Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort.

In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of ≥1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy.

Efficacy and safety of caspofungin therapy in elderly patients with proven or suspected invasive fungal infections.

Invasive fungal infections (IFIs) are serious complications in elderly adults. Caspofungin may provide a useful therapeutic option for elderly patients with or at high risk for IFIs. We retrospectively compared efficacy and safety outcomes in elderly (> or = 65 years of age) and non-elderly patients in three clinical trials of caspofungin: a double-blind, randomized trial versus amphotericin B for documented invasive candidiasis (IC); an open-label, non-comparative study of definite or probable invasive aspergillosis (IA); and a double-blind, randomized trial versus liposomal amphotericin B as empirical therapy (ET) in febrile neutropenic patients. A total of 159 elderly patients with a median age of 71 years (range, 65-84) received caspofungin in these studies. The median duration of caspofungin therapy was 12 days for IC and ET, and 28 days for IA. Point estimates for the favorable response rates to caspofungin were numerically higher in elderly versus non-elderly patients with IC (83% vs. 68%) or IA (64% vs. 44%) and were similar in patients receiving ET (36% vs. 34%). Adverse events related to caspofungin occurred in generally similar proportions of elderly versus non-elderly patients with IC (clinical, 33% vs. 27%; laboratory, 17% vs. 29%), with IA (clinical, 7% vs. 13%; laboratory, 13% vs. 14%), or receiving ET (clinical, 47% vs. 47%; laboratory, 24% vs. 22%). Nephrotoxicity and infusion-related toxicity developed in comparable proportions of elderly and non-elderly caspofungin recipients in all three studies. In this post-hoc analysis, caspofungin appeared to be as efficacious and well tolerated in elderly patients as in non-elderly patients.

Ertapenem versus cefepime for initial empirical treatment of pneumonia acquired in skilled-care facilities or in hospitals outside the intensive care unit.

The study presented here compared the efficacy and safety of ertapenem and cefepime as initial treatment for adults with pneumonia acquired in skilled-care facilities or in hospital environments outside the intensive care unit (ICU). Non-ventilated patients developing pneumonia in hospital environments outside the ICU, in nursing homes, or in other skilled-care facilities were enrolled in this double-blind non-inferiority study, stratified by APACHE II score (15) and randomized (1:1) to receive cefepime (2 g every 12 h with optional metronidazole 500 mg every 12 h) or ertapenem (1 g daily). After 3 days of parenteral therapy, participants demonstrating clinical improvement could be switched to oral ciprofloxacin or another appropriate oral agent. Probable pathogens were identified in 162 (53.5%) of the 303 randomized participants. The most common pathogens were Enterobacteriaceae, Streptococcus pneumoniae, and Staphylococcus aureus, isolated from 59 (19.5%), 39 (12.9%), and 35 (11.6%) participants, respectively. At the test-of-cure assessment 7-14 days after completion of all study therapy, pneumonia had resolved or substantially improved in 89 (87.3%) of 102 clinically evaluable ertapenem recipients and 80 (86%) of 93 clinically evaluable cefepime recipients (95% confidence interval for the difference, -9.4 to 11.8%), fulfilling pre-specified criteria for statistical non-inferiority. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. In this study population, ertapenem was as well-tolerated and efficacious as cefepime for the initial treatment of pneumonia acquired in skilled-care facilities or in hospital environments outside the ICU.

Impact of alternate definitions of fever resolution on the composite endpoint in clinical trials of empirical antifungal therapy for neutropenic patients with persistent fever: analysis of results from the Caspofungin Empirical Therapy Study.

