Clinical experience with linezolid in infants and children

The worldwide spread of multidrug-resistant organisms has required the development of new antimicrobials. Linezolid, the first oxazolidinone, has a broad spectrum of activity against Gram-positive bacteria, including resistant strains. Although approved by the Food and Drug Administration in 2002, the clinical experience with linezolid in the paediatric population is still limited, also given the fact that in most European countries the paediatric use of linezolid is off-label. In this paper we summarize the actual evidence on both licensed and off-label clinical uses of linezolid in children, including efficacy, safety and tolerability issues. Taking into account the potential bias in comparing heterogeneous clinical trials and reports, the available literature data suggest that linezolid is a safe and effective agent for the treatment of serious Gram-positive bacterial infections in neonates and children. At present, linezolid is reserved for those children who are intolerant to or fail conventional agents. A linezolid-containing regimen can be a valuable option for treating multidrug-resistant and extensively drug-resistant tuberculosis in children as well as disseminated non-tuberculous mycobacterial infections. Given the rare occurrence of serious side effects, careful monitoring of haematological parameters, possible drug interactions and neurological manifestations is recommended in linezolid-treated children, especially in case of prolonged treatments. Appropriate linezolid dosage and hospital infection control measures are essential to avoid the spread of linezolid resistance. Further studies are needed to establish novel paediatric indications for linezolid use and to assess the tolerability of long-term treatments.     

Evaluation of analgesics in children. Round table no. 5. XV

Despite recent progress, childhood pain in France is still underevaluated and undertreated and its treatment very heterogeneous among clinicians and health care providers. Pain assessment is often a difficult task in this population. The ontogeny of nociceptive pathways, their maturation, and their functionality during development are not completely understood. Painful sensations primarily involve the child's own experience but can be modified, influenced by his/her parents and the psychosocial environment with their own experience of pain and anxiety. The use of analgesics cannot be precisely quantified using retail sales data. However, the 'Pediadol' survey has demonstrated that their use in children experiencing painful situations is definitely insufficient. Also, another survey conducted among pharmacists showed that at least one-third of analgesics approved for adults are not licensed for paediatric use, sometimes due to inadequate drug formulation. The situation is even more critical for young infants and neonates for whom there are even fewer available approved analgesics. A number of issues need to be addressed in order to improve pain management in children. First of all, evaluation of pain should be generalized. Auto-evaluation should be used in children over 6 years of age. Under 6 years, the initial step would be to further evaluate and validate hetero-evaluation scores. Second, analgesics should be evaluated in order to be licensed for paediatric use. When possible, data obtained in adults or older children should be used and studies in younger infants performed only when necessary. Finally it is of paramount importance to continue to increase paediatricians' and health care providers' awareness of the existence of pain in children and to train them to evaluate pain and treat it appropriately.     

Genital herpes simplex virus infections

There has been a dramatic increase in patient visits to physicians for evaluation and treatment of genital herpes infections. This has resulted in part from an increase in genital herpes infections, particularly severe, first-episode genital herpes infections in adults without prior HSV-1 infection. Virus culture remains the most sensitive and specific method for diagnosis, and use of viral cultures is encouraged. Type-specific antibody tests have been employed in studies documenting the role of asymptomatic shedding of HSV in transmission of genital infections, the role of genital HSV in transmission of HIV, the predominance of asymptomatic and unrecognized infections in those infected with HSV-2, and the presence of past asymptomatic or unrecognized acquisition of HSV-2 in 25% of persons presenting with first-episode genital herpes. Unfortunately, commercially available serologic tests do not reliably differentiate between antibody to HSV-1 and HSV-2. Recent studies suggest that the annual risk of transmission from a sexual partner with genital herpes is about 10% in heterosexual couples. Currently, promotion of "safe sex" is the only available approach for prevention of transmission. However, ongoing research is focused on the development of an effective vaccine. Acyclovir should be used routinely in persons with first-episode genital herpes, but careful evaluation is needed in persons with recurrent genital herpes to determine whether episodic or suppressive treatment is indicated. Acyclovir should also be used routinely for episodic or suppressive treatment of HSV infections in persons with AIDS. Additional antiviral agents are needed for more effective suppressive therapy and for treatment of ACV-resistant HSV infections in the immunocompromised host.     

