Has the FDA Amendments Act of 2007 impaired drug development?

Perched at the midpoint of "v.4" of the Prescription Drug User Fee Act (PDUFA-4), better known as the US Food and Drug Administration Amendments Act (FDAAA), it seems presumptuous to draw critical conclusions based on an "interim analysis" of this work in progress. Because drug development is a complex process measured in decades, one must rely on "surrogate markers" to impute FDAAA outcomes. Even so, there are many indications that the FDAAA has doused the fires of innovation, in scope, spirit, and interim results.

Evaluation of new anti-infective drugs for the treatment of vascular access device-associated bacteremia and fungemia. The European Working Party of the European Society of Clinical Microbiology and Infectious Diseases.

For clinical trials of anti-infective drugs for the treatment of vascular access device-related bloodstream infections, patients should be identified and enrolled on the basis of current standards for the clinical diagnosis of such infections. To ensure comparability of patients, only those infected with staphylococci and Candida species should be included. A prospective, randomized, double-blind design is recommended. Future protocols may include abbreviated courses of therapy, treatment with combinations of drugs, or a progression from parenteral to oral therapy. Clinical response is judged as cure, failure, or indeterminate response; there is no "improved" category. Microbiological response is categorized as eradication, persistence, or relapse and is of paramount importance. Several months of follow-up may be necessary for the detection of late relapses or metastatic infections. This guideline does not apply to studies of bacteremia or fungemia secondary to non-device-related, organ-based primary infections (e.g., pneumonia, urinary tract infection), which should be assessed in relation to the primary disorder.

Adherence of microorganisms to breast prostheses: an in vitro study.

The quantitative and morphological characteristics of microbial adherence of four organisms--Staphylococcus epidermidis, S. aureus, Escherichia coli and Candida albicans--to the surfaces of different breast prostheses were observed. Semiquantitative adherence studies based on a modification of Maki's roll culture technique even after short contact times showed (1) increased microbial adherence at higher concentrations of the organisms and (2) differences in adherence properties between gram-positive bacteria and other organisms tested, noted also at lower organism concentrations. Scanning electron microscopy (SEM) to identify microorganisms on foam-covered prostheses, however, revealed organisms in the interstitial spaces that were not recovered by the plating technique. Other features on SEM were extracellular "slime" produced by S. epidermidis, which appears to act as a cement by which bacteria are held against prosthetic surfaces. These in-vitro findings suggest that brief exposure of the prostheses to a few organisms, particularly gram-positive bacteria, at the time of implantation would be sufficient inoculum for bacterial adherence to prosthetic surfaces.

Serial bilirubin determinations as a prognostic marker in clinical infections.

Patients with documented serious infection and total bilirubin values of greater than 2 mg/dl were surveyed for serial changes in bilirubin and other laboratory and clinical features. Of 19 patients studied, 12 (Group A) had persisting or increasing hyperbilirubinemia, and 7 (Group B) had decline in bilirubin after infection onset. None demonstrated marked changes in other liver tests. Only one patient had infection directly involving the hepatobiliary system. There were no significant differences between the two groups with respect to underlying illnesses, active hepatobiliary diseases, pathogens, bacteremia, or administration of cholestatic drugs. All Group A patients died because of uncontrolled infections, whereas all Group B patients survived with resolution of infection (p less than .001). Ten of 15 patients with available preinfection liver tests demonstrated serial bilirubin increases without marked changes in other liver tests prior to clinical recognition of infection. These findings demonstrate that hyperbilirubinemia disproportionate to increases in other tests may manifest before recognition of infection and that persistent or progressive hyperbilirubinemia is indicative of ongoing active infection.

Documentation and evaluation of fevers in hospital-based and community-based nursing homes.

We reviewed clinical evaluation practices and documentation of fever (greater than or equal to 100.2 degrees F) in all febrile patients over a two-month period in a hospital-based nursing home (HBNH) compared with a community-based nursing home (CBNH). Results showed 38 febrile (mean 101.9 degrees F) HBNH patients and 26 febrile (mean 101.5 degrees F) CBNH patients. Median time from fever onset to physician contact was 4 hours in HBNH and 12.5 hours in CBNH episodes (P less than 0.01). Laboratory studies were initially performed in 68% of HBNH and 31% of CBNH episodes (P less than 0.005), and diagnosis of fever source was documented in 76% of HBNH and 16% of CBNH episodes (P less than 0.005). Overall assessment stratification showed 81% febrile HBNH patients had both evaluation and therapy performed compared with 38% in CBNH (P less than 0.0001); 39% of febrile CBNH patients had no evaluation or therapy performed. Results indicate lack of documentation, and fever evaluation in CBNHs may preclude complete detection of nursing home-acquired infections and thereby hamper preventive responses to potential infection problems.

Prospective comparison of traditional and pharmacokinetic aminoglycoside dosing methods.

