Laurel C. Preheim

Pneumococcal Vaccine Response in Cirrhosis and Liver Transplantation

Cirrhosis is a major risk factor for severe pneumococcal infection, and patients evaluated for liver transplantation routinely receive pneumococcal vaccine. This study followed serologic antibody levels of 45 adults evaluated for transplantation and 13 age-matched control subjects. All received 23-valent pneumococcal polysaccharide vaccine (PPS). Serum anti-PPS levels and antibodies specific for capsular types 3 and 23 were measured by ELISA before and 1 and 6 months after vaccination. Antibody levels for the 25 patients who received transplants also were measured immediately before and 3 months after transplantation. Control subjects had higher IgG responses to the whole vaccine, whereas patients appeared to produce more IgM and IgA. IgA, and possibly IgM levels, also declined faster in patients than in control subjects. All anti-PPS levels were at or below prevaccination baselines by 3 months after transplantation. These data suggest that vaccination with PPS may not be effective for patients during and after liver transplantation.

Emergence of resistance to beta-lactam and aminoglycoside antibiotics during moxalactam therapy of Pseudomonas aeruginosa infections.

In four patients with Pseudomonas aeruginosa infections, the infecting strain developed resistance to moxalactam during therapy with this drug. In addition, P. aeruginosa isolates from two of these four patients showed increased resistance to aminoglycosides. Isolates from a third patient acquired cross-resistance to other antipseudomonal beta-lactams. In three of the cases, disk susceptibility tests failed to detect the resistance that was demonstrated in broth dilution assays. Isolate identities were confirmed by serotyping. No new plasmids were found by agarose gel electrophoresis. The mechanisms for this resistance did not involve enzymatic antibiotic degradation. These findings suggest that currently available expanded-spectrum cephalosporin derivatives should probably not be used alone for most serious infections due to P. aeruginosa. They also suggest that strains with multiple antibiotic resistance may become more prevalent in hospitals if these drugs are used extensively.

Methicillin-resistant Staphylococcus aureus in Veterans Administration Medical Centers.

To determine the frequency of isolation of methicillin-resistant Staphylococcus aureus (MRSA) at Veterans Administration Medical Centers, 163 hospitals were surveyed; 137 responded. Between 1975 and 1984, the number of Veterans Administration Medical Centers with known MRSA increased from 3 to 111. This increase was geographically widespread and occurred in hospitals of all sizes. In Veterans Administration Medical Centers, isolation policies for MRSA-infected patients were (% of hospitals using): strict (19%), contact (52%), site-related (28%), no isolation (1%). For patients colonized with MRSA policies were: strict (15%), contact (44%), site-related (35%), and no isolation (6%). Only 41% of Veterans Administration Medical Centers reported discharging known MRSA-colonized patients to nursing homes. Most attempts to eradicate MRSA carriage used trimethoprim-sulfamethoxazole plus rifampin with or without bacitracin ointment; success rates were low. MRSA incidence is increasing at Veterans Administration Medical Centers across the United States. Improved regimens to eliminate MRSA carriage are needed.

Pharmacodynamic Activity and Efficacy of Linezolid in a Rat Model of Pneumococcal Pneumonia

ABSTRACT 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 × 107 CFU of a penicillin-sensitive (MIC, 0.032 μg/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.

Pneumolysin-Induced Complement Depletion during Experimental Pneumococcal Bacteremia

ABSTRACT To quantify complement depletion by pneumolysin duringStreptococcus pneumoniae bacteremia, cirrhotic and control rats were infected intravenously with one of three isogenic mutant strains of S. pneumoniae expressing different forms of pneumolysin. Outcome measures included clearance of the organisms from the bloodstream, alterations in 50% serum hemolytic complement (CH50) activity and complement C3 levels during infection, and serum opsonic capacity at 18 h postinfection. Cirrhotic rats had significantly lower CH50 and C3 levels than control rats, both before and after infection. However, initial complement levels did not predict bacterial load after 18 h of infection. Changes in CH50 and C3 levels over the 18-h period correlated with numbers of H+C+ but not H+C− or PLY− organisms in the bloodstream at 18 h postinfection. The sera of cirrhotic rats infected with the H+C+ strain had significantly decreased levels of C3 and showed significantly lower opsonizing activity for S. pneumoniaethan sera from H+C+-infected control rats. These studies suggest that under limiting concentrations of complement, the expression of pneumolysin by pneumococci has a significant, negative effect on serum complement levels and reduces serum opsonic activity.

Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae

BackgroundThe 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.ResultsNo 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.ConclusionIncreased 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.

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.

Randomized, double-blind comparison of ciprofloxacin and trimethoprim-sulfamethoxazole for complicated urinary tract infections.

In a prospective, randomized, double-blind study, the effect of ciprofloxacin (250 mg orally, twice daily) was compared with that of trimethoprim-sulfamethoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole orally, twice daily) on 45 patients with complicated urinary tract infections. Pretherapy isolates were all members of the family Enterobacteriaceae. Isolates were eradicated from 18 (82%) of 22 patients treated with ciprofloxacin and 12 (52%) of 23 patients treated with trimethoprim-sulfamethoxazole during and 5 to 9 days after therapy (P = 0.035). Both groups had similar relapse and reinfection rates at 4 to 6 weeks posttherapy. Adverse effects were mild and reversible, occurring in 1 of 22 in the ciprofloxacin group and 6 of 23 in the trimethoprim-sulfamethoxazole group. Disk diffusion susceptibility tests correlated better with broth macrodilution for ciprofloxacin than for trimethoprim-sulfamethoxazole. Ciprofloxacin is a safe, effective alternative to trimethoprim-sulfamethoxazole for the treatment of complicated urinary tract infections.

Ceftriaxone therapy of serious bacterial infections in adults.

We evaluated the efficacy and safety of ceftriaxone in 50 adults with serious infections, usually giving 1 g every 12 h. Of the 35 patients who could be evaluated for clinical efficacy, 15 had failed on previous therapy, 15 had nosocomial infections, and all but 1 had underlying diseases. One patient had three sites of infection. Favorable responses were seen in 34 of 37 infections, including 11 of 13 respiratory tract infections, all 7 urinary tract infections, all 12 skin and soft tissue infections, 1 of 2 bone and joint infections, a catheter-related septicemia, a liver abscess, and an otitis media and externa. Favorable bacteriological responses were seen for 48 of 58 organisms. This included 6 of 7 Staphylococcus aureus strains, 14 of 16 other aerobic gram-positive cocci, 18 of 20 Enterobacteriaceae, 6 of 9 Pseudomonas aeruginosa, and 1 of 2 anaerobes. Peak plasma ceftriaxone levels on day 1 were 152 micrograms/ml by bioassay and 78 micrograms/ml by high-pressure liquid chromatography. Four of the 31 initial isolates of aerobic gram-negative rods developed resistance to ceftriaxone on disk diffusion testing. Diarrhea occurred in 3 of 50 patients. All three had received a higher than usual dose. Drug administration was stopped twice, once for a thrombocytopenia and once for a thrombocytopenia with leukopenia. Neither problem could be attributed exclusively to ceftriaxone. Other adverse reactions were eosinophilia, abdominal pain, inguinal candidiasis, and nonsuppurative phlebitis. Even among debilitated adults, ceftriaxone was safe and effective in a twice daily regimen.

Complicated urinary tract infections

The distinction between complicated and uncomplicated urinary tract infections is usually based on the presence or absence of some abnormality in the path of urine flow. Other differences include characteristic patient profiles, usual setting, likely pathogens and their antimicrobial susceptibility, and treatment options. Complicated infections are most common in older patients, usually men with prostatic enlargement. Gram-negative bacilli are the most frequent pathogens, but Escherichia coli plays a less dominant role. Isolates from patients with complicated infections are more likely to be resistant to older antibiotics, and therapy is usually parenteral. Many complicated urinary tract infections are hospital-acquired, and are often due to indwelling urinary catheters. Resistance to antimicrobials among isolates is common in this setting. Nosocomial urinary tract infections contribute substantially to morbidity, mortality, and health care costs. Numerous effective treatment options are available for uncomplicated infections. The types of patients, predisposing factors, and organisms limit antimicrobial choices for complicated infections. Although new antibiotics offer certain advantages, final therapeutic success usually depends on resolving the disorder that predisposes the patient to infection.