A biological pharmacology network to secure the risk of drug-drug interaction with nirmatrelvir/ritonavir.

Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent risk of adverse drug reaction and lack of efficacy. In this study, we aimed at describing the expert advices provided by the biological pharmacology network of the SFPT (i.e., the therapeutic drug monitoring specialists working in the laboratories of the pharmacology departments in France/Belgium). From February to August 2022, we collected all specialized advices provided by the biological pharmacology network of the SFPT. Seven pharmacology departments actively participated in the study (Brussels Saint-Luc Hospital in Belgium, Caen, Dijon, Nantes, Nancy, Rennes and Toulouse in France). We collected the following data: patient's age, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments, and advice provided. One hundred and six expert advice on 753 drugs were provided during the seven months of data collection. Two centers provided 83% of all the expert advice (around 8/month). Patients originated form a transplantation department in 65% of the cases. The most common request were for cardiac drugs (28%), immunosuppressive drugs (24%) and endocrine drugs (18%). The advice were distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment, and treatment switch in 59%, 28%, 11%, and 1.6% of the cases, respectively. Only 2 pieces of advice (0.3%) constituted treatment contra-indications. Drug monitoring was proposed in 10% of prescription lines. Expert advice provided by the biological pharmacology network of the SFPT allows securing the combination of nirmatrelvir/ritonavir with other concomitant drugs. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction.

What Place Is There for Long-Acting Antibiotics in the Management of Gram-Positive Infections? A Qualitative Cross-Sectional Study.

OBJECTIVES: To identify the current practices with long half-life lipoglycopeptides (LGPs) and potential use/position of oritavancin. RESULTS: Despite their indication being limited to skin and soft tissue infections (SSTIs), long half-life lipoglycopeptides are mainly used off-label to treat bone and joint infections (BJIs) and infective endocarditis. Oritavancin and dalbavancin are both semisynthetic lipoglycopeptide antibiotics with activity against Gram-positive organisms. The game-changing property of these two antibiotics is their one-time dosing. Due to its shorter half-life, oritavancin might have an advantage over dalbavancin for a treatment duration of less than 2 weeks, as it could be used both in prolonged treatments of complicated patients in BJIs or administered as a single-dose treatment for Gram-positive cocci infections usually treated by a 5- to 10-day antibiotic course. These infections include urinary tract infections, bacteremias, catheter-related infections, etc. In addition to the possibility of being used as an end-of-treatment injection, oritavancin could be used as an empiric therapy treatment in the postoperative period in the context of device-associated especially prosthetic joint infections to allow for the early discharge of the patient. METHODS: A qualitative survey was conducted in March 2022 including sixteen infectiologists, one internist, five hospital pharmacists, and one pharmacologist. CONCLUSION: Long half-life lipoglycopeptides contribute to changing the paradigm in the management of acute bacterial infections, as infectiologists now consider a range of indications and patient profiles for one single drug. Oritavancin strengthens the therapeutic arsenal in numerous infections from BJIs to urinary tract infections and could help to manage specific clinical situations, on top of providing potential benefits for the hospital's budget.

Therapeutic drug monitoring and virological response at week 48 in a cohort of HIV-1-infected patients switching to dolutegravir/rilpivirine dual maintenance therapy (ANRS-MIE-BIRIDER study).

AIMS: Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV-1 RNA viral load (VL) during maintenance dual therapy. METHODS: We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study. RESULTS: At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow-up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P = .015). CONCLUSION: A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin.

Dalbavancin plasma concentrations in 133 patients: a PK/PD observational study.

OBJECTIVES: Limited pharmacokinetics data support dalbavancin long-term use in off-label indications and the optimal dosing regimen is debated. We aimed to describe dalbavancin concentrations in an observational retrospective multicentre study. METHODS: Patients from 13 French hospitals, treated with 1500 mg doses of dalbavancin and for whom therapeutic drug monitoring was performed from June 2018 to March 2021 were included. Dalbavancin plasma concentrations were described at peak and 1, 2, 3, 4, 6 and 8 weeks after the last 1500 mg dose. Concentrations in patients weighing more or less than 75 kg and with a GFR greater or less than 60 mL/min were compared. Microbiological data were collected and dalbavancin MIC was measured when possible. RESULTS: One hundred and thirty-three patients were included (69% treated for bone and joint infections, 16% for endocarditis). Thirty-five patients received a single dose of dalbavancin and 98 received several administrations. Two, 3 and 4 weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24 mg/L for the first doses and 34.55, 22.60 and 19.20 mg/L for the second or subsequent doses. Weight and renal function had an impact on pharmacokinetics. Infection was documented in 105 patients (Staphylococcus spp. in 68% of cases). Staphylococcus aureus was isolated in 32.5% of cases (median MIC: 0.047 mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047 mg/L). CONCLUSIONS: Plasma concentrations of dalbavancin were consistent with those described in clinical trials and those sought during the industrial development of the molecule.

