Penicillin pharmacodynamics in four experimental pneumococcal infection models

Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates of Streptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 microg/ml and the other for which the penicillin MIC was 1.0 microg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (C(max)s) and times that the concentrations were greater than the MIC (T(>MIC)s). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T(>MIC) and to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (approximately 6 log10 CFU/ml), followed by the thigh (approximately 3 log10 CFU/thigh), and being the lowest in the lung (approximately 1 log10 CFU/lung). In the rabbit model the maximal effect was approximately 6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T(>MIC) was > or =65% of the experimental time and C(max) was > or =15 times the MIC, and in the rabbit model bactericidal activity became marked when T(>MIC) was > or =35%, Cmax was > or =5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio and T(>MIC), the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.     

Gemifloxacin is effective in experimental pneumococcal meningitis

In a rabbit model of Streptococcus pneumoniae meningitis, 5 mg of gemifloxacin mesylate (SB-265805) per kg/h reduced the bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as 10 mg of ceftriaxone per kg/h (Deltalog CFU/ml/h +/- standard deviation [SD], -0.25 +/- 0.09 versus -0.38 +/- 0.11; serum and CSF concentrations of gemifloxacin were 2.1 +/- 1.4 mg/liter and 0.59 +/- 0.38 mg/liter, respectively, at 24 h). Coadministration of 1 mg of dexamethasone per kg did not affect gemifloxacin serum and CSF levels (2.7 +/- 1.4 mg/liter and 0.75 +/- 0.34 mg/liter, respectively, at 24 h) or activity (Deltalog CFU/ml/h +/- SD, -0.26 +/- 0.11).     

BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis

BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intracisternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 microg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0.81 +/- 0.38, and 1.08 +/- 0.43 microg/ml, respectively; the elimination half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were -0.84 +/- 0.48, -1.09 +/- 0.32, and -1.35 +/- 0.05 Deltalog(10) CFU/ml/h. The BKR(0-5) of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.82 +/- 0.52 and -1.24 +/- 0.34 Deltalog(10) CFU/ml/h, respectively. The BKR(0-5) of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0.39 Deltalog(10) CFU/ml/h. The penetration of BMS-284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone.     

The physiology of recovery in experimental pneumococcal pneumonia

Lobar distribution of pulmonary perfusion, arterial PO2 (PaO2), intrapulmonary shunt (Qs/Qt) and post mortem lobe wts were measured in 12 dogs with experimental lobar pneumococcal pneumonia. Six dogs (group I) had both perfusion and gas exchange measurements performed 48 h after an inoculum of Streptococcus pneumoniae was placed in a left lower lobe bronchus. Six other dogs (group II) had perfusion determinations before the induction of pneumonia and again 96 h after inoculation, at which time gas exchange measurements were performed. To ensure that group II dogs were recovering from the acute pneumonia, penicillin treatment was instituted at 48 h and continued until the time of study at 96 h. An improvement in gas exchange between the acute and convalescent states was demonstrated and was associated with a 50% reduction in excess wet wt and a 25% reduction in perfusion of the infected lower lobe. We conclude that improvement in gas exchange during recovery from acute lobar pneumonia is due, in part, to air space clearing with improved ventilation and, in part, to reduced perfusion of poorly ventilated lung. The results suggest that arterial hypoxemia in acute pneumonia is aggravated by vasodilatation or blockade of local hypoxic vasoconstriction by some aspect of the acute inflammatory response, and that the hypoxic vasoconstrictor response is restored during convalescence.     

Gingivitis and cellulitis in diffuse pneumococcal infection

Gingivitis occurring with a cystic lesions in young patients with facial cellulitis is highly suggestive of a pneumococcal etiology. Two cases of pneumococcal cellulitis and gingivitis with bacteremia are reported, and the pertinent literature is reviewed.     

Rifampin for therapy of experimental pneumococcal meningitis in rabbits.

Rifampin at a maximally effective dose was less active than ceftriaxone (both drugs at 10 mg/kg of body weight.h) in a rabbit model of pneumococcal meningitis (delta log10 CFU/ml.h, -0.40 +/- 0.13 versus -0.77 +/- 0.18; P < 0.01). The bactericidal activity of rifampin decreased at concentrations in cerebrospinal fluid greater than those that are clinically achievable, and use of rifampin in combination with ofloxacin had no synergistic or additive effect.     

The role of the spleen in experimental pneumococcal bacteremia.

