Michael H. Miller

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.

Pharmacodynamics of Daptomycin in a Murine Thigh Model of Staphylococcus aureus Infection

ABSTRACT Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29–40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for threeS. aureus isolates were 0.1 to 0.2 μg/ml. In mouse serum, the MICs were 1.0 μg/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoidEmax (maximum effect) curve (r = 0.974; P ≪ 0.001). The density of S. aureus in untreated controls was 8.26 log10 CFU/g, and the Emax was 3.97 log10 CFU/g. The 50% effective dose (ED50) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED30, ED60, and ED80 doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.

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

Impact of the order of initiation of fluconazole and amphotericin B in sequential or combination therapy on killing of Candida albicans in vitro and in a rabbit model of endocarditis and pyelonephritis.

ABSTRACT In vitro time-kill studies and a rabbit model of endocarditis and pyelonephritis were used to define the impact that the order of exposure of Candida albicans to fluconazole (FLC) and amphotericin B (AMB), as sequential and combination therapies, had on the susceptibility of C. albicans to AMB and on the outcome. The contribution of FLC-induced resistance to AMB for C. albicans also was assessed. In vitro, AMB monotherapy rapidly killed each of four C. albicans strains; FLC alone was fungistatic. Preincubation of these fungi with FLC for 18 h prior to exposure to AMB decreased their susceptibilities to AMB for 8 to >40 h. Induced resistance to AMB was transient, but the duration of resistance increased with the length of FLC preincubation. Yeast sequentially incubated with FLC followed by AMB plus FLC (FLC→AMB+FLC) showed fungistatic growth kinetics similar to that of fungi that were exposed to FLC alone. This antagonistic effect persisted for at least 24 h. Simultaneous exposure of C. albicans to AMB and FLC [AMB+FLC(simult)] demonstrated activity similar to that with AMB alone for AMB concentrations of ≥1 μg/ml; antagonism was seen using an AMB concentration of 0.5 μg/ml. The in vitro findings accurately predicted outcomes in our rabbit infection model. In vivo, AMB monotherapy and treatment with AMB for 24 h followed by AMB plus FLC (AMB→AMB+FLC) rapidly sterilized kidneys and cardiac vegetations. AMB+FLC(simult) and FLC→AMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLC→AMB+FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMB→FLC regimen. However, FLC→AMB treatment was slower than AMB alone in clearing fungi from tissues. Thus, our in vitro and in vivo studies both demonstrate that preexposure of C. albicans to FLC reduces fungal susceptibility to AMB. The length of FLC preexposure and whether AMB is subsequently used alone or in combination with FLC determine the duration of induced resistance to AMB.

Occult polymicrobial endocarditis with haemophilus parainfluenzae in intravenous drug abusers

PURPOSE AND PATIENTS AND METHODS Fewer than 8 percent of intravenous drug abusers are found to have polymicrobial endocarditis. We report on cases of occult polymicrobial infective endocarditis with Haemophilus parainfluenzae in 10 intravenous drug abusers. Clinical and laboratory data on all 10 patients were obtained from hospital charts, and information on illicit drug use methods was given by five patients. Blood cultures were performed, as well as susceptibility testing to antibiotics. Subsequent molecular epidemiologic studies were performed on selected Staphylococcus aureus and H. parainfluenzae strains. Phage typing of S. aureus and biotyping of H. parainfluenzae strains were also done. RESULTS Results of the initial blood cultures were positive on the second to fifth days (mean, 2.6 days), demonstrating a gram-positive pathogen in nine patients and Bacteroides asaccharolyticus in one. Significantly, in each case, H. parainfluenzae alone was subsequently identified from additional blood cultures, with a mean delay of 20.4 days (range, five to 57 days) to the isolation of this organism. Epidemiologic data indicated that our cases did not represent a point-source outbreak. Antibiotic therapy uniformly failed until an agent active against H. parainfluenzae was added. The constellation of clinical, microbiologic, and epidemiologic findings was similar, and permitted prospective diagnosis and therapy in three patients. Despite the absence of S. aureus bacteremia in four, all 10 patients had right-sided endocarditis with septic pulmonary emboli. Five patients had initial blood cultures that were positive for two facultative gram-positive cocci (S. aureus and commensal oral streptococcal species). CONCLUSION Our findings suggest that polymicrobial endocarditis with H. parainfluenzae in intravenous drug abusers is a distinct clinical syndrome, and should be considered in all patients if the response to appropriate antibiotics is atypical or if pulmonary emboli continue with therapy.