Liposomal amphotericin B in critically ill paediatric patients

What is known and Objective: Literature provides much evidence regarding liposomal amphotericin B treatment for fungal infections in neonates and infants. Relevant data regarding critically ill paediatric patients of older age are scarce. We aimed to present our experience regarding liposomal amphotericin B use in critically ill paediatric patients from a tertiary‐care paediatric hospital in Athens, Greece. Methods: We prospectively identified all paediatric patients who received treatment with liposomal amphotericin B in the intensive care unit of a tertiary‐care paediatric hospital during a 3‐year period (2005–2008). Data were retrieved from the evaluation of the available medical records. Results and Discussion: Twenty‐three (nine females, mean age: 26·4 months, range: 5–39 months) critically ill paediatric patients were included; 12 had malignancy. In 16 of the 23 included children, liposomal amphotericin B was administered for the treatment of confirmed fungal infections (all but one were invasive), whereas in seven patients, it was used as pre‐emptive treatment. One patient received voriconazole concomitantly. Eleven of the 16 children with documented infections were cured; five improved. Six of the seven children who received pre‐emptive treatment also showed clinical improvement. Nine deaths were noted, all attributed to underlying diseases. Two cases of hepatotoxicity and one case of nephrotoxicity (all leading to drug‐discontinuation) occurred. Seven and five cases of mild reversible hypokalaemia and hyponatraemia, respectively, were also noted. What is new and Conclusion: According to the findings of our small case series, liposomal amphotericin B may provide a useful treatment option for fungal infections of vulnerable critically ill paediatric patients with considerable comorbidity.     

Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review

Polymyxins have re-emerged in clinical practice owing to the dry antibiotic development pipeline and worldwide increasing prevalence of nosocomial infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Polymyxin B and colistin (polymyxin E) have been ultimately considered as the last-resort treatment of such infections. Microbiological, pharmacokinetic, pharmacodynamic and clinical data available for polymyxin B are reviewed in this paper. Polymyxin B has rapid in vitro bactericidal activity against major MDR Gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Acquired resistance to this agent is still rare among these pathogens. However, optimized dosage regimens are not known yet. Good clinical outcomes have been observed in the majority of the patients treated with intravenous polymyxin B in recent studies. However, these studies failed to provide definitive conclusions due to limitations of study design and additional clinical trials are required. Although combination therapy may be an attractive option based on some currently available in vitro data, clinical data supporting such recommendations are lacking. Since polymyxins will be increasingly used for the treatment of infections caused by MDR bacteria, clinical pharmacokinetic, pharmacodynamic and toxicodynamic studies underpinning the optimal use of these drugs are urgently required.     

Current status of the clinical development and implementation of paediatric artemisinin combination therapies in Sub-Saharan Africa

Timely treatment of infected children with artemisinin based combination therapies is an essential tool for the effective control and potential elimination of malaria. Until recently only tablet formulations have been available for the treatment of children leading to problems of swallowability, palatability and dosing. In consequence, paediatric drug formulations of artemisinin-based combination therapy (ACT) have been developed, showing a clinically significant improvement of tolerability in young children and of their implementation is an increasingly important public health issue. In this mini-review, we focus on the recent development of paediatric ACTs and their use in practice. Paediatric ACTs are formulated as syrup, powder for suspension, dispersible tablets and granules. Overall, the use of paediatric formulation results in an improved management of clinical malaria in young children. To date, only two paediatric ACTs have been certified with WHO prequalification status as an internationally accepted quality standard. Many more paediatric ACTs are available and in use in sub-Saharan Africa despite a lack of publicly available evidence from stringent clinical development programs. The conduct of effectiveness studies to support the introduction of paediatric ACTs in official treatment recommendations is crucial in the global strategy of malaria elimination and quality assurance of available products is a public health priority.     