BACKGROUND: Sensitivity analyses were incorporated in a Phase III study of caspofungin vs. liposomal amphotericin B as empirical antifungal therapy for febrile neutropenic patients to determine the impact of varying definitions of fever resolution on response rates. METHODS: The primary analysis used a 5-part composite endpoint: resolution of any baseline invasive fungal infection, no breakthrough invasive fungal infection, survival, no premature discontinuation of study drug, and fever resolution for 48 h during the period of neutropenia. Pre-specified analyses used 3 other definitions for fever resolution: afebrile for 24 h during the period of neutropenia, afebrile at 7 days post therapy, and eliminating fever resolution altogether from the composite endpoint. Patients were stratified on entry by use of antifungal prophylaxis and risk of infection. Allogeneic hematopoietic stem cell transplants or relapsed acute leukemia defined high-risk patients. RESULTS: In the primary analysis, 41% of patients in each treatment group met the fever-resolution criteria. Low-risk patients had shorter durations of neutropenia but failed fever-resolution criteria more often than high-risk patients. In each exploratory analysis, response rates increased in both treatment groups compared to the primary analysis, particularly in low-risk patients. CONCLUSIONS: Response rates for the primary composite endpoint for both treatment groups in this study were driven by low rates of fever resolution. Requiring fever resolution during neutropenia in a composite endpoint can mask more clinically relevant outcomes.

Bowel colonization with resistant gram-negative bacilli after antimicrobial therapy of intra-abdominal infections: observations from two randomized comparative clinical trials of ertapenem therapy.

The selection of resistant gram-negative bacilli by broad-spectrum antibiotic use is a major issue in infection control. The aim of this comparative study was to assess the impact of different antimicrobial regimens commonly used to treat intra-abdominal infections on the susceptibility patterns of gram-negative bowel flora after completion of therapy. In two international randomized open-label trials with laboratory blinding, adults with complicated intra-abdominal infection requiring surgery received piperacillin-tazobactam (OASIS 1) or ceftriaxone/metronidazole (OASIS II) versus ertapenem for 4-14 days. Rectal swabs were obtained at baseline, end of therapy, and 2 weeks post-therapy. Escherichia coli and Klebsiella spp. were tested for production of extended-spectrum beta-lactamase (ESBL). Enterobacteriaceae resistant to the agent used were recovered from 19 of 156 (12.2%) piperacillin-tazobactam recipients at the end of therapy compared to 1 (0.6%) patient at baseline (p<0.001) in OASIS I, and from 33 of 193 (17.1%) ceftriaxone/metronidazole recipients at the end of therapy compared to 5 (2.6%) patients at baseline (p<0.001) in OASIS II. Ertapenem-resistant Enterobacteriaceae were recovered from 1 of 155 and 1 of 196 ertapenem recipients at the end of therapy versus 0 and 1 ertapenem recipients at baseline in OASIS I and II, respectively. Resistant Enterobacteriaceae emerged significantly less often during treatment with ertapenem than with the comparator in both OASIS I (p<0.001) and OASIS II (p<0.001). The prevalence of ESBL-producers increased significantly during therapy in OASIS II among 193 ceftriaxone/metronidazole recipients (from 4 [2.1%] to 18 [9.3%]) (p<0.001), whereas no ertapenem recipient was colonized with an ESBL-producer at the end of therapy in either study. Selection for imipenem-resistant Pseudomonas aeruginosa was uncommon in all treatment groups. In these studies, the frequency of bowel colonization with resistant Enterobacteriaceae substantially increased in patients treated with either piperacillin-tazobactam or ceftriaxone/metronidazole, but not in patients treated with ertapenem.

Changes in plasma gelsolin concentration during acute oxidant lung injury in mice.

Oxidant stress may contribute to acute lung injury under some circumstances. The rapid depletion of plasma gelsolin following major trauma in patients who subsequently develop respiratory distress suggests that this actin-scavenging protein might protect against delayed pulmonary complications. The specific aim of these experiments was to explore the temporal and quantitative relationship between gelsolin levels and lung damage. Gelsolin levels were measured in three murine models of oxidant injury: immunotargeting of pulmonary endothelium with an H2O2-generating enzyme; continuous exposure to >95% O2; and single high-dose thoracic radiation. The degree of lung injury was inversely related to gelsolin levels in mice treated with glucose oxidase-conjugated antibodies against platelet endothelial cell adhesion molecule-1 (p <0.0001). By 60-72 hours of hyperoxic exposure, gelsolin levels had dropped precipitously in all mice who sustained major lung damage (p <0.0001), establishing a quantitative association between gelsolin concentration and hyperoxic lung injury (r = -0.72; 95% confidence interval: ?0.81 to ?0.59). Gelsolin levels modestly but progressively fell in irradiated mice over the 3 days following treatment (p = 0.012) despite the development of only microscopic lung damage during this timeframe. These findings are consistent with the hypothesis that gelsolin depletion is involved in the pathogenesis of acute oxidant lung injury.

