Neal H. Steigbigel

Association of Streptococcus bovis with carcinoma of the colon.

Two patients with colonic adenocarcinoma and Streptococcus bovis endocarditis suggested a possible association between the two. Non-enterococcal Group D streptococci were isolated from fecal cultures of 11 of 105 controls, 35 of 63 patients with carcinoma of the colon, seven of 25 with inflammatory bowel disease, four of 21 with non-colonic neoplasms and five of 37 with other gastrointestinal disorders. All such streptococci examined for lactose fermentation were S. bovis. The prevalence of S. bovis in fecal cultures from patients with carcinoma of the colon was significantly increased (P less than 0.001) as compared to that in controls, and also to all other groups (P less than 0.001). No other group had results significantly different from those of controls (P less than 0.05) although patients with inflammatory bowel disease were more frequently carriers. The carrier state was unrelated to age, hospitalization status, colonic stasis, gastrointestinal bleeding or recent barium-enema examination. The implications of this association are unknown.

Immunodeficiency in Female Sexual Partners of Men with the Acquired Immunodeficiency Syndrome

Because the current outbreak of acquired immunodeficiency syndrome (AIDS) among previously healthy adults may be caused by a transmissible biologic agent, and because it may be preceded by immunologic abnormalities with or without a prodromal illness, we studied seven female sexual partners of male patients with the syndrome. The male patients were all drug abusers. One of the seven women was found to have the full-blown syndrome, a second had an illness consistent with the prodrome of AIDS (generalized lymphadenopathy, lymphopenia, and a decreased ratio of helper to suppressor T cells), and four others had generalized lymphadenopathy or lymphopenia, with or without a decreased ratio of helper to suppressor T cells. Only one woman had no abnormalities. These findings suggest that AIDS may be transmitted between heterosexual men and women.

Streptococcus bovis Septicemia and Carcinoma of the Colon

We prospectively studied patients with Streptococcus bovis septicemia for the presence of gastrointestinal lesions. This study was prompted by our reported findings of the association of fecal carriage of S. bovis with carcinoma of the colon. We studied 29 patients with 30 episodes of S. bovis septicemia. Fifteen completed gastrointestinal evaluations that included colonscopy, surgery, or autopsy. Eight of these had carcinoma of the colon, three had adenomatous polyps of the colon without carcinoma, and two had carcinoma of the esophagus. The 14 patients who did not have complete evaluations included one each with carcinoma of the stomach, gastric lymphoma, and adenomatous polyp of the colon and three with colonic masses not further delineated. Nineteen patients had no gastrointestinal signs or symptoms or stools positive for occult blood at admission. The results of our study suggest that all patients with S. bovis septicemia need aggressive evaluation of the gastrointestinal tract, especially the colon.

Septicemia in Patients on Chronic Hemodialysis

Bacterial sepsis, a major complication of chronic hemodialysis, is due mainly to infections of the vascular access site despite increasing use of internal fistulas. Sixty episodes of septicemia occurred in two chronic dialysis centers, with an incidence of 0.15 episodes of significant bacteremia per patient-dialysis-year in each. Forty-four of the 60 episodes were judged to be due to vascular access site infection by clinical, bacteriologic, and histologic criteria. Seventy percent (31 of 44) of the vascular access site-related episodes were due to staphylococci and 25% (11 of 44) to Gram-negative bacilli; nonvascular access site-related episodes were often due to transplant site infections caused by Gram-negative bacilli or streptococci. Mortality was about 18% in both vascular access site-related and nonrelated septic episodes. Bovine heterograft arteriovenous fistulas more often led to sepsis than did Brescia arteriovenous fistulas. Treatment with appropriate antibiotics was successful in most cases. Routine removal or ligation of the vascular access site was not necessary.

