Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae.

BACKGROUND: The risk of mortality from pneumonia caused by Streptococcus pneumoniae is increased in patients with cirrhosis. However, the specific pneumococcal virulence factors and host immune defects responsible for this finding have not been clearly established. This study used a cirrhotic rat model of pneumococcal pneumonia to identify defect(s) in innate pulmonary defenses in the cirrhotic host and to determine the impact of the pneumococcal toxin pneumolysin on these defenses in the setting of severe cirrhosis. RESULTS: No cirrhosis-associated defects in mucociliary clearance of pneumococci were found in these studies, but early intrapulmonary killing of the organisms before the arrival of neutrophils was significantly impaired. This defect was exacerbated by pneumolysin production in cirrhotic but not in control rats. Neutrophil-mediated killing of a particularly virulent type 3 pneumococcal strain also was significantly diminished within the lungs of cirrhotic rats with ascites. Levels of lysozyme and complement component C3 were both significantly reduced in bronchoalveolar lavage fluid from cirrhotic rats. Finally, complement deposition was reduced on the surface of pneumococci recovered from the lungs of cirrhotic rats in comparison to organisms recovered from the lungs of control animals. CONCLUSION: Increased mortality from pneumococcal pneumonia in this cirrhotic host is related to defects in both early pre-neutrophil- and later neutrophil-mediated pulmonary killing of the organisms. The fact that pneumolysin production impaired pre-neutrophil-mediated pneumococcal killing in cirrhotic but not control rats suggests that pneumolysin may be particularly detrimental to this defense mechanism in the severely cirrhotic host. The decrease in neutrophil-mediated killing of pneumococci within the lungs of the cirrhotic host is related to insufficient deposition of host proteins such as complement C3 on their surfaces. Pneumolysin likely plays a role in complement consumption within the lungs. Our studies, however, were unable to determine whether pneumolysin more negatively impacted this defense mechanism in cirrhotic than in control rats. These findings contribute to our understanding of the defects in innate pulmonary defenses that lead to increased mortality from pneumococcal pneumonia in the severely cirrhotic host. They also suggest that pneumolysin may be a particularly potent pneumococcal virulence factor in the setting of cirrhosis.

Streptococcus Gordonii Empyema: A Case Report and Review of Empyema.

Streptococcus gordonii (S. gordonii) is a pioneer oral bacteria that is recognized as an agent of bacterial endocarditis. However, an extensive review of the literature revealed no reported case of S. gordonii causing empyema. We present a case of a 65-year-old male who presented with respiratory distress. Physical examination revealed several dental caries with decreased breath sounds in the bibasilar regions. A computed tomography (CT) scan of the chest and abdomen demonstrated left-sided pleural effusion and a 4.3 cm x 2.8 cm splenic abscess. He received intravenous (IV) antibiotics, and his blood cultures remained negative. Drainage of the splenic abscess grew S. gordonii. A CT-guided thoracentesis yielded 450 ml of exudative fluid. Pleural fluid cultures grew S. gordonii. A CT scan of the head and neck ruled out an intra-oral abscess. He received six weeks of IV penicillin with a follow-up CT scan showing resolution of both the splenic abscess and the left parapneumonic effusion.

Other Slow-Growing Nontuberculous Mycobacteria.

The list of clinically important slow-growing nontuberculous mycobacteria (NTM) continues to expand as new species are identified and older ones are found to be pathogenic. Based on pigment production, the strains may be classified as photochromogenic, scotochromogenic, or unpigmented. Some of these organisms are not newly discovered but have heretofore been considered virtually nonpathogenic. Previously, many were regarded as contaminants when isolated from clinical specimens. Ubiquitous in nature, many NTM have been isolated from groundwater or tap water, soil, house dust, domestic and wild animals, and birds. Most infections result from inhalation or direct inoculation from environmental sources. They are not spread from person to person. The infections may be localized or disseminated. In most cases, the optimal regimen or duration of therapy has not been firmly established. The results of in vitro susceptibility testing may be used to select a therapeutic regimen. Many experts recommend clarithromycin with companion drugs such as rifampin and ethambutol for most, but not all, slowly growing species. Aminoglycosides, clofazimine, fluoroquinolones, linezolid, pyrazinamide, or trimethoprim-sulfamethoxazole also may be effective against some strains. Immunocompetent patients with clinically significant infections with NTM usually should receive 18 to 24 months of therapy. Infected immunocompromised patients, particularly those with disseminated infection, probably should receive therapy as long as their immune systems remain impaired. Some of the species discussed include Mycobacterium alsiense, M. celatum, M. gordonae, M. haemophilum, M. kyorinense, M. malmoense, M. simiae complex, M. szulgai, M. terrae complex, M. ulcerans, and M. xenopi.

Education and Communication in an Interprofessional Antimicrobial Stewardship Program.