Aminoglycoside (gentamicin, tobramycin) dosage regimens and subsequent serum concentrations were compared in 30 patients treated initially using traditional physician-determined methods and then switched to a pharmacokinetic-based treatment program. Patients received more drug during the kinetic phase (median 5 mg/kg) than during the traditional phase (median 3.6 mg/kg) and achieved greater peak serum concentration (5.9 vs. 4.4 micrograms/ml). Seventy-three percent of kinetic peak values but only 27% of traditional peak values exceeded 5.0 micrograms/ml. Trough concentrations were comparable in both phases of study and no nephrotoxicity was observed. This pharmacokinetic-based management program achieved more consistently greater therapeutic peak concentrations and provided more individualized therapy than did physicians. The use of pharmacokinetic consultants may be of benefit in administering safely optimal aminoglycoside therapy.

Survey of nursing personnel attitudes toward infections and their control in the elderly.

To better understand nursing practice in geriatric care settings as it relates to infections, a survey of nursing attitudes about a variety of infection control issues was undertaken. Nurses were recruited from four settings: a university-affiliated, private nursing home (N = 46), a hospital-based nursing home (N = 33), a private nursing home (N = 20), and a home care agency (N = 26). The nurses appropriately recognized the importance of pneumonia and influenza as major threats to health in these settings and also reported some indifference regarding the notification of physicians about fevers under 38.9 degrees C (102.0 degrees F). Among the groups, similar attitudes about infection control principles were recorded, except that the ratings by the home care agency nurses were different from those of the institution-based nurses in the following areas: isolation as a means to prevent infection spread, proper waste disposal methods, and frequency of catheter change. Assessment of personnel attitudes and practices are important in detecting problems, guiding in-service programing, and revising care practices.

Survival of enteric pathogens in common beverages: an in vitro study.

This in vitro study was undertaken to determine the potential for survival of enteric pathogens in common drinking beverages. Three carbonated soft drinks, two alcoholic beverages, skim milk, and water were inoculated with Salmonella, Shigella, and enterotoxigenic Escherichia coli, and quantitative counts were performed over 2 days. Our studies showed poorest survival of all three organisms in wine, and greatest growth in milk and water. Beer and cola allowed survival of small numbers of Salmonella and E. coli at 48 h, whereas sour mix and diet cola were sterile by 48 h. Survival features may correlate with pH of the beverages. These observations may be useful in guiding travellers for appropriate beverage consumption while visiting areas endemic for "traveller's diarrhea."

Comparison of methods for calculation and depiction of incidence infection rates in long-term care facilities.

Assessment of changes in endemic infections in health care facilities are often based on comparison of infection rates over time. This study compared two methods for calculating and depicting infection data at a hospital-based nursing home care unit. Prospective incidence surveillance of nursing home acquired infections was conducted over a 12-month period, during which time denominator information on census and patient care days was also collected. Monthly infection rates were calculated based on (a) census (number infections per month/average monthly census), and (b) care duration (number infections per month/average monthly resident stay days). Results showed average monthly infection incidence of 27.4 episodes, (range 19-37), with average monthly census of 166.2 (range 160.0-180.0) and average monthly patient days of 5056 (range 4631-5583). The average census based monthly infection rate was 16.5 (range 11.9-22.4); average care duration based monthly infection rate was 5.4 (range 3.8-7.2) episodes per 1000 patient care days. Results indicate care duration based rates demonstrate less marked rate fluctuation than census based findings, and that duration based rates are more similar to values observed in acute care hospital nosocomial infection rates, thus are less likely to be misunderstood or misinterpreted by staff. Institutions should consider analyzing their methods for depicting infection data to provide consistency and clarity in data reporting.

Cyclosporine therapy and refractory Pneumocystis carinii pneumonia. A potential association.

In surveillance of 75 patients receiving renal transplants in 1984 at our institution, five cases of Pneumocystis carinii pneumonia were detected. All five cases occurred in a subgroup of 11 patients who had received cyclosporine. A retrospective epidemiologic survey of the infected patients revealed all five were heterosexual white men with onset of Pneumocystis pneumonia two to six months after cadaveric transplantation. All received cyclosporine and corticosteroids, and four of five patients also received azathioprine; none was neutropenic or had evidence of concurrent cytomegalovirus infection. Only one of these patients responded to therapy with sulfamethoxazole and trimethoprim, one patient responded to pentamidine therapy, and the remaining three patients died. Cyclosporine use may be related to development of Pneumocystis infections that are refractory to conventional antiprotozoal therapy, and transplantation programs should closely survey patients for such complications.

Recurrent granulomatous synovitis due to Mycobacterium kansasii in a renal transplant recipient.

A 61-year-old woman received a cadaveric renal transplant in 1972 and was maintained on chronic immunosuppression. Nonspecific granulomatous synovitis of the left hand developed in 1982. After recurrence of synovitis in 1984, surgical exploration of the left hand demonstrated "rice bodies" in a region of chronic synovitis from which Mycobacterium kansasii was isolated. Despite therapy with isoniazid, rifampin, and ethambutol, to which the organism was susceptible in vitro, synovitis recurred. Recovery was completed after extensive synovectomies, decreased immunosuppression, and 24-months of therapy, with the drugs listed above; there was no evidence of mycobacterial infection at sites other than the left hand at any time. The occurrence of persistent Mycobacterium kansasii infection is distinctly unusual even in transplant recipients. In patients refractory to conventional antituberculous therapy, surgical management should be considered as an important therapeutic component.

