The lipopeptide daptomycin has been approved for use in skin and skin-structure infections but has failed to meet statistical noninferiority criteria in a clinical trial for severe community-acquired pneumonia. Daptomycin exhibited an unusual pattern of activity in pulmonary animal models: efficacy in Staphylococcus aureus hematogenous pneumonia and inhalation anthrax but no activity against Streptococcus pneumoniae in simple bronchial-alveolar pneumonia. Daptomycin was shown to interact in vitro with pulmonary surfactant, resulting in inhibition of antibacterial activity. This effect was specific to daptomycin and consistent with its known mechanism of action. This represents the first example of organ-specific inhibition of an antibiotic.

A turtle with a complete transection of the spinal cord, termed a spinal turtle, exhibits three types or "forms" of the scratch reflex: the rostral scratch, pocket scratch, and caudal scratch (21). Each scratch form is elicited by tactile stimulation of a site on the body surface innervated by afferents entering the spinal cord caudal to the transection. We recorded electromyographic (EMG) potentials from the hindlimb during each of the three forms of the scratch in the spinal turtle (see Fig. 1). Common to all scratch forms is the rhythmic alternation of the activity of the hip protractor muscle (VP-HP) and hip retractor muscle (HR-KF). Each form of the scratch displays a characteristic timing of the activity of the knee extensor muscle (FT-KE) with respect to the cycle of activity of the hip muscles VP-HP and HR-KF. In a rostral scratch, activation of FT-KE occurs during the latter portion of VP-HP activation. In a pocket scratch, activation of FT-KE occurs during HR-KF activation. In a caudal scratch, activation of FT-KE occurs after the cessation of HR-KF activation. The timing characteristics of these muscle activity patterns correspond to the timing characteristics of changes in the angles of the knee joint and the hip joint obtained with movement analyses (21). We recorded electroneurographic (ENG) potentials from peripheral nerves of the hindlimb during each of the three forms of the "fictive" scratch in the spinal turtle immobilized with neuromuscular blockade (see Fig. 4). Common to all forms of the fictive scratch is the rhythmic alternation of the activity of hip protractor motor neurons (VP-HP) and hip retractor motor neurons (HR-KF). Each form displays a characteristic timing of the activity of knee extensor motor neurons (FT-KE) with respect to the cycle of VP-HP and HR-KF motor neuron activity. The timing characteristics of these motor neuron activity patterns are similar to the timing characteristics of the muscle activity patterns obtained in the preparation with movement (cf. Figs. 1 and 4). The motor pattern for each scratch form is generated centrally within the spinal cord. In the spinal immobilized preparation, neuromuscular blockade prevents both limb movement and phasic sensory input, and complete spinal transection isolates the cord from supraspinal input.(ABSTRACT TRUNCATED AT 400 WORDS)

The scratch reflex is a motor task exhibited by the hindlimb of a turtle after complete transection of the spinal cord just posterior to the forelimb enlargement. The scratch is elicited by applying gentle tactile stimulation to a site innervated by spinal segments caudal to the level of the transection. During the scratch response, the ipsilateral hindlimb reaches toward and rubs against the stimulated site. Each scratch response consists of either a single rub or a rhythmic series of rubs. There are three types or "forms" of the scratch reflex in the spinal turtle: rostral scratch (previously termed the scratch reflex in Refs. 5, 43, 45), pocket scratch, and caudal scratch. We have characterized each scratch form according to which portion of the hindlimb is used to rub against the stimulated site. During a rostral scratch, the dorsum of the foot and/or toes is used to rub against the stimulated site. During a pocket scratch, the side of the thigh, knee, and/or calf is used to rub. During a caudal scratch, the heel or side of the foot is used to rub. Each scratch form has a distinct receptive field on the turtle shell and skin. A rhythmic scratch response to maintained tactile stimulation consists of as many as 10-25 cycles. We have divided each cycle of movement into a prerub, rub, and postrub phase. Extension of the knee joint occurs during the rub phase of each scratch cycle for all scratch forms. The timing of the extension phase of the knee joint movement within the protraction-retraction (flexion-extension) cycle of the hip joint is different for each form of the scratch. During a rostral scratch, extension of the knee joint occurs when the hip is protracted. During a pocket scratch, knee extension occurs when the hip is retracting. During a caudal scratch, knee extension occurs when the hip is retracted. The spinal turtle therefore shifts the timing of movements of a distal joint (knee) with respect to the timing of movements of a proximal joint (hip) to obtain appropriate scratching movements to different regions of the body. A narrow transition zone exists between the receptive field for one form of the scratch and the nearby receptive field for another form of the scratch. There is a rostral-pocket transition zone and caudal-pocket transition zone in the spinal turtle.(ABSTRACT TRUNCATED AT 400 WORDS)