Expert Opinion on Dose Regimen and Therapeutic Drug Monitoring for Long-Term Use of Dalbavancin: Expert Review Panel.

BACKGROUND: Dalbavancin is a lipoglycopeptide with a long elimination half-life and is currently licensed for the treatment of acute bacterial skin and skin structure infections in adults. Dalbavancin's potential in treating off-label complex Gram-positive infections is promising and real-world experience in treating such infections is growing. However, clear guidance on extended dosing regimens is lacking. OBJECTIVES: This study aimed to provide clear expert opinion based on recent pharmacokinetic literature and expert and real-world experience in infection areas that require > 2 weeks of treatment. METHODS: A single face-to-face meeting was held in September 2022 to collate expert opinion and present safety data of dalbavancin use in these clinical indications. A survey was completed by all authors on their individual experience with dalbavancin, which highlighted the heterogeneity in the regimens that were used. RESULTS: After review of the survey data and recent literature, this study presents expert panel proposals that accommodate different healthcare settings and resource availability, and centre around the length of treatment duration including up to or exceeding 6 weeks. To achieve adequate dalbavancin concentrations for up to 6 weeks, 3000 mg of dalbavancin should be given over 4 weeks for the agreed complex infections requiring > 2 weeks of treatment. Therapeutic drug monitoring (TDM) is advised for longer treatment durations and in cases of renal failure. Specific dosing recommendations for other special populations require further investigation. CONCLUSIONS: These proposals based on expert opinion have been defined to encourage best practice with dalbavancin, to optimise its administration beyond the current approved licenced dose across different healthcare settings.

Safety and Efficacy of Ceftaroline in Neonates With Staphylococcal Late-onset Sepsis: A Case Series Analysis.

Treatment of late-onset neonatal staphylococcal sepsis is sometimes challenging with feared side effects of vancomycin, increasing minimal inhibitory concentrations and questions about catheter management. In case of failure, ceftaroline was administered as a compassionate treatment in 16 infants (gestational age of less than 32 weeks and less than 28 postnatal days), whose first-line treatment failed. We report 11 successes and no severe adverse drug reactions. Larger data are required to confirm these encouraging results.

A multifaceted strategy to optimize pharmacokinetics of antimicrobial therapy in patients with hospital-acquired infections-a monocentre quality improvement project.

OBJECTIVE: We assessed the efficacy of a quality improvement programme to optimize the delivery of antimicrobial therapy in critically ill patients with hospital-acquired infections (HAI). PATIENTS AND METHODS: Before-after trial in a university hospital in France. Consecutive adults receiving systemic antimicrobial therapy for HAI were included. Patients received standard care during the pre-intervention period (June 2017 to November 2017). The quality improvement programme was implemented in December 2017. During the intervention period (January 2018 to June 2019), clinicians were trained to dose adjustment based on therapeutic drug monitoring and continuous infusion of ß-lactam antibiotics. The primary endpoint was the mortality rate at day 90. RESULTS: A total of 198 patients were included (58 pre-intervention, 140 intervention). The compliance with the therapeutic drug monitoring-dose adaptation increased from 20.3% to 59.3% after the intervention (P < 0.0001). The 90-day mortality rate was 27.6% in the pre-intervention period and 17.3% in the intervention group (adjusted relative risk 0.53, 95%CI 0.27-1.07, P = 0.08). Treatment failures were observed in 22 (37.9%) patients before and 36 (25.7%) patients after the intervention (P = 0.07). CONCLUSIONS: Recommendations for therapeutic drug monitoring-dose adaptation and continuous infusion of ß-lactam antibiotics were not associated with a reduction in the 90-day mortality rate in patients with HAI.

Development and validation of a dosing nomogram for continuous infusion cloxacillin in infective endocarditis.