ACUTE (ASCENDING) CHOLANGITIS

Cholangitis is an infection of an obstructed biliary system, most commonly due to common bile duct stones. Bacteria reach the biliary system either by ascent from the intestine or by the portal venous system. Once the biliary system is colonized, biliary stasis allows bacterial multiplication, and increased biliary pressures enable the bacteria to penetrate cellular barriers and enter the bloodstream. Patients with cholangitis are febrile, often have abdominal pain, and are jaundiced. A minority of patients present in shock with hypotension and altered mentation. There is usually a leukocytosis, and the alkaline phosphatase and bilirubin levels are generally elevated. Noninvasive diagnostic techniques include sonography, which is the recommended initial imaging modality. Standard CT, helical CT cholangiography, and magnetic resonance cholangiography often add important information regarding the type and level of obstruction. Endoscopic sonography is a more invasive means of obtaining high-quality imaging, and endoscopic or percutaneous cholangiography offers the opportunity to perform a therapeutic procedure at the time of diagnostic imaging. Endoscopic modalities currently are favored over percutaneous procedures because of a lower risk of complication. Treatment includes fluid resuscitation and antimicrobial agents that cover enteric flora. Biliary decompression is required when patients do not rapidly respond to conservative therapy. Definitive therapy can be performed by a surgical, percutaneous, or endoscopic route; the last is favored because it is the least invasive and has the lowest complication rate. Overall prognosis depends on the severity of the illness at the time of presentation and the cause of the biliary obstruction.

Gentamicin Uptake in Wild-Type and Aminoglycoside-Resistant Small-Colony Mutants of Staphylococcus aureus

Gentamicin uptake and killing were studied in aminoglycoside-susceptible wild-type Staphylococcus aureus strains and aminoglycoside-resistant small-colony mutants selected by gentamicin from these strains. In wild-type S. aureus three phases of gentamicin accumulation were noted, and killing occurred during the last and most rapid phase of uptake. Uptake and killing were abolished by anaerobic growth and sodium azide, suggesting that energy-dependent active drug transport required respiration. Treatment of wild-type strains with the uncouplers N,N′-dicyclohexyl carbodiimide (DCCD) and carbonyl cyanide-m-chlorophenyl hydrazone showed disparate effects on gentamicin uptake, producing enhanced and diminished accumulations, respectively. Small-colony mutants demonstrated markedly deficient uptake compared with the wild-type strains and were not killed by gentamicin in concentrations up to 10 μg/ml. Several classes of aminoglycoside-resistant mutant strains are described. One mutant strain was a menadione auxotroph which, when grown in the presence of menadione, exhibited normal gentamicin uptake and killing. Gentamicin uptake and killing in this strain were abolished by KCN when the strain was grown in a medium supplemented with menadione. The membrane adenosine triphosphatase inhibitor DCCD was lethal for this mutant but not for other mutants or wild-type strains. Preincubation with menadione prevented the lethal effect of DCCD, and this strain demonstrated normal gentamicin accumulation when exposed to both DCCD and menadione. A second mutant strain demonstrated both gentamicin uptake and killing in the presence but not the absence of DCCD. Studies with small-colony mutants of S. aureus indicated that the defect in aminoglycoside uptake is very likely related to an inability to generate or maintain energized membranes from respiration. These studies suggest that the membrane energization associated with active aminoglycoside accumulation requires electron transport for the generation of a protonmotive force.

Single and Combination Antibiotic Therapy of Staphylococcus aureus Experimental Endocarditis: Emergence of Gentamicin-Resistant Mutants

The efficacy of nafcillin and gentamicin used alone and in combination at doses giving serum concentrations comparable to those achieved in patients was studied in rabbits with experimental Staphylococcus aureus endocarditis. The organism used was a penicillinase-producing, methicillin-susceptible, clinical isolate. The addition of gentamicin to nafcillin significantly increased the rate of killing of organisms in valvular vegetations, compared to the effect of nafcillin alone. Gentamicin alone delayed mortality but was not effective in reducing the bacterial populations of the vegetations. Bacteremia persisted in the animals treated with gentamicin alone, in contrast to the groups treated with nafcillin or the combination. Selection of a subpopulation of aminoglycoside-resistant small-colony variants occurred in animals treated with gentamicin alone. This variant was subsequently employed in the rabbit model and produced endocarditis, metastatic infection, and bacteremia comparable to those caused by the parent strain. Animals with infection produced by the variant died later than animals infected by the parent strain. Nafcillin was equally effective in reducing the population of both parent and variant strains in vitro and in therapy of the infected animals. Population studies showed the variant to be a mutant emerging at a rate of 1.9 × 10−7. It was shown to differ from the parent strain in coagulase and hemolysin production, colonial morphology, and aminoglycoside susceptibility, but was similar by light and electron microscopy and in phage type, pigmentation of colonies, deoxyribonuclease production, mannitol fermentation, and growth rate. Images

