Inadequate efficacy of a new formulation of fosmidomycin-clindamycin combination in Mozambican children less than three years old with uncomplicated Plasmodium falciparum malaria

The combination of fosmidomycin and clindamycin (F/C) is effective in adults and older children for the treatment of malaria and could be an important alternative to existing artemisinin-based combinations (ACTs) if proven to work in younger children. We conducted an open-label clinical trial to assess the efficacy, safety, and tolerability of F/C for the treatment of uncomplicated P. falciparum malaria in Mozambican children <3 years of age. Aqueous solutions of the drugs were given for 3 days, and the children were followed up for 28 days. The primary outcome was the PCR-corrected adequate clinical and parasitological response at day 28. Secondary outcomes included day 7 and 28 uncorrected cure rates and fever (FCT) and parasite (PCT) clearance times. Fifty-two children were recruited, but only 37 patients were evaluable for the primary outcome. Day 7 cure rates were high (94.6%; 35/37), but the day 28 PCR-corrected cure rate was 45.9% (17/37). The FCT was short (median, 12 h), but the PCT was longer (median, 72 h) than in previous studies. Tolerability was good, and most common adverse events were related to the recurrence of malaria. The poor efficacy observed for the F/C combination may be a consequence of the new formulations used, differential bioavailability in younger children, naturally occurring variations in parasite sensitivity to the drugs, or an insufficient enhancement of their effects by naturally acquired immunity in young children. Additional studies should be conducted to respond to the many uncertainties arising from this trial, which should not discourage further evaluation of this promising combination.     

Pharmacokinetics of two paediatric artesunate mefloquine drug formulations in the treatment of uncomplicated falciparum malaria in Gabon

OBJECTIVES: Paediatric drug formulations of artemisinin combination therapies and pharmacokinetic data supporting their use in African children are urgently needed for the effective treatment of young children suffering from falciparum malaria in sub-Saharan Africa. PATIENTS AND METHODS: In this study, the pharmacokinetic characteristics of a novel paediatric granule formulation of artesunate-mefloquine therapy were evaluated in comparison to the standard tablet formulation in the treatment of uncomplicated malaria in paediatric patients. Twenty-four patients were assigned to treatment according to body weight with either a fixed-dose paediatric granule co-formulation (10-20 kg body weight) or a free-dose co-blister tablet formulation of artesunate-mefloquine (>20-40 kg body weight). RESULTS: Median values for C(max) (861 and 930 ng/mL), T(max) (1.5 and 1.5 h) and AUC(0-)(t) (2,050 and 2,470 ng.h/mL) were comparable for dihydroartemisinin in the two groups. Exploratory analysis of mefloquine plasma levels revealed a trend towards higher concentrations in the younger age group during the absorption phase (2,550 and 1,815 ng/mL, 54 h after initiation of treatment, respectively). Median mefloquine concentrations at day 28 were 197 and 343 ng/mL, respectively. CONCLUSIONS: The pharmacokinetic characteristics of the two paediatric dosage forms, i.e. the novel fixed-dose co-formulation and the standard co-blister of artesunate-mefloquine show comparable results in the two treatment groups. The novel fixed-dose paediatric formulation is an interesting option for outpatient treatment of uncomplicated malaria in African children.     

Artemisinin-based combination therapies and their introduction in Japan

Artemisinin was discovered in 1971 from a herb, Artemisia annua, which had been used for more than 2,000 years in China against intermittent fever. Now, the artemisinin and its derivatives have become essential components of artemisinin-based combination therapies (ACTs). The ACTs are the recommended first-line treatments of malaria because they are effective against all four human malarias, produce rapid parasite/fever clearance, and show fewer adverse effects. Some ACTs are particularly important in cases of severe and complicated falciparum malaria, including cerebral malaria. However, neither the artemisinin and its derivatives nor any ACTs are registered in Japan. Indeed, the only licensed drugs for the treatment of malaria in Japan are quinine, mefloquine, and sulfadoxine/pyrimethamine. Although indigenous malaria has been eradicated in Japan since 1959, 60–100 imported malaria cases have been reported annually for the past decade. Some of the patients were, in fact, dying of the severe complications. Thus, the introduction of the ACTs and their application to imported malaria patients in Japan are urgently needed. A few clinical studies using the ACTs have been reported in Japan. The first application of an ACT, intramuscular artemether plus mefloquine, was reported in 1988 to be very effective against cerebral malaria with coma. Five cases with intravenous artesunate plus mefloquine were reported through 2001–2007, for severe or drug-resistant falciparum cases, resulting in successful treatment with some side effects such as hemolytic anemia or postmalaria neurological syndrome. Currently, a fixed-dose ACT, artemether–lumefantrine, is prescribed successfully for uncomplicated falciparum cases, with a limited number of recrudescences.     