BACKGROUND: Cloxacillin is the first-line treatment for methicillin-susceptible staphylococcal infective endocarditis (IE). The recommended dose is 12 g per day regardless of the patient characteristics, despite the importance of renal function on its pharmacokinetics. OBJECTIVES: We sought to build a population pharmacokinetics model of continuous infusion cloxacillin in IE patients to evaluate the influence of multiple covariates and then develop a nomogram based on significant covariates for individual adaptation. PATIENTS AND METHODS: We included patients of a local IE cohort who were treated with cloxacillin administered by continuous infusion, excluding those who received intermittent or continuous dialysis, extracorporeal membrane oxygenation or extracorporeal circulation. The population pharmacokinetic analysis was performed using Pmetrics. The influence of weight, ideal weight, height, body mass index, body surface area, glomerular filtration rate (GFR) calculated with the Chronic Kidney Disease Epidemiology Collaboration formula (both expressed in mL/min/1.73 m² and in mL/min) and serum protein level on cloxacillin pharmacokinetics was assessed. Accounting for relevant covariates, a dosing nomogram was developed to determine the optimal daily dose required to achieve a steady-state plasma concentration range of 20-50 mg/L with a probability ≥0.9. RESULTS: A total of 114 patients (331 plasma concentrations) were included. A one-compartment model including GFR expressed in mL/min as a covariate was chosen. Using the nomogram, achieving the cloxacillin concentration target requires a daily dose ranging from 3.5 to 13.1 g for a GFR ranging from 20 to 125 mL/min. CONCLUSIONS: This work provided a practical tool for cloxacillin dose adjustment in IE according to renal function.

Development of a Predictive Dosing Nomogram to Achieve PK/PD Targets of Amikacin Initial Dose in Critically Ill Patients: A Non-Parametric Approach.

French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD-EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient's TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology.

Impact of Inflammation on Midazolam Metabolism in Severe COVID-19 Patients.

Midazolam is a benzodiazepine frequently used for sedation in patients hospitalized in the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19). This drug is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes. Several studies have suggested that inflammation, frequently observed in these patients, could modulate CYP3A activity. The objective of this work was to study the impact of inflammation on midazolam pharmacokinetics in patients with COVID-19. Forty-eight patients hospitalized in the ICU for COVID-19 and treated with midazolam administered by continuous infusion were included in this study. Midazolam and α-hydroxymidazolam concentrations were measured and patient data, including the use of CYP3A inhibitors, were collected. Total and unbound concentrations of midazolam and α-hydroxymidazolam were measured in plasma using a validated liquid-chromatography coupled with mass spectrometry method. Inflammatory condition was evaluated by C-reactive protein (CRP) level measurement. Both drug concentrations and CRP measurements were performed on 354 plasma samples. CRP elevation was significantly associated with the α-hydroxymidazolam/midazolam plasma ratio decrease, whether for the unbound fraction or for the total fraction. Conversely, inflammation was not associated with protein binding modifications. Logically, α-hydroxymidazolam/midazolam plasma ratio was significantly reduced when patients were treated with CYP3A inhibitors. In this study, we showed that inflammation probably reduces the metabolism of midazolam by CYP3A. These results suggest that molecules with narrow therapeutic margins and metabolized by CYP3A should be administrated with care in case of massive inflammatory situations.

Management of drug-drug interactions with nirmatrelvir/ritonavir in patients treated for Covid-19: Guidelines from the French Society of Pharmacology and Therapeutics (SFPT).

OBJECTIVES: Nirmatrelvir in association with ritonavir (PAXLOVID™, Pfizer) is an antiviral agent targeting the 3-chymotrypsin-like cysteine protease enzyme (3C-like protease or Mpro) which is a key enzyme of the viral cycle of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This combination with a well-known pharmacokinetic enhancer leads to a high risk for drug-drug interactions in a polymedicated elected population for treatment. The aim of this work was to provide recommendations on behalf of the national French society of pharmacology (French Society of Pharmacology and Therapeutics; SFPT), by suggesting optimal and pragmatic therapeutic strategies if nirmatrelvir/ritonavir is to be given together with drugs commonly used, in order to ensure secured physicians' prescription. METHODS: Six clinical pharmacologists search the scientific literature to provide a first draft of recommendations. Thereafter, twelve other clinical pharmacologists verified the recommendations and proposed modifications. The final draft was then validated by all 18 participants. RESULTS: Five distinct recommendations were issued: i) contra-indications, ii) "PAXLOVID™ not recommended with the comedication", iii) "PAXLOVID™ possible whether the comedication is discontinued", iv) "PAXLOVID™ possible only after an expert advice" and v) "PAXLOVID™ possible without modification of the associated treatment". The final document comprises recommendations for 171 drugs/therapeutic classes aiming to secure prescription. In complex situations, clinicians are advised to contact their pharmacology department to obtain specific recommendations on the management of drug-drug interactions with nirmatrelvir/ritonavir. CONCLUSION: These recommendations intend to be a help for clinicians willing to prescribe nirmatrelvir/ritonavir and to prevent drug-drug interactions leading to adverse drug reactions or loss of efficacy. They constitute a guideline for primary care situations. Of course, some complex situations may require expert advices and here, again, clinical pharmacologists are at the forefront in providing therapeutic advice.