Penicillin Therapy of Experimental Endocarditis Induced by Tolerant Streptococcus sanguis and Nontolerant Streptococcus mitis

The response of tolerant Streptococcus sanguis and nontolerant Streptococcus mitis infections to penicillin therapy was compared in the rabbit model of endocarditis. The minimal inhibitory and bactericidal concentrations of penicillin were 0.1 and 0.1 μg/ml, respectively, for S. mitis and 0.05 and 6.2 μg/ml, respectively, for S. sanguis. Time-kill studies done in vitro with penicillin concentrations of 2 and 20 μg/ml demonstrated minimal killing of the tolerant strain, with a 3 log difference in survival between the two strains after 24 and 48 h. Both strains produced endocarditis with comparable bacterial densities on the valvular vegetations. Rabbits were treated with procaine penicillin G in two dosage regimens, 80,000 or 5,000 U/kg given every 8 h. There was no difference between bacterial densities in valvular vegetations removed from rabbits infected with either strain after 2, 4, or 6 days of treatment with the high-dose regimen (serum penicillin concentration at 0.5 h, 9.4 μg/ml), despite the fact that serum bactericidal activity against the tolerant strain at 0.5 h was minimal. With the low-dose penicillin regimen (serum concentration at 0.5 h, 2.5 μg/ml), therapy was significantly less effective in the tolerant group only after 6 days of treatment. Similar results were obtained when penicillin was administered in low and high doses to prevent infection. In this animal model of infection, penicillin tolerance was associated with a diminished response to penicillin therapy only when the dose was severely restricted. In the high-dose regimen, there was no difference in the response to penicillin therapy between animals infected with either strain, despite the presence of only minimal serum bactericidal activity in the rabbits infected with the tolerant strain.

Antibiotic activity in vitro against methicillin-resistant Staphylococcus epidermidis and therapy of an experimental infection.

Staphylococcus epidermidis is a major pathogen in early prosthetic valve endocarditis and cerebrospinal fluid shunt infections. Approximately 10 to 15% of hospital isolates are methicillin resistant. Ten clinically significant isolates of the latter were collected for antibiotic studies in vitro and in an experimental infection in animals. Time-kill studies of five strains showed gentamicin to be the single most effective antibiotic; however, dwarf colony variants emerged as survivors with two of these strains when challenged with gentamicin alone. The addition of a second antibiotic to gentamicin did not significantly improve the bactericidal rate but prevented the emergence of variant strains. A blood culture isolate of methicillin-resistant S. epidermidis combined with 5% hog gastric mucin was used to establish an experimental intraperitoneal infection in mice. Neither methicillin nor nafcillin treatment reduced mortality below that of untreated animals. Cephalothin treatment delayed early mortality but did not diminish overall mortality. Gentamicin was the most effective single antibiotic, and gentamicin in combination with vancomycin was the most effective regimen overall. The combination of rifampin plus vancomycin was as effective as gentamicin alone. The combinations of cephalothin or nafcillin with gentamicin and cephalothin with vancomycin demonstrated antagonism. The antagonism was not due to multiple injections or drug-drug inactivation.

Recombinant bactericidal/permeability-increasing protein reduced morbidity in children with severe meningococcal sepsis

Introduction: Meningococcal sepsis has a high mortality and morbidity and ranks among the most frequent causes of death from infection in children. Its pathogenesis is greatly attributable to high levels of endotoxin released by rapidly replicating organisms in the bloodstream, which triggers damaging host inflammatory cascades directly or indirectly through secondary activation of proinflammatory cytokines [1]. Bactericidal/permeability-increasing protein (BPI), a product of the granules of polymorphonuclear leukocytes and a recombinant 21-kD modified Nterminal fragment of human BPI (rBPI21), is capable of neutralizing soluble and membrane-bound endotoxin, and has shown promise in animal models of endotoxemia and infection, and in limited studies in humans.