Unlicensed and off-label uses of drugs in paediatrics: a review of the literature

The off-label and unlicensed use of drugs to treat children is a common practice that occurs either in hospital or in the community. This derives from the fact that research for establishing drug efficacy and safety in children has not been carried out due to ethical problems, logistical difficulties, financial and legal concerns. In this work we report the studies available in literature documenting the extent of drug use in the paediatric field outside the recommendations of the license. From our analysis, a widespread attitude to prescribe medicines to children outside their product license either in the hospitals or in the community is confirmed. This suggests an immediate action for a more rationale use of drugs in paediatrics, to avoid exposing children and infants to unnecessary risks, but also to avoid depriving them of potentially effective and sometimes life-saving therapies.     

Pertussis immunisation in adolescents and adults--Bordetella pertussis epidemiology should guide vaccination recommendations

Pertussis, or whooping cough, is an infectious disease that is caused by Bordetella pertussis, affects all age groups and is vaccine preventable. Recently, an increase in reported cases of pertussis in adolescents and adults has been noted in many countries despite high immunisation rates in children. Today pertussis outnumbers all other paediatric vaccine-preventable diseases in some countries. This observation can best be explained by an increased awareness of the disease, the availability of new diagnostic tests and, perhaps, suboptimal efficacy of some pertussis vaccines. In general, B. pertussis infections in adolescents and adults are of concern as they are the most important source of transmission of B. pertussis infections to young, unprotected infants. Many studies with diphtheria and tetanus toxoid, acellular pertussis component combination vaccines, specifically designed for use in adolescents and adults, have been performed and excellent tolerability and immunogenicity have been demonstrated. With the availability of two such products, booster doses in adolescents have been introduced in Canada, Austria, Australia, France, Germany and the US, and many other countries are considering similar expansion of their immunisation programmes at present. In addition, universal immunisation of adults (Austria, every 10 years) or targeting high risk groups (e.g., parents of newborns and other care-givers to children; Germany) have been recommended. If lifelong regular booster doses against pertussis were to be recommended and universal implementation was obtained, the authors believe that the morbidity of pertussis and its spread to infants can be dramatically reduced, and it is possible that the circulation of B. pertussis could be eliminated.     

Superficial fungal infections in children and adolescents.

Children with superficial fungal infections are commonly seen in clinical practice. Although tinea capitis and tinea corporis are the most common childhood mycoses, thrush and candida diaper dermatitis also occur frequently in infants. At times, diagnosis can be a challenge, but is made easier with the use of the potassium hydroxide microscopy and fungal cultures. Most childhood superficial fungal infections are adequately treated with topical antifungal medication. These medications are effective and the majority are safe for use in children. Oral antifungal drugs are required for children with tinea capitis, tinea unguium, and those who are immunosuppressed either from disease or therapy. Griseofulvin is the current systemic drug of choice to use in children. Several newer systemic antimycotics are currently being investigated for pediatric use. Terbinafine appears to have the best safety profile and the least risk of drug interactions. Itraconazole and fluconazole are also potential substitutes for griseofulvin in the future. The new agents, fluconazole, itraconazole, and terbinafine, have definitely improved the treatment of tinea unguium. Despite the availability of effective medications for treatment of superficial fungal infections, failure to take local and environmental measures to prevent transmission and reinfection will nullify the use of any treatment.     

Ceftriaxone‐associated biliary pseudolithiasis in children: do we know enough?

Ceftriaxone is an antibiotic agent frequently used in paediatric hospital practice for the treatment of severe bacterial infections. The use of this agent can result in cholelithiasis and/or biliary sludge, more commonly in children than in adults. This systematic review was aimed at analysing available literature concerning ceftriaxone‐associated biliary pseudolithiasis in paediatric patients, with a special emphasis on the clinical aspects. A literature analysis was performed using Medline and Embase electronic databases (articles published in English up to December 2019), with the search terms and combinations as follows:’ceftriaxone’, ‘cholelithiasis’, ‘biliary sludge’ ‘gallstones’ ‘neonates’ ‘children’ ‘clinical aspects’ ‘management’. Several case reports, case series and prospective/retrospective studies have documented a relationship between ceftriaxone treatment and biliary pseudolithiasis in the paediatric population, even though literature data regarding neonates and infants are scarce. Ceftriaxone‐associated biliary pseudolithiasis is dose‐dependent and usually asymptomatic but, sometimes, it may present with abdominal pain, nausea and emesis. Abdominal ultrasonography should be performed when this complication is suspected. Generally, ceftriaxone‐associated cholelithiasis resolves over a variable period of time (days to months) after cessation of therapy. Therefore, a conservative approach to this condition is advocated, but a prolonged follow‐up may be necessary. A personalized assessment of factors predisposing to ceftriaxone‐associated biliary pseudolithiasis before prescribing the drug can allow to minimize the risk of developing it, with significant advantages in terms of human and economic costs.     

