Prevention of emergence of resistance is often cited as a reason for combination therapy in the management of definitive infections with Gram-negative organisms; however, emergence of resistance on therapy is uncommon, occurring in 5% to 10% of Gram-negative infections. In most circumstances, long-term combination therapy is not needed and may be harmful as it increases toxicity from adverse drug reactions. It can be considered in the treatment of a deep-seated infection (such as pneumonia or severe osteomyelitis) when the organism being treated is already resistant to one or more classes of antibiotics. Discontinuing one of the agents after 5 to 7 days of therapy when the bacterial burden has decreased is an option. In all cases, attention should be given to appropriate dosing of antibiotics and to obtaining follow-up cultures if the patient is failing therapy. Of note is that when organisms that produce inducible
beta-lactamases (e.g., Enterobacter, Serratia, Citrobacter) are treated with beta-lactam agents, emergence of resistance on therapy can occur in ∼20% of cases. Monotherapy with beta-lactam agents is best avoided for treatment of serious infections in these patients if other agents are available.