The immobilized, low-spinal turtle produces 3 forms of the fictive scratch reflex in response to tactile stimulation of specific sites on its body surface (Robertson et al., 1985). We used complete transections of the spinal cord at different rostrocaudal levels to reveal the minimum length of spinal cord sufficient to produce each scratch form. Additional transections revealed the progressive loss of elements of the motor pattern and the eventual loss of rhythmogenesis. We have identified, therefore, spinal cord segments containing key elements of each scratch form's central pattern generator (CPG). The turtle spinal cord consists of 8 cervical segments (C1-C8), 10 dorsal segments (D1-D10), 2 sacral segments (S1, S2) and about 16 caudal segments (Ca1-Ca16; Kusuma et al., 1979). The cell bodies of motor neurons innervating the hindlimb muscles are located in the hindlimb enlargement, segments D8-S2 (Ruigrok and Crowe, 1984). The receptive field for the rostral scratch is innervated by segments D3-D6; the pocket scratch receptive field is innervated by segments D6-D8; the caudal scratch receptive field is innervated by segments S2, Ca1, and more caudal segments (Mortin and Stein, 1985). A rostral scratch motor pattern could be produced with as few as 5 or 6 segments, i.e., segments D5-D9 or D3-D8. The anterior 3 segments of the hindlimb enlargement, D8-D10, could produce a pocket scratch motor pattern. A single segment, either D7 or D8, is capable of rhythmogenesis in response to stimulation of sites in its part of the pocket receptive field. A caudal scratch motor pattern could be produced by D8-End (the hindlimb enlargement and more caudal segments). The posterior 40-80% of the hindlimb enlargement is not necessary for the production of a rostral or pocket motor pattern. The anterior segment of the enlargement is necessary for the production of a normal caudal scratch motor pattern. Key elements of the CPG for each of the 3 scratch forms reside in segments D7-D10. The pattern-generating capacity of the anterior half of the hindlimb enlargement is greater than the posterior half; such an asymmetric distribution of pattern-generating elements in the enlargement of the spinal cord has been described for cat scratching (Deliagina et al., 1983). These results are consistent with the hypothesis that the CPGs producing different motor patterns for the hindlimb share neuronal elements (Grillner, 1981; Robertson et al., 1985; Currie and Stein, 1988, 1989).

CB-183,315 is a novel lipopeptide antibiotic structurally related to daptomycin currently in phase 3 clinical development for Clostridium difficile-associated diarrhea (CDAD). We report here the in vitro mechanism of action, spontaneous resistance incidence, resistance by serial passage, time-kill kinetics, postantibiotic effect, and efficacy of CB-183,315 in a hamster model of lethal infection. In vitro data showed that CB-183,315 dissipated the membrane potential of Staphylococcus aureus without inducing changes in membrane permeability to small molecules. The rate of spontaneous resistance to CB-183,315 at 8؋ the MIC was below the limit of detection in C. difficile. Under selective pressure by serial passage with CB-183,315 against C. difficile, the susceptibility of the bacteria changed no more than 2-fold during 15 days of serial passages. At 16؋ the MIC, CB-183,315 produced a >3-log reduction of C. difficile in the time-kill assay. The postantibiotic effect of CB-183,315 at 8؋ the MIC was 0.9 h. At 80؋ the MIC the postantibiotic effect was more than 6 h. In the hamster model of CDAD, CB-183,315 and vancomycin both demonstrated potent efficacy in resolving initial disease onset, even at very low doses. After the conclusion of dosing, CB-183,315 and vancomycin showed a similar dose-and time-dependent pattern with respect to rates of CDAD recurrence.