Scaling adult doses of antifungal and antibacterial agents to children

My general pharmacokinetic scaling theory is discussed for the important matter of determining pediatric dosing for existing and new therapeutic drugs when optimal, or near-optimal, dosing for adults is known. The basis for the scaling is the requirement of a time-scaled likeness of the free-drug concentration time histories of children and adults. Broad categories of single and periodic dosing are considered. The former involves the scaling of dosage, and the latter involves both the dosage and schedule. The validity of the scaling relations is demonstrated by using measurements from previously reported clinical trials with adults and children (with ages generally 1 year or older) for the relatively new antifungal agent caspofungin and for the relatively new antibacterial agent linezolid. Standard pharmacodynamic effectiveness criteria are shown to be satisfied for the scaled dosage and schedule for children to the same extent that they are for the referenced adult. Consideration of scaling from adults to children is discussed for the case of new agents where no pediatric data are available and needed parameters are determined from in vitro measurements and preclinical animal data. A connection is also made between the allometric representation of clearance data and the dosing formulas. Limitations of the scaling results for infants because of growth and maturational matters are discussed. The general conclusion from this work is that the scaling theory does indeed have application to pediatric dosing for children, for both confirmation and refinement of present practice and guidance in pediatric treatment with new therapeutic agents.     

Paediatric anaesthesia: inhaled or intravenous technique?

Total intravenous anaesthesia has recently gained more interest in paediatric anaesthesia. However, the global experience with children is limited, therefore, the knowledge acquired in adult practice is often applied uncritically to the paediatric patient. Induction of anaesthesia by mask is a widely used and generally accepted technique; it has gained even more popularity since the introduction of sevoflurane into clinical practice. This drug has markedly improved the safety because of the reduced cardiovascular side-effects. The availability of venous access is a prerequisite for intravenous induction. Pain on injection, bradycardia, and difficulties in dosing the individual patient are the main drawbacks. Inhaled anaesthetics allow to monitor breath by breath the individual pharmacokinetics. On the other hand, maintenance of anaesthesia by an intravenous infusion of propofol is mainly based on assumptions, even when the drug is administered by computer-controlled pumps. Large aberrations from the predicted values can occur in the individual patient. Intraoperative awareness is possible, however, its incidence is generally underestimated. Paravenous infusion and pump dysfunction are typical complications of an intravenous technique. A reduced incidence of postoperative vomiting and agitation are recognised advantages of an intravenous technique. Propofol-infusion-syndrome results from prolonged administration in children and in adults. It can even occur after the use of the substance for a few hours. The duration of a safe period for administration is completely unknown, especially for neonates and infants. In summary, both techniques can be used in children; both have advantages and drawbacks. Because the experience with small children is very limited, we have to re-evaluate our practice with a critical eye day by day.     

Antibiotic therapy for severe infections in infants and children.

In infants and children, the absorption, distribution, metabolism, and excretion of drugs may differ considerably in comparison with these factors in adults; consequently, differences exist in therapeutic efficacy and toxicity of various antibiotic agents. Because of known toxicity, certain drugs--such as chloramphenicol in high doses, the sulfonamides, and tetracycline--should not be used in neonates. Antibiotic therapy should be modified in neonates because of biologic immaturity of organs important for the termination of drug action. Because of poor conjugation, inactivation, or excretion, the serum concentrations of many antibiotics may be higher and more prolonged in neonates than in older infants; thus, lower doses and longer intervals between administration may be necessary. In this article, we suggest dosages of antimicrobial agents for severe infections in children, older infants, and neonates. Included in the discussion are the cephalosporins, especially the third-generation cephalosporins that have assumed an important role in empiric treatment of bacterial meningitis in pediatric patients because of their ability to penetrate the central nervous system and their effectiveness against beta-lactamase-positive and negative strains of Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis, and many gram-negative bacteria in the Enterobacteriaceae group. In patients with congenital or acquired immunodeficiencies, antifungal, antiviral, or anti-Pneumocystis agents are often added to the antimicrobial regimen for severe infections. We review the agents available for such treatment in children, the drugs used for childhood tuberculosis, and certain new antibiotics (aztreonam, ticarcillin-clavulanate, ciprofloxacin, and imipenem-cilastatin) that have proved useful in select cases but whose precise role in pediatric practice will necessitate additional clinical experience.     

