David E. Nix

Antibiotic tissue penetration and its relevance : impact of tissue penetration on infection response

Fluid penetration. Giventhatdistribution inextracellular fluid (ECF)isimportant, avariety ofmethods havebeen applied tothecollection andstudy ofdataonECFdistribution. Antibiotic concentrations havebeenmeasured inthe lymphatic drainage oforgans andtissues (95,96),fluids obtained fromtissue cagereservoirs (82, 90), chemically or mechanically induced skinblisters (1,81),surgically implanted cotton threads (28, 81), implanted fibrin clots (3), and directly frominflammatory exudates (72). Thisdiversity of modelshasconfused theinterpretation ofantibiotic extravascular fluid distribution, particularly incomparisons between members ofthesameclass ofcompounds. Wheneverpossible, comparisons ofdrugs should bemadeunder identical conditions. Antibiotics leave thevasculature andenter ECFviapassive diffusion through thespaces between vascular endothelial cells. Thus, thesurface areaofvascular tissue inrelation tothetotal volumeofthetissue tobesampled isthemost important consideration inthemodeling ofECF(26). The commonly usedtissue penetration models differ inthevascular tissue surface area/volume ratio atthemeasurement site (28, 77,81,93). Inaddition, theinflammatory response induced bytheprocedure (81,104)andthepresence of cellular debris inthesample (i.e., paperdisks orcotton threads) (81) mayinfluence results. Giventhesemultiple sources ofconfusion, itisvital todefine general principles of antibiotic extravascular fluid penetration andtheninterpret theoutcomes ofspecific fluid models within this context. Inthetissue cagemethod, small, inert spheres ortubes are surgically implanted insubcutaneous tissue (12). Thesurface ofthedevice contains multiple pores, each1to2mm in diameter. Theimplantation procedure causes aninflammatoryresponse that maycontinue for2to3weeks(31). After 4weeks, thefluid contained inthereservoir isbiochemically similar toECF(25, 31). Onegreat advantage ofthis method isthatmultiple samples canbeobtained overaperiod of daysorweeks. Onemustbecareful tomaintain sterility whenpuncturing thedevice tocollect fluid samples, or infection maycomplicate thedata. After several weeks, the growth ofvascular orfibrous tissue maylimit theproper functioning ofthedevice. Thetissue cagedevice itself is usually spherical, witharelatively small diffusion surface areainrelation toalarge fluid volume. Asaresult, thepeak antibiotic concentration inthedevice generally lags behind thepeakantibiotic concentration intheblood orintrue ECF (30, 93). Steady-state concentrations normally reflect complete equilibration between thefluid inthedevice andthe free drugconcentration inserum(30, 92). Skinblister models areperhaps moreuseful inestimating antibiotic concentrations inECF.Noninflammatory blisters

Effects of aluminum and magnesium antacids and ranitidine on the absorption of ciprofloxacin

The effect of an antacid (Maalox) and ranitidine administration on the absorption of ciprofloxacin was evaluated in healthy male volunteers who were enrolled in three separate studies. Each study was designed as a three‐ or four‐period crossover and included the administration of 750 mg ciprofloxacin alone as a control treatment. Treatments that were evaluated included the administration of ciprofloxacin 5 to 10 minutes, 2 hours, 4 hours, and 6 hours after a single 30 ml dose of antacid; the administration of antacid 2 hours after ciprofloxacin was given; and the administration of ciprofloxacin 2 hours after a 200 mg ranitidine tablet. Administration of antacid within 4 hours before ciprofloxacin dose resulted in a significant decrease in ciprofloxacin absorption (p < 0.05). Percentages of relative bioavailability compared with control values were 15.1%, 23.2%, and 70% for the 5 to 10 minute, 2 hour, and 4 hour antacid pretreatments, respectively. Administration of antacid 6 hours before or 2 hours after the ciprofloxacin dose did not affect absorption. Ranitidine did not alter ciprofloxacin absorption. Antacids that contain magnesium and aluminum salts may reduce the absorption of ciprofloxacin. The extent of this interaction appears to increase as the time between administration of the two drugs decreases. Ranitidine is suggested as an alternative to antacids for patients receiving treatment with ciprofloxacin.

Coccidioidomycosis as a Common Cause of Community-acquired Pneumonia

The early manifestations of coccidioidomycosis (valley fever) are similar to those of other causes of community-acquired pneumonia (CAP). Without specific etiologic testing, the true frequency of valley fever may be underestimated by public health statistics. Therefore, we conducted a prospective observational study of adults with recent onset of a lower respiratory tract syndrome. Valley fever was serologically confirmed in 16 (29%) of 55 persons (95% confidence interval 16%–44%). Antimicrobial medications were used in 81% of persons with valley fever. Symptomatic differences at the time of enrollment had insufficient predictive value for valley fever to guide clinicians without specific laboratory tests. Thus, valley fever is a common cause of CAP after exposure in a disease-endemic region. If CAP develops in persons who travel or reside in Coccidioides-endemic regions, diagnostic evaluation should routinely include laboratory evaluation for this organism.