Safety and tolerability of caspofungin acetate in the treatment of fungal infections.

Caspofungin acetate is the first member of the novel echinocandin class of antifungal drugs to be marketed in the United States. It has recently been approved for use in patients with invasive aspergillosis who are refractory to or intolerant of conventional therapy. Accordingly, its safety profile is particularly important to review. The safety and tolerability of caspofungin have been examined in 623 persons, including 295 patients who received >/= 50 mg/day for at least one week in clinical studies. In the 263 patients, given caspofungin in randomized double-blind active-control trials to date, there have been no serious clinical or laboratory drug-related adverse events; caspofungin was discontinued in only 2% of these patients because of drug-related adverse experiences. Caspofungin may have potentially important drug interactions with cyclosporine and tacrolimus.

A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis.

Caspofungin is a new broad-spectrum antifungal drug. A multicenter, double-blind, randomized trial was conducted to assess the efficacy, safety, and tolerability of caspofungin relative to amphotericin B in adults with endoscopically documented symptomatic Candida esophagitis. By use of a modified intent-to-treat analysis, endoscopically verified clinical success was achieved in 74% (95% confidence interval [CI], 59%-86%) and 89% (95% CI, 72%-98%) of patients receiving caspofungin at 50 and 70 mg/day, respectively, and in 63% (95% CI, 49%-76%) of patients given amphotericin B at 0.5 mg/kg/day. Therapy was stopped because of drug-related adverse events in 24% of patients in the amphotericin B group and 4% and 7%, respectively, for the caspofungin groups. This report provides the first demonstration of clinical utility for an echinocandin compound. Caspofungin appeared in this study to be as effective as and better tolerated than amphotericin B for the treatment of esophageal candidiasis.

Indinavir did not increase the short-term risk of adverse cardiovascular events relative to nucleoside reverse transcriptase inhibitor therapy in four phase III clinical trials.

A retrospective person-time analysis of the randomized and non-randomized extension phases of four phase III trials was performed to assess the incidence of adverse cardiovascular events in 2680 HIV-infected patients receiving indinavir or nucleoside reverse transcriptase inhibitor therapy, or both. The observed rate of cardiovascular events was not increased in patients receiving indinavir-based regimens compared with therapy without a protease inhibitor. Extrapolation of these findings is limited by the brief length of therapy and the small number of cases.

Skepticism: a lost clinical art.

Under the contemporary avalanche of new biomedical discoveries, most physicians find themselves in a losing battle to keep up to date. An underappreciated but important consequence of this struggle has been an abdication of the traditional responsibility of clinicians to critically review novel findings. We appear as a group to prefer our data predigested. Understandably, but unfortunately, we have become too accepting of formal guidelines and trusting of expert advice. Imprecision in our thinking and misapplication of cutting edge technologies have resulted, often to the detriment of the individual patient and the society at large. This essay illustrates some specific examples that demonstrate how superficial knowledge and blind faith can promote suboptimal care and inappropriate use of resources. Reflexive approaches to problems erode the individuality of diagnostic and treatment plans. Accordingly, I challenge my colleagues to be more skeptical about the validity and utility of how they are directed to practice medicine.

Relationship of admission plasma gelsolin levels to clinical outcomes in patients after major trauma.