Effect of nutritional status on response to treatment with artemisinin-based combination therapy in young Ugandan children with malaria

The relationship between malnutrition and malaria in young children is under debate, and no studies evaluating the association between malnutrition and response to artemisinin-based combination therapies (ACTs) have been published. We evaluated the association between malnutrition and response to antimalarial therapy in Ugandan children treated with ACTs for repeated episodes of malaria. Children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years. All HIV-exposed and HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis (TS). The primary exposure variables included height-for-age and weight-for-age z scores. Outcomes included parasite clearance at days 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. Two hundred ninety-two children were randomized to DP or AL, resulting in 2,013 malaria treatments. Fewer than 1% of patients had a positive blood smear by day 3 (DP, 0.2%; AL, 0.6% [P = 0.18]). There was no significant association between height-for-age or weight-for-age z scores and a positive blood smear 2 days following treatment. For children treated with DP but not on TS, decreasing height-for-age z scores of <-1 were associated with a higher risk of recurrent parasitemia than a height-for-age z score of >0 (hazard ratio [HR] for height-for-age z score of <-1 and ≥-2 = 2.89 [P = 0.039]; HR for height-for-age z score of <-2 = 3.18 [P = 0.022]). DP and AL are effective antimalarial therapies in chronically malnourished children in a high-transmission setting. However, children with mild to moderate chronic malnutrition not taking TS are at higher risk for recurrent parasitemia and may be considered a target for chemoprevention.     

Tailoring a Pediatric Formulation of Artemether-Lumefantrine for Treatment of Plasmodium falciparum Malaria

Specially created pediatric formulations have the potential to improve the acceptability, effectiveness, and accuracy of dosing of artemisinin-based combination therapy (ACT) in young children, a patient group that is inherently vulnerable to malaria. Artemether-lumefantrine (AL) Dispersible is a pediatric formulation of AL that is specifically tailored for the treatment of children with uncomplicated Plasmodium falciparum malaria, offering benefits relating to efficacy, convenience and acceptance, accuracy of dosing, safety, sterility, stability, and a pharmacokinetic profile and bioequivalence similar to those of crushed and intact AL tablets. However, despite being the first pediatric antimalarial to meet World Health Organization (WHO) specifications for use in infants and children who are ≥5 kg in body weight and its inclusion in WHO Guidelines, there are few publications that focus on AL Dispersible. Based on a systematic review of the recent literature, this paper provides a comprehensive overview of the clinical experience with AL Dispersible to date. A randomized, phase 3 study that compared the efficacy and safety of AL Dispersible to those of crushed AL tablets in 899 African children reported high PCR-corrected cure rates at day 28 (97.8% and 98.5% for AL Dispersible and crushed tablets, respectively), and the results of several subanalyses of these data indicate that this activity is observed regardless of patient weight, food intake, and maximum plasma concentrations of artemether or its active metabolite, dihydroartemisinin. These and other clinical data support the continued use of pediatric antimalarial formulations in all children <5 years of age with uncomplicated malaria when accompanied by continued monitoring for the emergence of resistance.     

Drug-resistant tuberculosis: controversies and challenges in pediatrics

Tuberculosis remains one of the top two causes of death caused by a single infectious disease worldwide, despite curative therapy. Children with tuberculosis are especially difficult to detect, since acid fast bacilli smears and cultures are usually negative and clinical signs are nonspecific or lacking. Multidrug-resistant tuberculosis, or tuberculosis resistant to at least isoniazid and rifampin, has emerged in most areas of the world over the past 20 years. Treatment of multidrug-resistant tuberculosis is more expensive and difficult. The second-line tuberculosis medications required for treatment are more toxic and less efficacious than standard treatment. These medications are not readily available in many areas of the world where drug resistance is most common. Fluoroquinolones are one of the most promising classes of second-line medications, but are not generally recommended for use in children. Ethambutol is recommended in the initial treatment of tuberculosis in children treated in areas where there is a risk of drug-resistant disease and the susceptibility of the source case is not known. Some experts have been hesitant to use ethambutol due to the risk of visual impairment associated with the drug and the difficulties in monitoring vision in young children. Pediatric drug formulations are not available for most antituberculosis medications, even the first-line tuberculosis drugs. Treatment of children exposed, infected or ill with multidrug-resistant tuberculosis is reviewed with special emphasis on second-line drugs, including recommended dosage, available formulations and necessary monitoring. While new cases of multidrug-resistant tuberculosis have decreased in most developed countries over the past 10 years, cases continue to increase in many developing countries and among immigrants from high-risk areas. Tuberculosis and multidrug-resistant tuberculosis are serious threats requiring worldwide strategies to control and treat. Better diagnostic tests, medications, public health strategies and vaccines will all be needed to eliminate tuberculosis.     