The importance of the spleen in host defense against pneumococcal bacteremia has been suggested by a number of experimental models as well as the occurrence of the syndrome of overwhelming pneumococcal sepsis in asplenic individuals. We studied the mechanism of splenic protection against pneumococcal bacteremia using a guinea pig model. Rates of removal of pneumococci from the blood stream in normal and splenectomized guinea pigs were compared with the extent of hepatic and splenic sequestration of radiolabeled organisms for three different types of pneumococci. A relationship was found between the virulence of a pneumococcus for normal guinea pigs, the extent to which it is cleared by the spleen, and the magnitude of the defect in blood stream sterilization induced by splenectomy. The spleen plays an increasingly important role in the clearance of progressively more virulent organisms, for which hepatic clearance cannot compensate. Thus, the division between hepatic and splenic clearance of bacteremia is a key determinant of the outcome of experimental pneumococcal infection.     

Reduction of intracranial pressure by nimodipine in experimental pneumococcal meningitis

OBJECTIVE: In this study, we investigated the effect of the calcium channel blocker nimodipine on the pathophysiologic alterations during experimental pneumococcal meningitis in rats. DESIGN: Prospective, controlled trial. SETTING: University center, animal laboratory. SUBJECTS: A total of 37 adult male Wistar rats (290-360 g). INTERVENTIONS: Meningitis was induced by the intracisternal injection of pneumococci. Anaesthetized animals were treated with nimodipine (30 microg/kg/hr iv) either 15 mins before (pretreatment) or 5 hrs after (posttreatment) pneumococcal challenge. MEASUREMENTS AND MAIN RESULTS: Treatment with nimodipine (30 microg/kg/hr iv) significantly decreased the pneumococci-induced rise in intracranial pressure irrespective of the time of administration. Moreover, pretreament with nimodipine also significantly reduced the pneumococci-induced increase in cerebrospinal fluid white blood cell counts. To ascertain possible mechanisms of the beneficial effect, we investigated the influence of nimodipine on reactive oxygen species (ROS) and cytokine production. By using lucigenin-enhanced chemiluminescence, we found that nimodipine inhibited the pneumococci-induced production of ROS in human whole blood samples. Moreover, nimodipine significantly reduced the pneumococci-induced increase in the interleukin-6 concentrations in the cerebrospinal fluid. CONCLUSION: Our results demonstrate that nimodipine decreases the intracranial pressure during experimental pneumococcal meningitis, possibly by mechanisms including the reduction of ROS and interleukin-6 production.     

The immune response to pneumococcal proteins during experimental human carriage

Colonization of the nasopharynx is the initial step in all infections caused by Streptococcus pneumoniae. The antibody response to carriage was examined in an experimental model of human colonization in healthy adults. Asymptomatic colonization was detected in 6/14 subjects and continued for up to 122 d. Susceptibility to carriage did not correlate with total serum immunoglobulin (Ig)G to the homotypic capsular polysaccharide. All of the colonized subjects, in contrast, developed a serum IgG and secretory IgA response to a 22 kD protein, whereas 7 of 8 subjects who did not become colonized had preexisting antibody to this protein. Analysis of the 22 kD protein identified it as the NH(2)-terminal region of pneumococcal surface protein A (PspA). Our findings provide evidence for the role of antibody to this protein fragment in preventing pneumococcal carriage by humans.     

Quinolone antibiotics in therapy of experimental pneumococcal meningitis in rabbits.

Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the beta-lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg.h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (delta log10 CFU/ml.h, +0.20 +/- 0.14). Ofloxacin (delta log10 CFU/ml.h, -0.13 +/- 0.12), temafloxacin (delta log10 CFU/ml.h, -0.19 +/- 0.18), and levofloxacin (delta log10 CFU/ml.h, -0.24 +/- 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (delta log10 CFU/ml.h, -0.59 +/- 0.21) and Win 57273 (delta log10 CFU/ml.h, -0.72 +/- 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg.h (delta log10 CFU/ml.h, -0.80 +/- 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone.     

Monovalent latex agglutination reagents for the diagnosis of nonmeningitic pneumococcal infection

The pneumococcus is a leading cause of serious bacterial infection worldwide. Given the difficulties with available assays for the diagnosis of invasive nonmeningitic pneumococcal infection, we evaluated monovalent slide latex agglutination reagents among patients with blood culture-confirmed pneumococcal infection and control patients in Baltimore, Maryland, USA; São Paulo, Brazil; and Cairo, Egypt. Among 50 patients with invasive nonmeningitic pneumococcal infection, 23 had a positive urine test for a sensitivity of 46% (95% confidence intervals of 32% and 61%). Among 39 healthy children, 36 had a negative assay, for a specificity of 92% (95% confidence intervals of 78% and 98%). Among 80 children with pneumonia without a positive blood culture for Streptococcus pneumoniae, the specificity was 88% (95% confidence intervals of 78% and 94%). Although the assay was fairly specific, the positive predictive value using optimistic assumptions was only 73%–83%. This study suggests that this assay has a sensitivity and positive predictive value that may limit its value in some settings.     