Actin-scavenging proteins, e.g., plasma gelsolin, counteract the pathophysiological consequences of actin leaked into the circulation from dying cells, but the capacity of this defense system can be overwhelmed by massive tissue injury. We examined the prognostic implications of plasma gelsolin levels obtained near the time of admission to our level I Trauma Unit on the subsequent clinical course in a group of patients with severe traumatic injuries. Blood samples were obtained from 13 patients shortly after major trauma and 11 healthy volunteers who served as the control group. Plasma gelsolin levels were assayed by quantitative Western blotting. Duration of mechanical ventilation, stay in the Trauma Intensive Care Unit, and development of acute respiratory distress syndrome (ARDS) were measured as clinical outcomes reflecting the complexity of the hospital course. Subsequently, we evaluated an additional 52 patients after major and minor trauma to extend our earlier observations. Plasma gelsolin concentrations were significantly lower in our 13 original patients compared with healthy controls. Levels below 250 mg/L (> 2 standard deviations below the mean of the control group) were associated with prolonged mechanical ventilation and a stay in the intensive care unit >/= 13 days. Both patients whose gelsolin level was < 100 mg/L in this first series developed ARDS. Including all 65 patients, 6 of the 10 patients who developed ARDS had admission gelsolin levels less than 250 mg/L, compared with only 7 of the 55 patients without ARDS (p = 0.0028). The mean gelsolin levels were 193 and 400 mg/L in patients with and without ARDS, respectively (p < 0.0001) and 398 mg/L in survivors versus 259 mg/L for patients who expired (p < 0.0001). Ten of the 13 patients (77%) with gelsolin levels at the time of admission more than 2 SD below the control mean had "bad outcomes," defined as mechanical ventilation for >/= 13 days in the Trauma Intensive Unit, ARDS, and/or death. Plasma gelsolin levels appear to be an early prognostic marker in patients experiencing major trauma. Whether circulating gelsolin serves a biologically vital function or is simply depleted after massive trauma cannot be determined from our study. The potential therapeutic benefits of infusions of recombinant human plasma gelsolin for patients in whom multiorgan dysfunction commonly follows a serious but self-limited insult have not yet been investigated.

Amphotericin B lipid complex in pediatric patients with invasive fungal infections.

BACKGROUND: Lipid formulations of amphotericin B have been recently introduced for treatment of invasive fungal infections. However, little is known about their role in pediatric populations. METHODS: We studied the safety and antifungal efficacy of amphotericin B lipid complex (ABLC, Abelcet) in 111 treatment episodes in pediatric patients through an open label, emergency use multicenter study. Patients with invasive fungal infections were enrolled if they had mycoses refractory to conventional antifungal therapy, if they were intolerant of previous systemic antifungal agents or concomitant nephrotoxic drugs or if they had preexisting renal disease. RESULTS: All 111 treatment episodes were evaluable for safety and 54 were evaluable for efficacy. The mean serum creatinine for the study population did not significantly change between baseline (1.23 +/- 0.11 mg/dl) and cessation of ABLC therapy (1.32 +/- 0.12 mg/dl) during 6 weeks. There were no significant differences observed between initial and end-of-therapy levels of serum potassium, magnesium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and hemoglobin. However, there was an increase in mean total bilirubin (3.66 +/- 0.73 to 5.31 +/- 1.09 mg/dl) at the end of therapy (P = 0.054). Among 54 cases fulfilling criteria for evaluation of antifungal efficacy, a complete or partial therapeutic response was obtained in 38 patients (70%) after ABLC therapy. Complete or partial therapeutic response was documented in 56% of cases with aspergillosis (n = 25) and in 81% (n = 27) with candidiasis. Among premature infants (n = 8) and allogeneic marrow recipients (n = 14), response rates were 88 and 57%, respectively. Response was similar in those patients enrolled because of intolerance to previous antifungal therapy or because of progressive infection. CONCLUSIONS: These data support the use of ABLC for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy.

Erythrocyte membrane fractions contain free barbed filament ends despite sufficient concentrations of retained capper(s) to prevent barbed end growth.