Drug-resistant tuberculosis: controversies and challenges in pediatrics

Tuberculosis remains one of the top two causes of death caused by a single infectious disease worldwide, despite curative therapy. Children with tuberculosis are especially difficult to detect, since acid fast bacilli smears and cultures are usually negative and clinical signs are nonspecific or lacking. Multidrug-resistant tuberculosis, or tuberculosis resistant to at least isoniazid and rifampin, has emerged in most areas of the world over the past 20 years. Treatment of multidrug-resistant tuberculosis is more expensive and difficult. The second-line tuberculosis medications required for treatment are more toxic and less efficacious than standard treatment. These medications are not readily available in many areas of the world where drug resistance is most common. Fluoroquinolones are one of the most promising classes of second-line medications, but are not generally recommended for use in children. Ethambutol is recommended in the initial treatment of tuberculosis in children treated in areas where there is a risk of drug-resistant disease and the susceptibility of the source case is not known. Some experts have been hesitant to use ethambutol due to the risk of visual impairment associated with the drug and the difficulties in monitoring vision in young children. Pediatric drug formulations are not available for most antituberculosis medications, even the first-line tuberculosis drugs. Treatment of children exposed, infected or ill with multidrug-resistant tuberculosis is reviewed with special emphasis on second-line drugs, including recommended dosage, available formulations and necessary monitoring. While new cases of multidrug-resistant tuberculosis have decreased in most developed countries over the past 10 years, cases continue to increase in many developing countries and among immigrants from high-risk areas. Tuberculosis and multidrug-resistant tuberculosis are serious threats requiring worldwide strategies to control and treat. Better diagnostic tests, medications, public health strategies and vaccines will all be needed to eliminate tuberculosis.     

Advances in paediatric pharmacotherapy.

Marked differences in body composition and organ function development have been demonstrated among neonates, infants, and children versus adults. Specific dosage guidelines for the paediatric population, however, are still not available for the majority of marketed drugs. Much needs to be learned about the pharmacokinetics, pharmacodynamics, comparative efficacy and safety of drugs in infants and children. Recent developments in paediatric therapeutics include the availability of several new antibiotics for the treatment of infections including, streptococcal pharyngitis, otitis media, bacterial meningitis, herpes encephalitis, neonatal herpes, and AIDS. Corticosteroids and intravenous immunoglobulin have become important adjunctive treatments for certain infections. A variety of drugs are available to treat asthma but the mortality due to this disease is still increasing. The identification of a gene defect in patients with cystic fibrosis could lead to more effective treatment in the future. Ondansetron, marketed for use in adults only, shows promise as a more effective and safer antiemetic in children receiving cancer chemotherapy. Numerous drugs are not available in suitable dosage forms for paediatric use and extemporaneous formulations are required. Documentation on the stability of the reformulated drugs is therefore needed. Studies have shown that the methods used for intravenous delivery can influence the serum concentrations of drugs in infants and children. Large numbers of children could be saved worldwide solely with improved vaccination and control of diarrhoea. Despite this, it is encouraging to witness the continued advances being made in paediatric pharmacotherapy.     

Intermittent preventive treatment against malaria: an update

Intermittent preventive treatment (IPT) against malaria is a malaria control strategy aimed at reducing the burden of malaria in certain high-risk groups, namely pregnant women and children. Three strategies – IPT in pregnancy (IPTp), infants (IPTi) and children (IPTc) – are reviewed here focusing on the mechanism of action, choice of drugs available, controversies and future research. Drugs for IPT need to be co-formulated, long acting, safe and preferably administered as a single dose. There is no obvious replacement for sulfadoxine–pyrimethamine, the most commonly utilized drug combination. All strategies face similar problems of rising drug resistance, falling malaria transmission and a policy shift from controlling disease to malaria elimination and eradication. IPT is an accepted form of malaria control, but to date only IPTp has been adopted as policy.     