Highly Conserved gsc1 Gene of Pneumocystis jirovecii in Patients with or without Prior Exposure to Echinocandins.

Echinocandins are noncompetitive inhibitors of the GSC1 subunit of the enzymatic complex involved in synthesis of 1,3-beta-d-glucan, a cell wall component of most fungi, including Pneumocystis spp. Echinocandins are widely used for treating systemic candidiasis and rarely used for treating Pneumocystis pneumonia. Consequently, data on P. jirovecii gsc1 gene diversity are still scarce compared to that for the homologous fks1 gene of Candida spp. In this study, we analyzed P. jirovecii gsc1 gene diversity and the putative selection pressure of echinocandins on P. jirovecii. gsc1 gene sequences of P. jirovecii specimens from two patient groups were compared. One group of 27 patients had prior exposure to echinocandins, whereas the second group of 24 patients did not, at the time of P. jirovecii infection diagnoses. Two portions of the P. jirovecii gsc1 gene, HS1 and HS2, homologous to hot spots described in Candida spp., were sequenced. Three single-nucleotide polymorphisms (SNPs) at positions 2204, 2243, and 2303 close to the HS1 region and another SNP at position 4540 more distant from the HS2 region were identified. These SNPs represent synonymous mutations. Three gsc1 HS1 alleles, A, B, and C, and two gsc1 HS2 alleles, a and b, and four haplotypes, Ca, Cb, Aa, and Ba, were defined, without significant difference in haplotype distribution in both patient groups (P = 0.57). Considering the identical diversity of P. jirovecii gsc1 gene and the detection of synonymous mutations in both patient groups, no selection pressure of echinocandins among P. jirovecii microorganisms can be pointed out so far.

CSF concentration of cefotaxime in adult patients with pneumococcal meningitis: a multicentre retrospective study.

BACKGROUND AND OBJECTIVES: Pneumococcal meningitis is a devastating disease that requires adequate meningeal antibiotic penetration to limit the mortality. Despite a large usage in this indication, data about CSF concentration of cefotaxime during pneumococcal meningitis in adults are scarce. Therefore, we aimed to describe the CSF concentration obtained after high-dose cefotaxime administration in adult patients treated for Streptococcus pneumoniae meningitis. PATIENTS AND METHODS: In this multicentre, observational, retrospective study, cases of adult patients with S. pneumoniae meningitis hospitalized between January 2013 and October 2019 for whom cefotaxime concentration was measured in CSF were reviewed. RESULTS: Cefotaxime concentration was analysed in 44 CSF samples collected among 31 patients. Median (IQR) age was 61 years (52-69). Dexamethasone was administered in 27 subjects. Median (IQR) cefotaxime daily dosage was 15 g (12-19), corresponding to 200 mg/kg (150-280). CSF samples were collected approximately 5 days after cefotaxime initiation. Median (IQR, range) cefotaxime CSF concentration was 10.3 mg/L (4.8-19.3, 1.2-43.4). Median (range) MIC for Streptococcus pneumoniae was 0.25 mg/L (0.008-1) (n = 22). The median (IQR, range) CSF/MIC ratio was 38 (12-146, 4-1844). Twenty-five CSF concentrations (81%) were above 10 times the MIC. Cefotaxime was discontinued in two patients for toxicity. In-hospital mortality rate was 29%. CONCLUSIONS: Adult patients with pneumococcal meningitis treated with a high dose of cefotaxime (200 mg/kg/day) had elevated CSF concentrations with satisfying pharmacokinetics/pharmacodynamics parameters and tolerability profile. This study brings reassuring pharmacological data regarding the use of high-dose cefotaxime monotherapy for treating pneumococcal meningitis with susceptible strains to cefotaxime.