Many cellular functions depend on rapid cytoskeletal rearrangements localized to specific cytoplasmic domains. Tight regulation of the submembranous microfilament network is accomplished in large part in erythrocytes and granulocytes by actin binding proteins that cap the fast-growing barbed filament ends. Study of this dynamic system is necessarily hampered by the confounding perturbations of cell lysis and dilution. In this paper, we characterize the functional properties of the membrane-associated spectrin-actin complex from human erythrocytes as it exists after hypotonic lysis. Purified spectrin-actin "seeds" extracted from erythrocyte membranes effectively nucleated actin elongation from their barbed ends. However, polymerization from spectrin-actin complexes associated with the membrane fraction prematurely slowed despite the presence of G-actin in great excess of the critical monomer concentration. The addition of cytochalasin B decreased (rather than augmented) the slowing of elongation attributable to the membrane fraction, indicating that capping of barbed filament ends (not monomer sequestration) was the major mechanism underlying this effect. The paradoxical implication of our findings is that, despite the presence of excess capper(s) in the membrane fraction, the membrane-associated spectrin-actin seeds were not capped until after dilution into physiological ionic strength buffer containing monomeric actin. Furthermore, by comparing the degrees of contamination of the extracted and membrane-associated spectrin-actin preparations, it appeared that recognized capping proteins (including gelsolin and capping protein beta2) were not the predominant cappers found in the membrane pellet after hypotonic lysis. We hypothesize that the barbed ends of membrane-associated spectrin-actin complexes, while not excluding actin monomers, may be selectively inaccessible to certain cappers (perhaps simply as the result of steric hindrance). Growth from such complexes in vivo could be limited by the availability of polymerization-competent G-actin.

Nucleation and elongation of actin filaments in the presence of high speed supernate from neutrophil lysates: modulating effects of Ca2+ and phosphatidylinositol-4,5-bisphosphate.

Cell motility depends on the rapid growth of cortical actin filaments whose barbed ends are capped in the resting cell. High speed supernates (HSS) of dilute neutrophil lysates contain actin monomers and/or oligomers that can be induced to polymerize by certain stimuli. We questioned whether some of the actin remaining in the supernate after high speed centrifugation exists as occult nucleation sites which can elongate when uncapped. Phosphatidylinositol-4,5-bisphosphate (PIP2) may play a critical role as an intracellular messenger in cytoskeletal rearrangement after stimulation by removing cappers from barbed filament ends. The experiments reported here examine the separate and interactive effects of PIP2 micelles and micromolar [Ca2+] on the rates of nucleation and elongation of pyrenyl-G-actin in the presence of HSS. HSS slowed the nucleation and elongation rates of gel-filtered pyrenyl-G-actin polymerized at submicromolar [Ca2+]. Under these conditions, PIP2 only slightly increased the number of nucleation sites, but delayed the slowing of the elongation rate in the presence of HSS. Nucleating activity in HSS could be induced by the addition of micromolar [Ca2+] and totally abolished by immunoprecipitation of gelsolin from HSS; incubation of HSS with PIP2 at micromolar [Ca2+] slightly decreased the number of calcium-induced nucleation sites in the supernate. Incubation of HSS with PIP2 before the addition of calcium led to a greater reduction in Ca2+-inducible nucleation sites. HSS possessed more nucleation sites after simultaneous exposure to PIP2 and Ca2+, followed by chelation of Ca2+ with EGTA, than HSS preincubated at micromolar [Ca2+] without PIP2. At submicromolar [Ca2+], PIP2 only generated a few barbed end nucleation sites in the HSS, but lessened the gradual slowing of elongation seen with HSS in the absence of PIP2, presumably by preventing capping by capping protein-beta2 in the supernate. Pointed end nucleating sites in HSS, attributable to gelsolin, could be created by adding micromolar [Ca2+]. The preincubation of HSS with PIP2 in the absence of micromolar [Ca2+] decreased the number of Ca2+-inducible nucleation sites in the HSS. Under conditions mimicking the sequential rise and fall of cytosolic [Ca2+] after stimulation, PIP2 accelerated actin polymerization despite the inhibitory action of HSS by maintaining Ca2+-activated nucleation sites. These observations suggest that a possible role for PIP2 in modulating cytoskeletal growth in vivo may be to regulate nucleation sites activated by sequential changes in cytosolic [Ca2+].

Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases.

The safety and antifungal efficacy of amphotericin B lipid complex (ABLC) were evaluated in 556 cases of invasive fungal infection treated through an open-label, single-patient, emergency-use study of patients who were refractory to or intolerant of conventional antifungal therapy. All 556 treatment episodes were evaluable for safety. During the course of ABLC therapy, serum creatinine levels significantly decreased from baseline (P < .02). Among 162 patients with serum creatinine values > or = 2.5 mg/dL at the start of ABLC therapy (baseline), the mean serum creatinine value decreased significantly from the first week through the sixth week (P < or = .0003). Among the 291 mycologically confirmed cases evaluable for therapeutic response, there was a complete or partial response to ABLC in 167 (57%), including 42% (55) of 130 cases of aspergillosis, 67% (28) of 42 cases of disseminated candidiasis, 71% (17) of 24 cases of zygomycosis, and 82% (9) of 11 cases of fusariosis. Response rates varied according to the pattern of invasive fungal infection, underlying condition, and reason for enrollment (intolerance versus progressive infection). These findings support the use of ABLC in the treatment of invasive fungal infections in patients who are intolerant of or refractory to conventional antifungal therapy.

High concentrations of phosphatidylinositol-4,5-bisphosphate may promote actin filament growth by three potential mechanisms: inhibiting capping by neutrophil lysates, severing actin filaments and removing capping protein-beta2 from barbed ends.

Cell locomotion requires rapid growth of cortical actin filaments whose barbed ends are capped in the resting cell. Phosphatidylinositol-4,5-bisphosphate (PIP2) may play a critical role as an intracellular messenger in cytoskeletal rearrangement after stimulation. We have examined the effects of PIP2 micelles on the Ca2+-independent actin filament capping activity in high speed supernatants of neutrophil lysates which we had previously demonstrated to be almost entirely due to capping protein-beta2, a homologue of cap Z. High concentrations of PIP2 totally prevented the capping of exogenous spectrin-F-actin seeds by dilute supernatants of neutrophil extracts. Capping could also be inhibited, albeit less effectively, by PIP and PI, but not by other phospholipids. When incubated with filaments in the absence of supernatant, PIP2 increased the number of growing ends. PIP2 also uncapped previously capped actin filaments, as demonstrated by incubating supernatant-capped and uncapped seeds with and without PIP2 and then comparing the initial elongation rates after addition of pyrenyl-G-actin. Incubation of capped seeds with high concentrations of PIP2 increased the number of free barbed ends to a level comparable to that of the uncapped seeds exposed to PIP2. PIP2 caused uncapping to occur too quickly to be explained simply by the off-rate of capping protein-beta2, implying that PIP2 interacted directly with capping protein on the filament ends. In fact, PIP2 transiently uncapped capped seeds in the presence of excess free capping protein. From our data, we estimate that millimolar concentrations of PIP2 (almost 100-fold higher than the amount predicted from the effective concentration in purified systems) would be required to inhibit all the capping protein-beta2 in the cytosol. This discrepancy probably results, in large part, from sequestration of PIP2 by other PIP2-binding proteins in the cytoplasm. If PIP2 mediates differential cytoskeletal growth after chemoattractant stimulation in vivo, very high concentrations may be required subjacent to the plasma membrane for regional severing and uncapping of actin filaments to occur quickly near the perturbed membrane.

Prophylactic use of antibiotics and vaccines in patients with rheumatologic disorders.

In patients with serious underlying medical conditions, preventive interventions are a prudent, cost-effective, but underused strategy that could lessen morbidity and even mortality. In particular, immunization status should be assessed in all patients with rheumatologic disorders. Tuberculin reactivity is optimally documented before initiation of steroid therapy. It is often easier (and wiser) to prevent an infection than to treat it in a compromised host.