Advances and challenges in malaria vaccine development

Malaria caused by Plasmodium falciparum remains a major public health threat, especially among children and pregnant women in Africa. An effective malaria vaccine would be a valuable tool to reduce the disease burden and could contribute to elimination of malaria in some regions of the world. Current malaria vaccine candidates are directed against human and mosquito stages of the parasite life cycle, but thus far, relatively few proteins have been studied for potential vaccine development. The most advanced vaccine candidate, RTS,S, conferred partial protection against malaria in phase II clinical trials and is currently being evaluated in a phase III trial in Africa. New vaccine targets need to be identified to improve the chances of developing a highly effective malaria vaccine. A better understanding of the mechanisms of naturally acquired immunity to malaria may lead to insights for vaccine development.     

Evaluation of chloroquine as a potent anti-malarial drug: issues of public health policy and healthcare delivery in post-war Liberia

Chloroquine-resistant plasmodium falciparum malaria is a serious public health threat that is spreading rapidly across Sub-Saharan Africa. It affects over three quarters (80%) of malarial endemic countries. Of the estimated 300-500 million cases of malaria reported annually, the vast majority of malarial-related morbidities occur among young children in Africa, especially those concentrated in the remote rural areas with inadequate access to appropriate health care services. In Liberia, in vivo studies conducted between 1993 and 2000 observed varying degrees of plasmodium falciparum malaria infections that were resistant to chloroquine, including sulfadiazine-pyrimethamine. As the country emerges from a prolonged civil war, the health care delivery system may not be adequately prepared to implement an effective nation-wide malarial control strategy. As a result, the management of uncomplicated malaria in Liberia poses a significant public health challenge for the government-financed health care delivery system. Therefore, based on extensive literature review, we report the failure of chloroquine as an effective first-line drug for the treatment of uncomplicated plasmodium falciparum malaria in Liberia and recommend that national health efforts be directed at identifying alternative drug(s) to replace it.     

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.     

Augmentin (amoxicillin/clavulanate) in the treatment of community-acquired respiratory tract infection: a review of the continuing development of an innovative antimicrobial agent

Amoxicillin/clavulanate (Augmentin) is a broad-spectrum antibacterial that has been available for clinical use in a wide range of indications for over 20 years and is now used primarily in the treatment of community-acquired respiratory tract infections. Amoxicillin/clavulanate was developed to provide a potent broad spectrum of antibacterial activity, coverage of beta-lactamase-producing pathogens and a favourable pharmacokinetic/pharmacodynamic (PK/PD) profile. These factors have contributed to the high bacteriological and clinical efficacy of amoxicillin/clavulanate in respiratory tract infection over more than 20 years. This is against a background of increasing prevalence of antimicrobial resistance, notably the continued spread of beta-lactamase-mediated resistance in Haemophilus influenzae and Moraxella catarrhalis, and penicillin, macrolide and quinolone resistance in Streptococcus pneumoniae. The low propensity of amoxicillin/clavulanate to select resistance mutations as well as a favourable PK/PD profile predictive of high bacteriological efficacy may account for the longevity of this combination in clinical use. However, in certain defined geographical areas, the emergence of S. pneumoniae strains with elevated penicillin MICs has been observed. In order to meet the need to treat drug-resistant S. pneumoniae, two new high-dose amoxicillin/clavulanate formulations have been developed. A pharmacokinetically enhanced tablet dosage form of amoxicillin/clavulanate 2000/125 mg twice daily (available as Augmentin XR in the USA), has been developed for use in adult respiratory tract infection due to drug-resistant pathogens, such as S. pneumoniae with reduced susceptibility to penicillin, as well as beta-lactamase-producing H. influenzae and M. catarrhalis. Amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses (Augmentin ES-600) is for paediatric use in persistent or recurrent acute otitis media where there are risk factors for the involvement of beta-lactamase-producing strains or S. pneumoniae with reduced penicillin susceptibility. In addition to high efficacy, amoxicillin/clavulanate has a well known safety and tolerance profile of the two new high-dose formulations are not significantly different from those of conventional formulations. Amoxicillin/clavulanate is included in guidelines and recommendations for the treatment of bacterial sinusitis, acute otitis media, community-acquired pneumonia and acute exacerbations of chronic bronchitis. Amoxicillin/clavulanate continues to be an important agent in the treatment of community-acquired respiratory tract infections, both now and in the future.     

Transition from paediatric to adult service in epidermolysis bullosa

Children with chronic health needs are living longer than they have in the past (Department of Health, 2006) and are becoming adults with complex health needs. This has implications for the health service, which needs to address the arrangements for transfer of young adults from paediatric to adult centres. This article describes the transitional care arrangements established at Great Ormond Street Hospital to address the needs of children with severe epidermolysis bullosa as they move on to adult care. It emphasises the close liaison between paediatric and adult clinical nurse specialists, and recognizes the role of the wider family who also have long-standing links with staff in the paediatric environment and can find transfer to an adult unit traumatic. The article concludes by recognizing that the young adult and specialist teams need to work together to continue the transition process for future generations.     

Bench-to-bedside review: Paediatric viral lower respiratory tract disease necessitating mechanical ventilation--should we use exogenous surfactant?

Treatment of infants with viral lower respiratory tract disease (LRTD) necessitating mechanical ventilation is mainly symptomatic. The therapeutic use of surfactant seems rational because significantly lower levels of surfactant phospholipids and proteins, and impaired capacity to reduce surface tension were observed among infants and young children with viral LRTD. This article reviews the role of pulmonary surfactant in the pathogenesis of paediatric viral LRTD. Three randomized trials demonstrated improved oxygenation and reduced duration of mechanical ventilation and paediatric intensive care unit stay in young children with viral LRTD after administration of exogenous surfactant. This suggest that exogenous surfactant is the first beneficial treatment for ventilated infants with viral LRTD. Additionally, in vitro and animal studies demonstrated that surfactant associated proteins SP-A and SP-D bind to respiratory viruses, play a role in eliminating these viruses and induce an inflammatory response. Although these immunomodulating effects are promising, the available data are inconclusive and the findings are unconfirmed in humans. In summary, exogenous surfactant in ventilated infants with viral LRTD could be a useful therapeutic approach. Its beneficial role in improving oxygenation has already been established in clinical trials, whereas the immunomodulating effects are promising but remain to be elucidated.     

Bench-to-bedside review: Paediatric viral lower respiratory tract disease necessitating mechanical ventilation – should we use exogenous surfactant?

Treatment of infants with viral lower respiratory tract disease (LRTD) necessitating mechanical ventilation is mainly symptomatic. The therapeutic use of surfactant seems rational because significantly lower levels of surfactant phospholipids and proteins, and impaired capacity to reduce surface tension were observed among infants and young children with viral LRTD. This article reviews the role of pulmonary surfactant in the pathogenesis of paediatric viral LRTD. Three randomized trials demonstrated improved oxygenation and reduced duration of mechanical ventilation and paediatric intensive care unit stay in young children with viral LRTD after administration of exogenous surfactant. This suggest that exogenous surfactant is the first beneficial treatment for ventilated infants with viral LRTD. Additionally, in vitro and animal studies demonstrated that surfactant associated proteins SP-A and SP-D bind to respiratory viruses, play a role in eliminating these viruses and induce an inflammatory response. Although these immunomodulating effects are promising, the available data are inconclusive and the findings are unconfirmed in humans. In summary, exogenous surfactant in ventilated infants with viral LRTD could be a useful therapeutic approach. Its beneficial role in improving oxygenation has already been established in clinical trials, whereas the immunomodulating effects are promising but remain to be elucidated.     

CNSs' support for condom advertising for the prevention of AIDS

The need for public education on methods of preventing transmission of human immunodeficiency virus (HIV) is universally accepted. Less widely accepted is the use of advertisements in the media for condoms. Opponents of condom advertising argue that a message of sexual permissiveness is conveyed and the rights of parents to directly educate their children is infringed upon. Clinical nurse specialists are influenced by this debate in as much as they provide health education and health care for many at risk of HIV infection. Although State Nurses' Association position papers on acquired immunodeficiency syndrome (AIDS) have not commented on this issue, clinical nurse specialists are urged to actively support the mass media in a t least airing public service announcements about condom use. It is possible for such announcements to provide a clear portrayal of the health promotion aspects of condom use with out condoning extramarital sexual activity. In addition, clinical nurse specialists are encouraged to make themselves available by phone for those who hear the public service announcements or advertisements and have questions. A further recommendation is for clinical nurse specialists to visit colleges, high schools, and middle schools to discuss the material on AIDS prevention presented in the mass media with young people.