CONTEXT: Interprofessional education/interprofessional practice (IPE/IPP) is an essential component in medical education and training. A collaborative interprofessional team environment ensures optimal patient-centered care. OBJECTIVE: To describe the implementation of 2 interprofessional antimicrobial stewardship program (ASP) teams using IPE/IPP and to assess the acceptance rate by the primary medical and surgical teams of ASP recommendations for antimicrobial interventions. METHODS: A business plan for the ASP was approved at 2 academic medical centers used for the present study. During a 3-year study period, 2 interprofessional ASP teams included an attending physician specializing in infectious disease (ID), an ID physician fellow, an ASP pharmacist, physician residents, medical students, pharmacy residents, and pharmacy students. Educational seminars were presented for all adult-admitting physicians to discuss the need for the ASP and the prospective audit and feedback process. Cases were presented for discussion during ASP/ID rounds and recommendations were agreed upon by the ASP team. A motivational interviewing face-to-face technique was frequently used to convey the ASP team recommendation to the primary medical or surgical team in a noncoercive and educational manner. The ASP team recommendations for ASP interventions were documented in the medical records. RESULTS: The overall acceptance rate of recommendations by the primary medical and surgical teams were greater than 90% (2051 of 2266). The most frequent interventions provided were streamline therapy (601), route of administration change (452), bug-drug mismatch (190), and discontinuation of therapy (179). Route of administration change was also the most frequently accepted intervention (96%). CONCLUSIONS: The motivational face-to-face communication technique was particularly useful in conveying ASP team member recommendations to the primary medical or surgical teams. Communicating recommendations as a multidisciplinary team in an educational manner seems to have resulted in to greater acceptance of recommendations.

Effect of cirrhosis on antibiotic efficacy in a rat model of pneumococcal pneumonia.

A rat model was used to study the effects of cirrhosis on antibiotic therapy of pneumococcal pneumonia. Cirrhotic and control male Sprague-Dawley rats were infected transtracheally with type 3 Streptococcus pneumoniae. Treatment began 18 h later with phosphate-buffered saline (PBS), azithromycin (50 mg/kg), trovafloxacin (50 mg/kg), or ceftriaxone (100 mg/kg) injected subcutaneously twice daily for 5 days. Antibiotic concentrations were measured by high-performance liquid chromatography. Azithromycin, trovafloxacin, and ceftriaxone were all equally effective at preventing mortality in both cirrhotic and normal rats. Free fraction area under the curve to minimum inhibitory concentration ratio (AUC/MIC) and maximum calculated serum concentration to MIC ratio (C(max)/MIC) and percent time that the serum concentration exceeded the MIC (%T > MIC) were greater for ceftriaxone compared with azithromycin or trovafloxacin. Azithromycin achieved higher concentrations in bronchoalveolar lavage fluid (BALF), epithelial lining fluid (ELF), and BAL white blood cells than ceftriaxone or trovafloxacin in cirrhotic rats. Macrolide, beta-lactam, or fluoroquinolone antibiotic efficacy in a pneumococcal pneumonia model does not appear to be affected by hepatic cirrhosis.

Effect of ethanol on fluoroquinolone efficacy in a rat model of pneumococcal pneumonia.

This investigation compared the effect of ethanol on fluoroquinolone antibiotic efficacy and pharmacodynamics in an ethanol-fed rat model of pneumococcal pneumonia. Male Sprague-Dawley rats received a liquid diet containing 36% of total calories as ethanol. Paired controls (pair-fed controls) were fed a liquid diet without ethanol or received rat chow. Diets began 7 days before and continued for 10 days after transtracheal infections with 10 times the 50% lethal dose of type 3 Streptococcus pneumoniae. Beginning 18 h after infection, the rats received once daily subcutaneous phosphate-buffered saline, levofloxacin, moxifloxacin, or trovafloxacin at 50 or 100 mg/kg of body weight. White blood cell counts were determined, blood samples were collected for culture, and mortality was recorded. Additional rats were killed on day 5 for pharmacodynamic studies and quantitative cultures of bronchoalveolar lavage fluid. Bacteremia occurred by day 3 in 20 of 22 untreated rats. All 22 untreated rats died by day 9. Moxifloxacin treatment was effective in all diet groups at both the 50- and 100-mg/kg doses. In contrast, 50-mg/kg doses of levofloxacin and trovafloxacin improved survival in ethanol-fed rats but were ineffective in chow-fed rats. High-dose trovafloxacin at 100 mg/kg was associated with increased mortality in pair-fed rats. The free-fraction area under the concentration-time curve/MIC ratio exceeded 50 with all antibiotics in the ethanol group but dropped below 30 with levofloxacin and trovafloxacin in the pair- and chow-fed rats, with higher mortality. Achievement of adequate antibiotic-free fraction area under the concentration-time curve/MIC ratios helps overcome ethanol-induced immune defects induced in experimental pneumococcal pneumonia.

Pharmacodynamic activity and efficacy of linezolid in a rat model of pneumococcal pneumonia.

