Empiric Therapy Choices
In order to cover for the range of pathogens encountered in the setting of FN, the prompt administration of broad spectrum antibiotic therapy is essential.
The use of monotherapy vs. combination therapy with an aminoglycoside has been much debated in the literature. However multiple trials and meta-analyses in adult patients has showed no significant benefit for the combination therapy in terms of survival or treatment failure, while adverse events (i.e.: nephrotoxicity) are more common with combination treatment 9. The paediatric data is somewhat more limited, but the recent evidence seems to show similar efficacy using monotherapy vs. combination with an aminoglycoside 10-13.
Regimens using a cephalosporin, usually ceftazidime with or without an aminoglycoside, has shown efficacy in the past 14.
Ceftazidime has good activity against Pseudomonas aeruginosa and most gram negative bacilli. However, its lack of reliable activity on Gram positive organisms such as Streptococcus spp. and Staphylococcus aureus has been a growing concern in an era of increasing infections with those organisms 4.
Ceftriaxone has also been used for empiric coverage in FN with success 15,16. It is also to be used with caution because although it has better coverage of Streptococcus spp., ceftriaxone lacks of any activity against Pseudomonas aeruginosa. Additionally, cephalosporins do not have any activity against Enterococcus spp.
Cefipime, a 4th generation cephalosporin has an expanded spectrum of activity on Gram positive pathogens, having reliable activity on Staphylococcus aureus, Viridans Group Streptococci while displaying enhanced Gram negative coverage, being resistant to Amp-C type 1 β-lactamases produced by an increasing number of Enterobacteriaceae. It lacks activity against Enterococcus faecalis. Cefepime monotherapy has been reported as a feasible option for treatment of childhood cancer patients with FN 13,17. In a clinical trial comparing cefipime with ceftazidime monotherapy, it was shown that the addition of vancomycin was required less frequently with cefipime 18.However, it is important to note that a recent FDA warning (March 2008) has been issued after a meta-analysis sowed an increased risk of mortality compared with similar drugs19.
The carbapenems imipenem and meropenem have excellent in vitro activity on Gram positives, gram negatives and anaerobes.
They are active agents against Pseudomonas aeruginosa and are resistant to β-lactamase producing organisms.
However, there are now increasing concerns regarding the emergence of new carbapenemases in some gram negative bacilli.
There is little difference between meropenem and imipenem.
- Better in vitro activity against gram negatives with minimal inhibitory concentrations (MIC) 10 fold lower for most Gram negative organisms compared with imipenem 20.
- Meropenem has potential advantages over imipenem regarding the gastro-intestinal toxicities and reported lower threshold for the onset of seizure in seriously ill patients with imipenem use 7.
- Meropenem has been well studied as an agent for children with FN 11,21,22 and has demonstrated clinical superiority to ceftazidime and amikacin in a randomized clinical trial 12.
- Imipenem has better in vitro activity for Gram positive organisms.
The combination of a β-lactam antibiotic with a β-lactamase inhibitor has been increasingly popular for use in children.
Examples are piperacillin/tazobactam and ticarcillin/clavulanate.
These antibiotics are well suited in the context of FN, as they possess a wide spectrum of activity on most Gram positive, negative and anaerobic organisms.
It is important to note that ticarcillin/clavulanate is less active in vitro than piperacillin/tazobactam against Streptococcus spp., E. faecalis, Klebsiella and Pseudomonas spp. 23.
Piperacillin/tazobactam display a good safety profile and has been shown to be an effective agent in children with FN 24-26.