Mathematical Examination of Dual Individualization Principles (I): Relationships between AUC above MIC and Area under the Inhibitory Curve for Cefmenoxime, Ciprofloxacin, and Tobramycin

Traditional antibiotic dosage adjustments target predetermined serum concentrations, whereas a host of in vitro studies and recent clinical trials establish that bacteria vary in their susceptibility. Dual individualization, which considers the variance in both antibiotic pharmacokinetics and bacterial susceptibility, has been employed to describe different rates of bacterial eradication in relation to varying serum concentrations. In patients with nosocomial pneumonia, one of the model compounds studied was cefmenoxime, where a target six-hour area under the serum concentration-time curve (AUC) of 140 μg·h/mL above minimum inhibitory concentration (MIC) was previously associated with bacterial eradication in an average of four days. The target AUC value of 140 μg·h/mL above MIC is unique to cefmenoxime. Ideally, there should be a dual individualized target useful to adjust the dose of any antibiotic. Computer simulations performed to evaluate this hypothesis suggested that each antibiotic had a unique value for target AUC above MIC. These simulations indicated that an optimal AUC above MIC was about 80 percent of the total AUC above the MIC. Predictable rates of bacterial eradication would presumably result from maintaining these relationships across the range of bacterial susceptibility and the range of serum concentration profiles. Each antibiotic has a unique and different 24-hour AUC over MIC value associated with bacterial eradication in 4 days. For cefmenoxime, the target was 540 area units over MIC per 24 hours, tobramycin with 34 area units, and ciprofloxacin with 23 area units per 24 hours. Because it would clearly be desirable to have a target for dosing adjustment that is independent of the particular antibiotic, we then used computer simulations to determine whether the AUIC (area under the inhibitory curve, or integrated AUC above MIC vs. time) could be descriptive of bacterial eradication with the cephalosporin, cefmenoxime; the aminoglycoside, tobramycin; and the fluoroquinolone, ciprofloxacin. Computer simulation revealed that appropriate doses of all three of these antibiotics yield 24-hour AUIC values in the range of 125. On the basis of these simulations, we propose that target AUIC values are likely to be applicable across antibiotic classes, whereas AUC above MIC targets must be unique values to the particular antibiotic. Furthermore, these relationships can be used to make comparisons of antibiotic activity either across different antibiotic classes or within the same class.

Clinical and Economic Analysis of Methicillin-Susceptible and -Resistant Staphylococcus aureus Infections

BACKGROUND: The rate of methicillin-resistant Staphylococcus aureus (MRSA) has increased significantly over the last decade. Previous cohort studies of patients with MRSA bacteremia have reported higher mortality rates, increased morbidity, longer hospital length of stay (LOS), and higher costs compared with patients with methicillin-susceptible S. aureus (MSSA) bacteremia. The clinical and economic impact of MRSA involving other sites of infection has not been well characterized. OBJECTIVE: To determine the clinical and economic implications of MRSA compared with MSSA infections across a variety of infection sites and severity of illnesses. METHODS: A retrospective, case—control analysis comparing differences in clinical and economic outcomes of patients with MRSA and MSSA infections was conducted at an academic medical center. Case patients with MRSA infection were matched (1:1 ratio) to control patients with MSSA infection according to age, site of infection, and type of care. RESULTS: Thirty-six matched pairs of patients with S. aureus infection were identified. Baseline characteristics of patients with MSSA and MRSA infection were similar. Patients with MRSA infections had a trend toward longer hospital LOS (15.5 vs 11 days; p = 0.05) and longer antibiotic-related LOS (10 vs 7 days; p = 0.003). Median hospital cost associated with treatment of patients with MRSA infections was higher compared with patients with MSSA infections (

Antibiotic tissue penetration and its relevance: models of tissue penetration and their meaning.

16 575 vs

In vitro selection of resistant Helicobacter pylori.

12 862; p = 0.11); however, this difference was not statistically significant. Treatment failure was common in patients with MRSA infection. Among patients with MSSA infections, treatment failure was associated with vancomycin use. CONCLUSIONS: Patients with MRSA infections had worse clinical and economic outcomes compared with patients with MSSA infections.

Development of a population pharmacokinetic model and optimal sampling strategies for intravenous ciprofloxacin.

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Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection.

Four strains of Helicobacter pylori were subjected to an in vitro serial passage technique to compare the propensity of the organisms to develop resistance to seven classes of antibacterial agents. The passages were made on serially doubling concentrations of antibacterial agents incorporated into agar starting at one-half the base-line MIC. The frequency of spontaneous resistance was also determined for each strain at four and eight times the MIC of each antibacterial agent. Strains resistant to ciprofloxacin, metronidazole, erythromycin, and tobramycin were isolated. The experiments failed to select organisms resistant to bismuth subsalicylate, furazolidone, or amoxicillin, although the MIC of amoxicillin was increased 4- to 16-fold. With the exception of erythromycin, organisms with the selected resistance were stable after at least three passages on antibacterial agent-free medium. Spontaneous resistance rates were generally of a low magnitude and were not predictive of the serial passage results.

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean +/- standard deviation = 7 +/- 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patients pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CLT in liters per hour) was related to body size and renal function (creatinine clearance [CLCR] in milliliters per minute per 1.73 m2) by the equation CLT = (0.00145.CLCR + 0.167).weight. However, only 30% of the variance in CLT was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CLT (by 44%; P < 0.001) than weight- and CLCR- matched stable volunteers. OSSs provided parameter estimates that showed good to excellent estimates of CLT (or area under the concentrations-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was > 0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens.