An article in this week’s edition of The Lancet reports that doses of antibiotics and other antimicrobial agents should take into account the patient’s bodyweight, to maximize their potential effectiveness. The viewpoint is the work of Dr Matthew E Falagas, Alfa Institute of Biomedical Sciences, Athens, Greece, and Tufts University School of Medicine, Boston, MA USA; and Dr Drosos Karageorgopoulos, Alfa Institute of Biomedical Sciences, Athens, Greece.

The authors explain: “For most widely used antimicrobial agents, dosing recommendations in adults do not take into account adjustment to body size measures. Even when such recommendations are made for an agent, the degree of their application in routine clinical practice can be inadequate.”

For instance, a male patient with community-acquired pneumonia who weighs 90 kg and is 1.90 m tall (198 pounds and 6.2 feet) has a calculated lean body mass twice that of a female patient who weighs 56 kg and is 1.50 m tall (123 pounds and 4.9 feet). Still, they both have a body-mass index of 24•9 kg/m², within the healthy weight range. However, according to present treatment guidelines, these patients would both receive the same dosage of antibiotics. In addition to this kind of disparities, the obesity epidemic suggests there are many more patients with increased weight worldwide.

Existing information maintain the concept that antimicrobial agents should be given in higher doses to patients with large body size to better attain the drug’s pharmacodynamic targets, such as:

• several β-lactams which are commonly used for respiratory tract infection
• vancomycin, fluoroquinolones which are commonly used for urinary tract infections
• macrolides, linezolid, sulphonamides, and fluconazole which are approved as flat dosing regimens

Furthermore, specific antimicrobial agents have been approved for clinical use at dosages in adults that should be related to bodyweight. These agents are mainly those with a narrow therapeutic window, such as:

• amino-glycosides
• daptomycin
• colistin
• amphotericin B

As well as agents given at high doses for specific indications, such as:

• cotrimoxazole
• metronidazole

The authors remark: “We believe that tailoring the dosing of antimicrobial agents in adults to the physical characteristics of individual patients could be an important way to achieve maximum effectiveness and safety of antimicrobial therapy. This goal seems more important than ever, considering the increasing proportion of patients seen in clinical practice who have various risk factors for acquisition of infection or impaired immunological mechanisms for response to infection.”

The authors add with respect to children: “Considerations about appropriate antibiotic dosing for adult patients might also be necessary for children, as the proportion of children who are overweight increases in the general population. Even though a mg/kg antibiotic dosing strategy is routinely used in children, greater attention to pharmacokinetic and pharmacodynamic indices might be required for optimum dosing of some antimicrobial agents in paediatric patients. Careful use of antibiotics in children is also warranted, in view of the high rate of community-acquired infection by resistant pathogens reported in this population.”

The authors consider how doctors’ long-established attitudes to antimicrobial drug prescribing will have to adjust in order for bodyweight-related dosing to take effect. This will require time-consuming and complicated mathematical formulas to compute the exact dose. This may not hold well with the time constraints of general practice. The authors note: “These difficulties could be overcome, however, with the use of novel technologies such as personal digital assistants or the aid of computerised pharmacy dosing systems… the routine dosing of antibiotics on a mg/kg basis in children suggests that similar strategies cannot be a far-fetched goal for adults.”

They write in conclusion: “We believe that the one-size-fits-all strategy for prescribing antimicrobial agents to adults is outdated in the era of increasing antimicrobial drug resistance. The individual body size and composition characteristics of patients could substantially affect pharmacokinetic indices and clinical effectiveness of several antimicrobial agents. Appropriate studies are needed to provide guidance to clinicians on the common clinical question of how to achieve optimum effectiveness and safety of antimicrobial therapy for patients whose physical characteristics deviate from average.”

An associated Lancet editorial concludes: “Doctors might be willing to implement the practice of adjusting treatment for an individual’s body weight if robust clinical trials showed benefits to their patients. Since doctors often prescribe via computer, appropriate algorithms could easily be incorporated – as in paediatric practice, in which dose adjustment can be made fairly easily by the use of liquids and solutions. Such forms of treatment are often expensive and have a limited shelf-life, so if evidence pointed to the therapeutic advantages of dose adjustment per bodyweight, a wider range of tablet strength options would need to be widely available: good for pharmaceutical business perhaps?”

“Adjustment of dosing of antimicrobial agents for bodyweight in adults”
Matthew E Falagas, Drosos E Karageorgopoulos
Lancet 2010; 375: 248 – 51
The Lancet

Written by Stephanie Brunner (B.A.)