Protection against systemic fatal pneumococcal infection by maternal intranasal immunization with pneumococcal surface protein A (PspA)

Streptococcus pneumoniae is a leading causative pathogen responsible for various types of bacterial infectious diseases in children. The aim of this study was to evaluate the protection conferred against fatal pneumococcal infections during infancy by maternal intranasal immunization with pneumococcal surface protein A (PspA). Four-week-old female BALB/c mice were immunized with PspA mixed with, or without, cholera toxin B (CTB) intranasally twice a week for 3 weeks. After the final immunization, they were mated with male mice to obtain offspring. Offspring at 10 days old were intraperitoneally inoculated with a pneumococcus strain, TIGR4, serotype 4. After the infections their survival periods were monitored. Anti-PspA-specific IgG antibody was induced in sera and breast milk at birth and maintained for 14 days during nursing periods in the PspA-immunized mother mice. At birth, offspring delivered from PspA-immunized mother mice had levels of anti-PspA-specific IgG antibody in sera same to those in their mothers on the day of birth. The survival times to death of offspring delivered from PspA-immunized mother mice after systemic fatal pneumococcal infections were significantly extended compared to those of controls. These findings suggest that maternal intranasal immunization with PspA could be an attractive procedure to employ against pneumococcal infections in early childhood.     

Pharmacokinetics and bacteriological efficacies of apalcillin and cefpiramide in experimental pneumococcal meningitis

Rabbits with experimentally induced pneumococcal meningitis were given single 25-mg/kg doses of apalcillin or cefpiramide. Mean percentages of the drug concentration in cerebrospinal fluid versus that in blood serum were 7.6% with apalcillin and 3.9% with cefpiramide. Bactericidal activity in cerebrospinal fluid resulted in mean reductions of from 4 to 5 log10 CFU/ml, and cerebrospinal fluid cultures became sterile for four of six animals treated with each drug.     

Evaluation of anti-pneumococcal capsular antibodies as adjunctive therapy in experimental pneumococcal meningitis

OBJECTIVE: Bacteraemia concomitant with meningitis has been shown to greatly affect outcome. Consequently, the efficacy of serotype-specific anti-pneumococcal antiserum (APAS) was investigated in a rat model of pneumococcal meningitis. METHODS: Rats were infected with Streptococcus pneumoniae serotype 3. All rats received ceftriaxone starting 26 h post-infection. APAS was administered either at the time of infection or 26 h post-infection and effects were compared with rats treated with antibiotics only. RESULTS AND CONCLUSION: A significant clinical benefit was found when APAS was given at the time of infection whereas no effect was found when administered 26 h after infection. This work indicates that the clinical value of using APAS in pneumococcal meningitis may be limited.     

Evaluation of combined ceftriaxone and dexamethasone therapy in experimental cephalosporin-resistant pneumococcal meningitis

The treatment of meningitis caused by strains of Streptococcus pneumoniae with decreased susceptibility to third-generation cephalosporins is an increasingly frequent and difficult problem. In this study a rabbit model of meningitis was used to determine the efficacy of ceftriaxone at different dosages, and to establish the effect of the addition of dexamethasone to the chemotherapeutic regimen. Groups of eight rabbits were inoculated with 10(6) cfu/mL of a cephalosporin- resistant strain of S. pneumoniae (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours after inoculation, ceftriaxone (50 or 100 mg/kg/day) with or without dexamethasone (0. 25 mg/kg/ day) was administered for a period of 48 h. The ceftriaxone dose of 50 mg/kg/day was not fully effective in this model (therapeutic failure rate 28%). With a dose of 100 mg/kg/day there were no therapeutic failures and all CSF cultures were below the level of detection at 48 h. CSF ceftriaxone concentrations, area under the time-concentration curve and time above the MIC were not significantly different with or without dexamethasone. However, concomitant use of dexamethasone resulted in higher CSF bacterial counts and a higher number of therapeutic failures (57% with the 50 mg/kg/day dose and 28% with the 100 mg/kg/day dose). Increasing doses of ceftriaxone might be an effective mode of therapy for meningitis caused by S. pneumoniae with MIC 相似文献