Quantitative epifluorescence assay of adherence of coagulase-negative staphylococci.

A quantitative epifluorescence assay was developed to assess the adherent qualities of clinical isolates of coagulase-negative staphylococci. This method compared favorably with the standardized tube adherence assay, yet demonstrated a wide range of surface binding affinities among the slime-producing and non-slime-producing strains of coagulase-negative staphylococci examined. This technique can also be adapted to evaluate the adherence of bacteria to other plastics and biomedical materials used to manufacture implantable medical devices.

Institution-specific versus published in vitro antimicrobial susceptibility data in making formulary decisions.

The results of susceptibility testing of 549 isolates of gram-negative organisms to 17 antimicrobial agents were compared with published reports of the sensitivity of those organisms to those agents. All gram-negative bacilli isolated from cultures obtained from hospitalized patients during a three-month period were preserved for antimicrobial sensitivity testing. Standard Kirby-Bauer disk diffusion susceptibility tests were performed using 17 broad-spectrum antimicrobial agents that either were included in the hospital formulary or were being considered for inclusion. Organisms were recorded as being sensitive or resistant to each drug, and the results were compared with the published results of in vitro sensitivity studies. When the results of actual antimicrobial sensitivity testing varied from published results, the discordant results were assigned a ranking of 1 to 4 based on the percentage difference. In 34 of 77 drug-organism pairs tested, the results of susceptibility testing differed by more than 10% cumulative susceptibility from published values; 26 of these represented instances in which the results of actual testing were at least 10% less than published values. For seven of the antimicrobial agents that were being considered for inclusion in the hospital formulary, results indicating unexpectedly suboptimal activity against institutional pathogens were a determinant in eliminating the agents from further consideration. In vitro testing of antimicrobial susceptibility of local pathogens can be a better method of predicting the susceptibility of such pathogens to new antimicrobial agents than relying on published susceptibility data. Pharmacy and therapeutics committees should consider testing prevalent institutional pathogens for susceptibility to all antimicrobial agents that are proposed additions to the formulary.

Aminoglycoside serum concentration sampling via central venous catheters: a potential source of clinical error.

Two patients receiving aminoglycosides via central venous Silastic catheters were noted to have serum drug concentrations markedly divergent from expected results. Study of these patients, and of four additional patients prospectively selected for study, demonstrated that three of five patients had higher peak and/or trough aminoglycoside serum concentrations--when blood was obtained from the central venous catheter--than were contained in simultaneous samples from peripheral blood; these divergent results were noted after the catheter had been in use for more than 1 week; divergent results were not improved by additional catheter flushing prior to central venous blood sampling. These observations suggest that spurious aminoglycoside serum concentration results may sometimes be obtained when blood sampling is performed from central venous Silastic catheters, and can result in improper drug dosage alterations. It is necessary to access the timing, processing, and reliability of serum drug-monitoring practices on a routine basis to preclude such problems, and to reassess individual patient-monitoring studies which are inconsistent with anticipated results.

Persistent in vitro survival of coagulase-negative staphylococci adherent to intravascular catheters in the absence of conventional nutrients.

The in vitro survival of coagulase-negative staphylococci in media devoid of routine nutritional supplementation was assessed in the presence and absence of catheter materials to evaluate bacterium-device interactions. Strains of slime- and non-slime-producing coagulase-negative staphylococci were suspended in phosphate-buffered saline together with multiple segments of polyvinyl chloride (PVC), Teflon, Silastic, and polyurethane catheters and in control suspensions without catheters. Catheters were removed at 2 min and 24, 48, 72, and 96 h of incubation and washed thoroughly, and semiquantitative roll cultures were performed on blood agar. In addition, after 96 h catheters were introduced into tryptic soy broth (TSB), and roll cultures were performed after 18 h of incubation. Results demonstrated that after 96 h, 6 of 32 catheter specimens (4 PVC) had greater than 10 CFU of coagulase-negative staphylococci per catheter; after TSB addition, 18 of 32 catheter specimens had greater than or equal to 100 CFU per catheter (8 of 8 PVC catheters had greater than 1,000 CFU per catheter). In control suspensions, no growth was seen at 96 h or after TSB addition. No differences in the survival of slime- versus non-slime-producing strains were observed in control or catheter studies. These findings suggest that both slime- and non-slime-producing coagulase-negative staphylococci survive in vitro on catheters (especially PVC) in the absence of conventional nutrients and can proliferate on catheters when nutrients are added. Catheter-adherent coagulase-negative staphylococci appear to possess survival mechanisms under adverse conditions which may relate to the genesis of occult foreign-body-associated infections.