Original articleEvaluation of the adequacy of the antimicrobial therapy of invasive Haemophilus influenzae infections: A pharmacokinetic/pharmacodynamic perspectiveEvaluación de la adecuación del tratamiento antimicrobiano de las infecciones invasivas por Haemophilus influenzae: perspectiva farmacocinética/farmacodinámica
Introduction
Being part of the microflora of the human upper respiratory tract, Haemophilus influenzae, a pleomorphic Gram-negative coccobacillus, may cause a wide range of infections, among which is severe invasive disease, including meningitis, septicemia and pneumonia.1, 2 H. influenzae is divided into capsulated (serotypes a–f) and non-capsulated strains. Non-capsulated strains are commonly referred to as non-typeable H. influenzae (NTHi).1, 3 Among capsulated strains, serotype b (Hib) is known to be the most pathogenic. In the past, Hib was one of the most frequent organisms causing invasive infections in industrialized countries, mainly among healthy children less than 5 years of age due to their lack of T-cell independent immune response to polysaccharides. The widespread of conjugated Hib vaccination in national immunization programmes provided herd protection leading to a sharp reduction of infections caused by Hib3, 4 and to a decrease in the prevalence of carriers, but there is no clear evidence of carriage or disease replacement by no-type b H. influenzae serotypes.1, 2, 3 At present, NTHi and/or non-Hib capsulated strains are the predominant serotype of invasive H. influenzae disease.2 In Europe, NTHi is the main cause of invasive H. influenzae disease in adults, who frequently presents underlying conditions, associated with a high mortality rate.1 In a previous study carried out in Spain,5 the incidence of invasive H. influenzae disease was 2.12/100,000, similar to that reported in USA and in Europe; and it increased with age (6.8/100,000 in patients ≥ 65 years-old).
Invasive H. influenzae disease is commonly treated with β-lactam antibiotics, being aminopenicillins and cephalosporins the first choice of the treatment. However, the prevalence of many well documented resistance mechanisms in this pathogen, such as TEM-1 and ROB-1 β-lactamase production and ftsI gene encoding alterations in transpeptidase domain of penicillin-binding protein 3 (PBP-3), which may produce β-lactamase-negative ampicillin-resistant (BLNAR) strains,6, 7 may limit the choice of a suitable agent for the treatment.6, 8
When treating an infection, susceptibility patterns of the microorganism as well as patients’ characteristics determine the choice of the agent and the dosing regimen, which are the conditioning factors of the success of the therapy. Pharmacokinetic/pharmacodynamic (PK/PD) analysis combines information about the antibiotic time-course in the body and susceptibility of the pathogen against the antibiotic, employing minimum inhibitory concentration (MIC) as PD parameter, and provides the clinically relevant relationship between time and effect. Thus, the optimal agent and dosing regimen for each infectious process and patient may be chosen, enhancing the likelihood of the therapy success and minimizing adverse effects as well as the emergence of resistance.9
The main objective of this study was to determinate if the current antimicrobial treatments of invasive H. influenzae infections, including meningitis, in Spain (amoxicillin, amoxicillin/clavulanate, ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin) are adequate based not only on the susceptibility patterns of Spanish isolates, but also on the probability of achieving the PK/PD targets.
Section snippets
Methods
The study was performed by following three steps: (i) dosing regimen selection and acquisition of pharmacokinetic data of antimicrobials; (ii) microbiological data acquisition; and (iii) Monte Carlo simulation to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and to calculate the cumulative fraction of response (CFR), defined as the expected population PTA for a specific drug dose and
Results
Fig. 1 features the PTA values of amoxicillin (amoxicillin/clavulanate), ampicillin, cefotaxime, ceftriaxone, imipenem and ciprofloxacin for the studied dosing regimens. As expected, the highest PTA values were achieved with the highest doses. As shown in the figure, the calculated PTA values for amoxicillin and ampicillin were higher than 90% for MIC ≤2 mg/L with the lowest dosages and for MIC ≤8 mg/L with the highest dose level (2 g q4 h). High dosage of amoxicillin/clavulanate (2 g/0.2 g q8 h)
Discussion
In this study, we have evaluated by PK/PD analysis the adequacy of different dosing regimens of the antibiotics used to treat invasive H. influenzae disease; that is, the likelihood of success of the empirical therapy, considering the population MIC distribution of H. influenzae in Spain after the implantation of the conjugated Hib vaccination. This vaccine was implemented in Spain in 1997,27 and the data of the MIC distribution collected for this study corresponded to years 2004–2009.6
Conflict of interest
No conflicts of interest to report.
Acknowledgements
This work was supported by the University of the Basque Country UPV/EHU (GIU17/32), Spain. The authors would like to thank Silvia-García-Cobos and José Campos from the Antibiotic Laboratory of Centro Nacional de Microbiología, Instituto de Salud Carlos III (Majadahonda, Madrid, Spain), for providing MIC distribution from the surveillance study of invasive H. influenzae in Spain.
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