Combination antibiotic therapy with a -lactam (penicillins, cephalosporins, or carbapenems) and either an aminoglycoside or fluoroquinolone for 6 weeks is reasonable (Class IIa; Level of Evidence C). 3. Consultation with an infectious diseases expert in IE should be sought because of the various mechanisms of antibiotic resistance that can be found in the non- HACEK Gram-negative aerobic bacilli (Class I; Level of Evidence C). Culture-Negative Endocarditis Positive blood cultures are a major diagnostic criterion in IE and key to identifying an pathogenic agent and an optimal Continuous bacteremia and a high frequency of positive blood cultures are typical hallmarks of this infection. The intensity of bacteremia may not be great, however, with <50 colony-forming units per 1 mL blood detected in the majority of patients in an investigation.227 Failure to culture microorganisms that cause IE can be a major problem that complicates diagnosis and timely, effec- tive treatment. Although most previous studies have put the frequency of blood culture negative IE at 5% to 10%, a European study of IE that included 820 cases indicated that 20% of patients with confirmed IE had all negative blood This may be attributable to inadequate microbio- logical techniques, infection with highly fastidious bacteria or fungi, noncultivatable agents, or the previous administration of antimicrobial agents before blood cultures were obtained. Administration of antimicrobial agents to IE patients before blood cultures are obtained reduces the recovery rate of bac- teria by 35% to 40%.228 232 The antimicrobial susceptibility of the organism, the dose, and the duration and nature of pre- vious antimicrobial therapy together determine the length of time that blood cultures will remain negative.232 IE patients with blood cultures that are initially negative after only a few days of antibiotic therapy may have positive blood cultures after several days without antibiotics. 