Antiviral drugs 1983

A number of antiviral compounds are currently available, and several others are of great interest. Trifluridine, idoxuridine, and vidarabine are effective topically in herpes simplex virus keratoconjunctivitis infection. Vidarabine (and presumably acyclovir) is effective in herpes simplex virus encephalitis and in herpes zoster infections in the immunocompromised host. Acyclovir is effective topically, orally, and intravenously in primary herpes genitalis, and the oral and intravenous forms are effective in recurrent herpes genitalis as well. Amantadine and rimantadine are effective prophylactically and therapeutically in influenza A infections. Ribavirin and interferon, although not licensed, are of great interest. Ribavirin may be useful in respiratory syncytial virus infections, and interferon may be of benefit in common colds and related disorders.     

Pertussis immunisation in adolescents and adults – Bordetella pertussis epidemiology should guide vaccination recommendations

Pertussis, or whooping cough, is an infectious disease that is caused by Bordetella pertussis, affects all age groups and is vaccine preventable. Recently, an increase in reported cases of pertussis in adolescents and adults has been noted in many countries despite high immunisation rates in children. Today pertussis outnumbers all other paediatric vaccine-preventable diseases in some countries. This observation can best be explained by an increased awareness of the disease, the availability of new diagnostic tests and, perhaps, suboptimal efficacy of some pertussis vaccines. In general, B. pertussis infections in adolescents and adults are of concern as they are the most important source of transmission of B. pertussis infections to young, unprotected infants. Many studies with diphtheria and tetanus toxoid, acellular pertussis component combination vaccines, specifically designed for use in adolescents and adults, have been performed and excellent tolerability and immunogenicity have been demonstrated. With the availability of two such products, booster doses in adolescents have been introduced in Canada, Austria, Australia, France, Germany and the US, and many other countries are considering similar expansion of their immunisation programmes at present. In addition, universal immunisation of adults (Austria, every 10 years) or targeting high risk groups (e.g., parents of newborns and other care-givers to children; Germany) have been recommended. If lifelong regular booster doses against pertussis were to be recommended and universal implementation was obtained, the authors believe that the morbidity of pertussis and its spread to infants can be dramatically reduced, and it is possible that the circulation of B. pertussis could be eliminated.     

Clinical trials in paediatric oncology. Recommendations for the development of new anticancer agents

Childhood and adolescent cancers are rare diseases. Despite the progress in treatment (more than two-thirds of all cases are cured), cancer remains the leading cause of death by disease in children older than 1 year. Access to new drugs that are more efficacious or better tolerated is therefore an important public health priority. The objective of our round table was thus to take inventory of the situation and to propose recommendations aimed at facilitating coordinated, rational and more rapid access to new treatments. The active participation of paediatric oncologists, parents, pharmaceutical companies and regulatory authorities proved not only necessary but very constructive. Pharmaceutical companies have developed very few new anticancer agents for children during the past 10 years. The round table identified current trends that appear propitious: the mobilisation of parents and patients' associations; European initiatives to encourage companies to assess drugs in children; regulatory initiatives to guide drug development; and the existence of structured clinical research networks in paediatric oncology, including for the development of early treatment. The round table recommends the following measures to improve access to new treatments for children and adolescents with cancer: 1. Conduct preclinical paediatric evaluation of all anticancer agents that begin the development process for adults (research and validation of treatment targets; pharmacological evaluation in relevant experimental models) to help choose the agents to study in children. 2. Initiate paediatric clinical development before the first application for authorization for adults is filed, when sufficient safety and tolerability data are available, that is, after the phase I trials in adults and optimally during the phase II trials. 3. Optimise paediatric clinical evaluation by defining development plans early and by reducing the duration of studies (enlargement of the early treatment research network to ensure adequate recruitment; new evaluation methods; better extrapolation of pharmacological data from adults to children for dose-finding). 4. Improve information to and participation of parents and patients in clinical research for new treatments. The prerequisite for the success of this project became rapidly clear to all the round-table participants: cooperation and partnership between specialists and other scientists from academia, parent associations, pharmaceutical companies and regulatory authorities. Only with such cooperation can progress in treatment occur and new hopes for recovery be fulfilled.     

