maddocks S, Ben Zakour NL, Iredell JR, Westmead Bacteriophage Therapy Team. 2020. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol. 5(3):465–472). One potential problem with using these antibacterial agents is the evolution of resistance against them in the long term. Here, we studied the fitness landscape of the Escherichia coli TolC protein, an outer membrane efflux protein that is exploited by a pore forming toxin called colicin E1 and by TLS phage (Pagie L, Hogeweg P. 1999. Colicin diversity: a result of eco-evolutionary dynamics. J Theor Biol. 196(2):251–261; Andersen C, Hughes C, Koronakis V. 2000. Chunnel vision. Export and efflux through bacterial channel-tunnels. EMBO Rep. 1(4):313–318; Koronakis V, Andersen C, Hughes C. 2001. Channel-tunnels. Curr Opin Struct Biol. 11(4):403–407; Czaran TL, Hoekstra RF, Pagie L. 2002. Chemical warfare between microbes promotes biodiversity. Proc Natl Acad Sci U S A. 99(2):786–790; Cascales E, Buchanan SK, Duché D, Kleanthous C, Lloubès R, Postle K, Riley M, Slatin S, Cavard D. 2007. Colicin biology. Microbiol Mol Biol Rev. 71(1):158–229). By systematically assessing the distribution of fitness effects of ∼9,000 single amino acid replacements in TolC using either positive (antibiotics and bile salts) or negative (colicin E1 and TLS phage) selection pressures, we quantified evolvability of the TolC. We demonstrated that the TolC is highly optimized for the efflux of antibiotics and bile salts. In contrast, under colicin E1 and TLS phage selection, TolC sequence is very sensitive to mutations. Finally, we have identified a large set of mutations in TolC that increase resistance of E. coli against colicin E1 or TLS phage without changing antibiotic susceptibility of bacterial cells. Our findings suggest that TolC is a highly evolvable target under negative selection which may limit the potential clinical use of bacteriophages and bacterial toxins if evolutionary aspects are not taken into account.

Characterization of a carbapenem-resistant Citrobacter amalonaticus coharbouring bla IMP-4 and qnrs1 genes

Introduction. Members of the genus Citrobacter are facultative anaerobic Gram-negative bacilli belonging to the Enterobacterales [Janda J Clin Microbiol 1994; 32(8):1850-1854; Arens Clin Microbiol Infect 1997;3(1):53-57]. Formerly, Citrobacter species were occasionally reported as nosocomial pathogens with low virulence [Pepperell Antimicrob Agents Chemother 2002;46(11):3555-60]. Now, they are consistently reported to cause nosocomial infections of the urinary tract, respiratory tract, bone, peritoneum, endocardium, meninges, intestines, bloodstream and central nervous system. Among Citrobacter species, the most common isolates are C. koseri and C. freundii, while C. amalonaticus has seldom been isolated [Janda J Clin Microbiol 1994; 32(8):1850-1854; Marak Infect Dis (Lond) 2017;49(7):532-9]. Further, Citrobacter spp. are usually susceptible to carbapenems, aminoglycosides, tetracyclines and colistin [Marak Infect Dis (Lond) 2017;49(7):532-9].Hypothesis/Gap Statement. As C. amalonaticus is rare, only one clinical isolate, coharbouring carbapenem resistance gene bla IMP-4 and quinolone resistance gene qnrs1, has been reported.Aim. To characterize a carbapenem-resistant C. amalonaticus strain from PR China coharbouring bla IMP-4 and qnrs1.Methodology. Three hundred and forty nonrepetitive carbapenem-resistant Enterobacterales (CRE) strains were collected during 2011-2018. A carbapenem-resistant C. amalonaticus strain was detected and confirmed using a VITEK mass spectrometry-based microbial identification system and 16S rRNA sequencing. Minimum inhibitory concentrations (MICs) for clinical antimicrobials were obtained by the broth microdilution method. Whole-genome sequencing (WGS) was performed for antibiotic resistance gene analysis, and a phylogenetic tree of C. amalonaticus strains was constructed using the Bacterial Pan Genome Analysis (BPGA) tool. The transferability of the resistance plasmid was verified by conjugal transfer.Results. A rare carbapenem-resistant C. amalonaticus strain (CA71) was recovered from a patient with cerebral obstruction and the sequences of 16S rRNA gene shared more than 99 % similarity with C. amalonaticus CITRO86, FDAARGOS 165. CA71 is resistant to β-lactam, quinolone and aminoglycoside antibiotics, and even imipenem and meropenem (MICs of 2 and 4 mg l-1 respectively), and is only sensitive to polymyxin B and tigecycline. Six antibiotic resistance genes were detected via WGS, including the β-lactam genes bla IMP-4, bla CTX-M-18 and bla Sed1, the quinolone gene qnrs1, and the aminoglycoside genes AAC(3)-VIIIa, AadA24. Interestingly, bla IMP-4 and qnrs1 coexist on an IncN1-type plasmid (pCA71-IMP) and successfully transferred to Escherichia coli J53 via conjugal transfer. Phylogenetic analysis showed that CA71 is most similar to C. amalonaticus strain CJ25 and belongs to the same evolutionary cluster along with seven other strains.Conclusion. To the best of our knowledge, this is the first report of a carbapenem-resistant C. amalonaticus isolate coharbouring bla IMP-4 and qnrs1.

External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole.

The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study) (J. Autmizguine, C. Melloni, C. P. Hornik, S. Dallefeld, et al., Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more-traditional PK sample collection and independently developed new popPK models of TMP-SMX using this external data set. The POPS data set and the external data set were each used to evaluate both popPK models. The external TMP model had a model and error structure identical to those of the POPS TMP model, with typical values for PK parameters within 20%. The external SMX model did not identify the covariates in the POPS SMX model as significant. The external popPK models predicted higher exposures to TMP (median overprediction of 0.13 mg/liter for the POPS data set and 0.061 mg/liter for the external data set) and SMX (median overprediction of 1.7 mg/liter and 0.90 mg/liter) than the POPS TMP (median underprediction of 0.016 mg/liter and 0.39 mg/liter) and SMX (median underprediction of 1.2 mg/liter and 14 mg/liter) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for resistant pathogens with a MIC of 1 mg/liter, although the required dose increase based on the external model was lower. (The POPS and external studies have been registered at ClinicalTrials.gov under registration no. NCT01431326 and NCT02475876, respectively.).

Population Pharmacokinetic Analyses of Isoniazid in Tuberculosis Treatment: a Systematic Review

The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of isoniazid (INH) and to identify factors influencing INH pharmacokinetic variability. Pubmed and Embase databases were systematically searched from inception to July, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of INH written in English, conducted in human (either healthy subjects or pulmonary tuberculosis patients) were included in this review. Ten studies were included in this review. Most studies characterized a two-compartment model with first-order kinetics for INH with a transit-compartment model for absorption suggested. Frequently reported significant predictors for INH clearance is NAT2 acetylator types (slow/intermediate/fast), while weight is a significant covariate for INH volume of distribution (both central and peripheral). In children, enzyme maturation had a profound affect on INH clearance.
 Keywords:
 Population pharmacokinetics, Isoniazid.
 References
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