Linezolid is a new oxazolidinone antibiotic with potent activity against gram-positive bacteria, including Streptococcus pneumoniae. The pharmacodynamic activity and in vivo efficacy of linezolid were compared to those of ceftriaxone in an immunocompetent rat model of pneumococcal pneumonia. Rats infected intratracheally with 8 x 10(7) CFU of a penicillin-sensitive (MIC, 0.032 microg/ml) strain of S. pneumoniae were treated for 5 days beginning 18 h postinfection. Groups of rats were sham treated with oral phosphate-buffered saline or received oral liquid linezolid at 25 or 50 mg/kg of body weight twice a day (b.i.d.) or subcutaneous ceftriaxone at 100 mg/kg once daily. Mortality was monitored for 10 days postinfection; blood culturing was performed on day 1 (pretreatment) and on days 3, 5, and 10 postinfection for the determination of bacteremia. Serum also was collected for the determination of pharmacokinetic and pharmacodynamic parameters at 30 min and at 3, 5, and 12 h (linezolid) or 3, 5, and 24 h (ceftriaxone) postdose. The cumulative mortality rates were 100% for the sham-treated group, 58.3% for the low-dose linezolid group, 8.3% for the high-dose linezolid group, and 0% for the ceftriaxone group. Rats in each of the antibiotic treatment groups had significantly fewer bacteria (P < 0.00001) in their bronchoalveolar lavage fluid (BALF) on day 3 postinfection than sham-treated rats. There also were significantly fewer organisms in the BALF of rats treated with ceftriaxone than in the BALF of rats treated with either dose of linezolid. Oral linezolid at 50 mg/kg b.i.d. therefore was as effective as ceftriaxone in experimental pneumococcal pneumonia, whereas the 25-mg/kg b.i.d. dose was significantly less effective. All pharmacodynamic parameters reflected efficacy and were significantly different for the two dosage regimens of linezolid (P < 0.01). However, the free-fraction pharmacodynamic parameters predictive of outcome were a value of >39% for the percentage of time in the experimental dosing interval during which the linezolid concentration exceeded the MIC and a value of >147 for the ratio of the area under the serum concentration-time curve to the MIC.

Efficacy of liposome-encapsulated ciprofloxacin compared with ciprofloxacin and ceftriaxone in a rat model of pneumococcal pneumonia.

Encapsulation of ciprofloxacin in sterically stabilized liposomes results in a prolonged circulation time and improved pharmacokinetics. Liposome-encapsulated ciprofloxacin was compared with conventional ciprofloxacin and ceftriaxone in a rat model of pneumococcal pneumonia. Male Sprague-Dawley rats were infected transtracheally with type 3 Streptococcus pneumoniae and then treated with intravenous ceftriaxone (100 mg/kg), ciprofloxacin (40 or 80 mg/kg) or liposomal ciprofloxacin (40 or 80 mg/kg) administered once or twice daily for 3 days. White blood counts, development of bacteraemia and mortality were measured for 10 days. Antibiotic concentrations in serum, lung lavage fluid and white blood cells recovered from lung lavage fluid were determined. Liposomal ciprofloxacin concentrations were significantly higher in serum and lavage fluid compared with conventional ciprofloxacin, resulting in greater area under the serum concentration-time curve and maximum serum concentration. Despite these higher concentrations, survival rates were similar between groups treated with equivalent doses of liposomal ciprofloxacin versus ciprofloxacin. When antibiotics were given once daily, ceftriaxone was more effective than either form of ciprofloxacin.

A rat model to determine the biomedical consequences of concurrent ethanol ingestion and cigarette smoke exposure.

BACKGROUND: Although scientists have used animal models for years to study the effects of ethanol (EtOH) ingestion on humans, the compounding effect of cigarette smoking has been virtually ignored. Because 80 to 95% of human alcoholics smoke, it is imperative to consider the added effects of smoking when trying to determine the consequences of excessive alcohol ingestion. We therefore have developed a rat model for studying the separate and combined results of smoking and drinking on human health. METHODS: Male Sprague-Dawley rats were exposed daily for 12 weeks in whole-body chambers to cigarette smoke (smoke-exposed) or room air (sham-exposed). During the final 5 weeks of exposure, the rats were fed liquid diets that contained 0, 16, 26, or 36% EtOH calories. Smoke exposure was quantified by measurement of carboxyhemoglobin, nicotine, and cotinine levels. Body weights, food consumption, blood EtOH concentrations, and various assessments of liver damage and function also were followed. RESULTS: Smoke exposure in this rat model approximates that of a moderate to heavy human smoker. Smoke-exposed rats weighed significantly less and ate less food than sham-exposed controls, but both groups ingested equivalent amounts of EtOH for their body weights and had comparable blood EtOH levels. Liver aspartate and alanine aminotransferase levels remained normal. There was an EtOH-induced decrease in asialoglycoprotein receptor binding, but it was not exacerbated by smoke exposure. Alterations in blood cholesterol levels reflected what has been reported for humans, rising with increasing EtOH ingestion and decreasing with smoke exposure. CONCLUSION: Our rat model is relevant to what transpires in the vast majority of alcoholics. Both ethanol ingestion and smoke exposure can be manipulated to mimic light to moderate to heavy levels, making it appropriate for studying the separate and combined biomedical consequences of alcohol abuse and cigarette smoking.