Antiviral agents

Only a few agents with antiviral activity are available for routine clinical use. Amantadine hydrochloride is effective in the prophylaxis of influenza A. In addition, accumulated evidence shows that amantadine has some therapeutic effect when used early in the course of an influenza A infection. Idoxuridine and adenine arabinoside have found application as topical agents in the treatment of herpes simplex keratitis. Adenine arabinoside has also been approved for the treatment of disseminated infections due to herpes zoster and herpes simplex. Acyclovir sodium has been approved as a topical agent in the treatment of limited mucocutaneous herpes simplex viral infections in immunosuppressed patients and of initial episodes of genital herpes simplex infections in patients with normal immunity. Ribavirin, an experimental agent with a wide spectrum of activity in vitro, has not fulfilled expectations in clinical trials. Because of the eradication of smallpox, methisazone has become obsolete as a prophylactic agent in smallpox.     

Management of pediatric airway--anatomy, physiology and new developments in clinical practice

Due to the special features of paediatric anatomy and physiology, the expected and unexpected difficult paediatric airway is one of the major challenges to every anaesthesiologist, paediatrician and emergency physician. During the last years, some new devices have been made available to improve airway management in children and infants, and several studies have advanced our understanding of the risks and benefits of our clinical practice. Certain risk factors for airway related problems during anaesthesia in children having a "cold" have been identified, and there are new aspects of the controversy concerning the use of cuffed endotracheal tube (ETT) in children. New video assisted systems have been introduced for the management of the difficult airway in paediatric patients, and new applications for well-known devices have been suggested, e.g. the laryngeal mask airway (LMA) serving as guidance for fibreoptic intubation. Recent studies have also demonstrated specific problems with the LMA in infants, as well as possible advantages of a new prototype LMA for children, similar to the ProSeal. Furthermore, the following review presents data about the use of the Cuffed Oropharyngeal Airway (COPA) and the Laryngeal Tube (LT) in paediatric patients.     

Measurement of oral mucositis in children: a review of the literature

Goals of work The assessment of oral mucositis is important. There is a paucity of validated oral mucositis assessment instruments for use in children. This paper reviews the available mucositis measurement tools and their applicability to a paediatric population. Materials and methods Literature search of PUBMED™ and bibliography searches identified articles relevant to mucositis measurement tools and the measurement of mucositis in paediatrics. Results The relevant issues in the literature could be grouped into three categories: (1) development and evaluation of oral assessment tools, (2) oral assessment in the paediatric population, and (3) challenges to the assessment of oral mucositis in children. There were numerous validated mucositis assessment scales for use in adults. Only three of these scales have received limited evaluation for use in the paediatric population. The unique challenges presented by the paediatric population are excluded from much of the discussion in the literature. Conclusion The paper demonstrates the need to consider the issues specific to children. It must be determined whether previously developed tools are ideally suited for children enrolled on mucositis clinical trials.     

Intravenous substitution with immunoglobulins

A survey of clinical data shows that substitution with intravenous immunoglobulins constitutes an essential further step in the therapy of patients with immunodeficiencies: patients with primary and some secondary immunodeficiencies clearly benefit from intravenous immunoglobulin substitution. Some other diseases including idiopathic thrombocytopenic purpura and the Kawasaki syndrome also constitute indications for this kind of treatment. In other cases (infections in newborn preterm infants, children with AIDS, chronic inflammatory demyelinizing polyneuropathies and the Guillain-Barré syndrome and children with refractory seizures) there are reasons to believe that intravenous immunoglobulin therapy can be of benefit, although bigger controlled studies are still necessary to allow definitive conclusions to be reached. Further attempts will have to be made to improve understanding of the mode of action of intravenously administered immunoglobulin.