values greater than 4mg/mL have led the Clinical and Laboratory Standards Institute to lower
the MRSA vancomycin susceptibility breakpoint MIC to 2mg/mL. Although vancomycin
penetrates into the CSF, lung tissue, as well as other body tissues, the levels achieved are
variable and therefore higher troughs of 15 to 20mg/mL are recommended in serious
infections like endocarditis and meningitis. Overall incidence of nephrotoxicity from
vancomycin alone remains low, and occurs in 1% to 5% of patients, but is clearly augmented
by other concomitant nephrotoxic agents.
Linezolid is a bacteriostatic oxazolidinone that exhibits activity against a number of gram-
positive pathogens including MRSA, coagulase-negative staphylococci, and vancomycin-
resistantEnterococcus faecium. It has shown superiority over vancomycin in pneumonia due to
MRSA (33). Nausea, headache, and thrombocytopenia are the major side effects, the latter
usually occurring about two weeks into therapy. There are increasing reports of linezolid
resistance emerging during therapy inE. faecium,S. aureus, and coagulase-negative staphylo-
coccus infections (34,35).
Daptomycin is a bactericidal lipopeptide whose spectrum of activity includes most
aerobic gram-positive organisms including MRSA and VRE. It is comparable to vancomycin
forS. aureusbacteremia, including that associated with right-sided endocarditis (36). There is,
however, concern about increasing MICs while on prolonged treatment, and subsequent
potential for development of resistance. The recommended dose for skin and soft tissue
infections (SSTIs) is 4 mg/kg/day and 6 mg/kg/day in bacteremia. The dose should
be administered every 48 hours if the creatinine clearance is<30 mL/min. Daptomycin’s
adverse event profile involves an elevation in the serum creatine phosphokinase, and levels
should be monitored weekly during therapy.
The carbapenems are b-lactam agents with broad antimicrobial activity including
Pseudomonasspp., MSSA, ESBL-producing strains ofKlebsiella, and anaerobes. Meropenem and
imipenem are more or less equivalent; however, ertapenem lacks activity againstEnterococcus
andPseudomonas, and none of the carbapenems cover MRSA or VRE. Doripenem is a newer
agent that apparently has better activity againstPseudomonas. There are reports of carbapenem
resistance amongKlebsiellaspp., especially as these drugs are being used with increasing
frequency as empirical treatment in the critically ill patient.
Piperacillin/tazobactam is a penicillin derivative with an antimicrobial spectrum similar
to the broad-spectrum carbapenems and can be used as empirical treatment for HCAP, sepsis,
intra-abdominal infections, and SSTIs. As it is a time-dependent killer, prolonged infusions
over four hours can overcome intermediate MICs.
The fluoroquinolones are agents with a broad range of activity. However, there are
important interclass differences including decreased activity of ciprofloxacin against
S. pneumoniaeand enhanced anaerobic activity of moxifloxacin. In general, the fluoroquino-
lones should not be used as monotherapy for serious staphylococcal infections.
Cefepime is a fourth generation cephalosporin that may be used in HCAP, sepsis,
meningitis, and febrile neutropenia. Ceftobiprole, a “fifth” generation cephalosporin, has an
increased affinity to penicillin-binding proteins in MRSA and penicillin-resistant Str.
pneumoniaestrains, resulting in bactericidal activity against both these pathogens. In addition,
ceftobiprole demonstrates activity against vancomycin-intermediate and vancomycin-resistant
S. aureus.Ceftobiprole has good in vitro activity against Enterobacteriaceae. The main adverse
effects associated with ceftobiprole are nausea and taste disturbance, and currently it is only
approved for complicated skin and soft tissue infections (cSSTIs).
Aminoglycosides like gentamicin and tobramycin are agents with gram-negative
coverage and may be used as combination therapy for the “septic” patient until the
susceptibility patterns are available for therapy de-escalation. The main side effect is
nephrotoxicity, which can be diminished by extended-interval dosing as described above
(except when used for synergistic dosing in enterococcal and staphylococcal infections, burns,
pregnancy, or pediatric patients).
Tigecycline is a tetracycline derivative that has activity against MRSA, VRE, gram-
negative pathogens includingKlebsiellaspp. andAcinetobacterandanaerobes.However, it lacks
activity againstPseudomonas, is a bacteriostatic drug, and is currently only approved as
494 Ahuja et al.