Pharmacokinetics of amikacin and chloramphenicol in the aqueous humor of rabbits.

Composite data describing ocular pharmacokinetics are unreliable because of intersubject variation. To address this problem, an animal model was developed in which multiple aqueous samples from single subjects were obtained. Following direct anterior chamber or intravenous administration of amikacin or chloramphenicol, pharmacokinetic analysis of drug concentrations in the serum and anterior chamber was performed by using a nonlinear least-squares regression program. The number of anterior chamber paracenteses performed did not alter the beta elimination rates or percent penetration into the anterior chamber. The aqueous humor and peripheral-compartment terminal slopes were identical. These data indicate that complete ocular concentration-time curves can be obtained without altering antibiotic pharmacokinetics. Following direct injection into the anterior chamber, the elimination rates for both antibiotics followed a one-compartment model, whereas those following intravenous administration best fit an open, first-order, two-compartment model. Following intravenous administration, the anterior chamber elimination rate constants for both drugs were equal to that of the serum and significantly longer than that following direct injection. The elimination rates of both drugs following direct injection were similar. Systemic administration resulted in drug levels in aqueous humor that persisted longer than those following direct injection. Chloramphenicol, a lipophilic compound, gave higher mean concentrations in aqueous humor than did amikacin. Our model provides a new approach which rigorously examines ocular pharmacokinetics and provides data which suggest that for selected compounds the parenteral route of administration is preferable.

Adult meningoencephalitis caused by herpesvirus hominis type 2

Abstract Herpesvirus hominis (HVH) type 2 was isolated from cerebrospinal fluid of a 19 year old man whose meningoencephalitis was associated with marked lymphocytic pleocytosis (as high as 2,080 cells/mm 3 ), elevated cerebrospinal fluid protein (280 mg/ 100 ml) and hypoglycorrachia. Serologic studies showed significant antiherpes antibody increase during convalescence. The pathobiologic features of central nervous system infection with herpes simplex subtypes are discussed.

A Comparative Trial of Moxalactam Plus Ticarcillin and Clavulanic Acid or Piperacillin as Empiric Antibiotic Therapy for Febrile Cancer Patients

Resistance of bacteria to beta‐lactam antibiotics remains a difficult clinical problem that can be compounded in infected patients with serious underlying illness, especially those who are immunocompromised. In a prospective randomized safety and efficacy trial, febrile cancer patients received either ticarcillin disodium combined with the beta‐lacta‐mase inhibitor clavulante potassium (Timentin, Beecham Laboratories, Bristol, TN) plus moxalactam (T+M), or piperacillin plus moxalactam (P+M) as initial empiric antimicrobial therapy. Sixty‐six febrile episodes in 53 patients were studied. In the T+M group, 14 (78%) of 18 clinically evaluable infections in patients with profound granulocytopenia improved as did all 14 (100%) such infections in the P+M group. In the T+M group 17 of 21 (81%) similarly evaluable infections improved irrespective of granulocyte count, as did 14 (88%) of 16 of such infections in the P+M group. These results are not statistically significantly different. Serious side effects were infrequent and comparable with both regimens. There was one antibiotic related hemorrhage in the P+M group and a serious episode of nephrotoxicity in a patient who died without recovering renal function in the T+M group. These results suggest that the overall safety and efficacy of Timentin plus moxalactam, and piperacillin plus moxalactam are comparable and similar to previous empiric antibiotic trials.