A murine model to study the gut bacteria parameters during complex antibiotics like cefotaxime and ceftriaxone treatment.

BACKGROUND: The globally increasing resistance due to extended-spectrum beta-lactamase producing Enterobacteriaceae is a major concern. The objective of this work was to develop a murine model to study the gut bacteria parameters during complex antibiotics like cefotaxime and ceftriaxone treatment and to compare the fecal carriage of ESBL-producing Enterobacteriaceae. METHODS: SWISS mice were treated either with ceftriaxone or with cefotaxime or with NaCl 0.9% as a control group from day 1 to day 5. We performed a gavage at day 4 with a Klebsiella pneumonia CTX-M9. We collected stools and performed pharmacological measurements, cultures and 16S rRNA gene amplification and sequencing during the 12 days of the stool collection. RESULTS: Mice treated with ceftriaxone were more colonized than mice treated with cefotaxime after gavage (p-value = 0.008; Kruskal-Wallis test). Ceftriaxone and cefotaxime were both excreted in large quantity in gut lumen but they drove architecture of the gut microbiota in different trajectories. Highest levels of colonization were associated with particular microbiota composition using principal coordinate analysis (PCoA) which were more often achieved in ceftriaxone-treated mice and which were preceded by highest fecal antibiotics concentrations in both cefotaxime or ceftriaxone groups. Using LEfSe, we found that twelve taxa were significantly different between cefotaxime and ceftriaxone-treated mice. Using SplinectomeR, we found that relative abundances of Klebsiella were significantly higher in CRO than in CTX-treated mice (p-value = 0.01). CONCLUSION: Ceftriaxone selects a particular microbial community and its substitution for cefotaxime could prevent the selection of extended-spectrum beta-lactamase producing Enterobacteriaceae.

CYP1A2 and tobacco interaction: a major pharmacokinetic challenge during smoking cessation.

Smoking cessation is underestimated in terms of drug interactions. Abrupt smoking cessation is common in cases of emergency hospitalization and restrictions of movement. Tobacco is a known cytochrome P450 1A2 (CYP1A2) inducer, its consumption and withdrawal can lead to major pharmacokinetic drug interactions. Nevertheless, references do exist, but may have different results between them. The objective of our work was to establish the broadest and most consensual list as possible of CYP1A2 substrates treatments and propose a pharmacological approach. We searched the widest possible list of CYP1A2 substrates based on various international references. We compared the references and defined probability and reliability scores of our results to sort the substances based on the scores. For the 245 substances identified as CYP1A2 substrates, we focused on the 63 CYP1A2 substrates with both probability and reliability scores >50%. Our work establishes adaptive pharmacological approaches for the management of patients initiating smoking cessation which must be integrated into the management of smoking cessation. Pharmacologists can now adopt adaptive pharmacological approaches to complement patient-specific clinical information about smoking cessation by considering pharmacokinetic risk. This work establishes an unprecedented list. It should guide in the care of patients initiating smoking cessation to prevent pharmacokinetic drug interactions.

Phages versus Antibiotics To Treat Infected Diabetic Wounds in a Mouse Model: a Microbiological and Microbiotic Evaluation.

Diabetes is marked by a range of complications, including chronic infections that can lead to limb amputation. The treatment of infected wounds is disrupted by arteriopathies that reduce tissue perfusion as well as by the critical development of bacterial resistance. We evaluated the impact of a local application of bacteriophages compared to that of a per os administration of amoxicillin-clavulanic acid in a mouse model of Staphylococcus aureus wound infection. We found that phage treatment resulted in improved clinical healing and a reduction in local bacterial load at 7 and 14 days postinfection. Unlike antibiotics, phage therapy did not deplete the intestinal microbiota of treated animals. Amoxicillin resulted in a reduction of alpha and beta diversities of the murine microbiota and disturbed architecture even 7 days after the end of treatment, whereas phage treatment did not impinge on the microbiota.IMPORTANCE The management of diabetic foot infections is frequently a dead end for surgeons and infectious disease specialists. When the pathogen to be treated is not resistant to conventional antibiotics, the latter tend to unbalance the intestinal microbiota, which is linked to multiple pathologies. A local treatment with bacteriophages, in addition to being as much or even more effective than antibiotics from a clinical and microbiological point of view, makes it possible to respect the patient's microbiota. These results suggest that the use of this therapeutic alternative is a major avenue and that the introduction of recommendations for their use is now necessary.