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Biomedical subjects

A W Chow

Publications and source records attributed to A W Chow.

At least 37 records · Page 2Linked to original sources
PubMed1998

Splanchnic origin of cytokines in a porcine model of mesenteric ischemia-reperfusion.

BACKGROUND: The purpose of this study was to determine whether the gut or the liver was the source of tumor necrosis factor (TNF), interleukin-6 (IL-6), and endogenous endotoxin in a porcine model of mesenteric ischemia-reperfusion. METHODS: Endotoxin, TNF, and IL-6 levels were measured from the carotid artery (CA), portal vein (PV), and hepatic vein (HV) every 30 minutes for 330 minutes in anesthetized pigs after occlusion of the superior mesenteric artery (SMA; n = 7) and after sham operation (n = 7). In animals subjected to mesenteric ischemia, the SMA clamp was released twice: once at 240 minutes (for 40 seconds) and once at 300 minutes (for the remainder of the experiment). RESULTS: In control animals, TNF and IL-6 levels remained at baseline at all vascular sites for the duration of the experiment. In the SMA ligation group, TNF levels peaked before release of the SMA clamp. Compared with TNF levels in the CA (27 +/- 3.7 pU/ml, unchanged from baseline), TNF levels were higher in the PV and in the HV (47 +/- 1.7 and 44 +/- 4.0 pU/ml, respectively; p < 0.05). In contrast, IL-6 appeared in the circulation immediately after first release of the SMA clamp. At this instant, compared with levels in the CA (1381 +/- 305 pU/ml), IL-6 levels in the PV and HV were higher (1884 +/- 276 and 1795 +/- 213 pU/ml, respectively; p < 0.05). Endotoxin remained at baseline levels (1.0 +/- 0.3 endotoxin unit/ml) throughout the experiment in both groups of animals, and gut efflux of endotoxin never exceeded gut influx. CONCLUSIONS: TNF is produced in a partially perfused splanchnic bed during SMA clamping (e.g., pancreas, duodenum, liver, left colon). IL-6 is produced in gut during SMA clamping and is released when the SMA is unclamped. There is no apparent splanchnic release of endotoxin during or after SMA clamping in this model.

Animals↗
PubMed1997

Nasal reconstruction using a combination of alloplastic materials and autogenous tissues: a surgical alternative.

Re-creation of a functional and aesthetically acceptable nose after partial nasal defect requires accurate reproduction of nasal lining, support, and coverage. Most authors recommend an approach to reconstruction with cantilevered bone grafting and paramedian forehead flap placement. The authors propose an alternative approach for selected patients with total or near-total nasal defects combining both alloplastic and autogenous tissues. This method uses vitallium or titanium mesh for the dorsal framework formation, tissue-expanded paramedian forehead flap for soft tissue coverage, and composite chondrocutaneous auricular grafts for tip reconstruction. Nine individuals underwent nasal reconstruction using this method. The indications, details, and potential advantages of this technique are described with accompanying photographic results. A flexible approach using a combination of alloplastic materials and autogenous tissues provides additional reconstructive options for individuals with total or near-total nasal defects.

Adolescent↗
PubMed1996

Gut is not a source of cytokines in a porcine model of endotoxicosis.

BACKGROUND: We sought to determine whether ischemic gut is a source of endotoxin, tumor necrosis factor (TNF), and interleukin-6 (IL-6) in a porcine model of endotoxicosis. METHODS: Under general anesthesia pigs underwent neck dissection and laparotomy for placement of catheters in the carotid artery and portal vein and application of an ultrasonic flow probe around the portal vein. Endotoxin, TNF, and IL-6 levels were measured from the carotid artery and the portal vein during a 4 hour period in animals given endotoxin (50 mg/kg; n = 6) and in animals in the control group (n = 6). Gut fluxes of the substances of interest were calculated as the product of concentration and portal venous flow. A tonometer placed in the terminal ileum was used to monitor mucosal pH. RESULTS: Small bowel mucosal pH was significantly depressed in endotoxemic animals (6.8 +/- 0.1) when compared with baseline (7.1 +/- 0.1; p < 0.05) and control levels. In the control group portal venous levels of endotoxin, TNF, and IL-6 did not change significantly from baseline levels (1.5 +/- 0.4 endotoxin units (EU)/ml, 24 +/- 3 pU/ml, and 1.3 +/- 0.4 nU/ml, respectively). In the endotoxemic animals portal venous endotoxin and TNF levels peaked immediately after the endotoxin infusion (2186 +/- 437 EU/ml, and 293 +/- 125 pU/ml, respectively), and portal venous IL-6 levels peaked at 180 minutes (168 +/- 21 nU/ml). At no time did endotoxin, TNF, or IL-6 levels differ between arterial and portal venous blood, and at no time did efflux from the gut significantly exceed gut influx in either the control or endotoxemic animals. CONCLUSIONS: Ischemic gut as indicated by decreased mucosal pH is not associated with gut release of endotoxin, IL-6, or TNF in this porcine model of endotoxicosis.

Animals↗
PubMed1996

A mutation at glycine residue 31 of toxic shock syndrome toxin-1 defines a functional site critical for major histocompatibility complex class II binding and superantigenic activity.

Random mutagenesis with hydroxylamine was done on toxic shock syndrome toxin-1 (TSST-1) to identify the amino acid residues critical for binding to major histocompatibility complex (MHC) class II molecules of human monocytes. A double mutant with amino acid substitutions of glycine 31-->arginine and aspartic acid 184-->asparagine (G31R.D184N) demonstrated markedly reduced binding to human monocytes and induction of mitogenesis or cytokine secretion. Site-directed mutagenesis revealed that G31R, but not D184N, was at least 4 orders of magnitude less active than wild type recombinant (r) TSST-1 in these biologic activities and did not induce lethal shock in mice. The global structure of G31R remained highly similar to wild type rTSST-1 as evidenced by circular dichroism spectroscopy and binding to anti-TSST-1 polyclonal and monoclonal antibodies. These studies identified TSST-1 residue 31 as critical for binding to MHC class II molecules and for the consequent superantigenic and lethal properties of TSST-1.

Animals↗
PubMed1996

HSP60 gene sequences as universal targets for microbial species identification: studies with coagulase-negative staphylococci.

A set of universal degenerate primers which amplified, by PCR, a 600-bp oligomer encoding a portion of the 60-kDa heat shock protein (HSP60) of both Staphylococcus aureus and Staphylococcus epidermidis were developed. However, when used as a DNA probe, the 600-bp PCR product generated from S. epidermidis failed to cross-hybridize under high-stringency conditions with the genomic DNA of S. aureus and vice versa. To investigate whether species-specific sequences might exist within the highly conserved HSP60 genes among different staphylococci, digoxigenin-labelled HSP60 probes generated by the degenerate HSP60 primers were prepared from the six most commonly isolated Staphylococcus species (S. aureus 8325-4, S. epidermidis 9759, S. haemolyticus ATCC 29970, S. schleiferi ATCC 43808, S. saprophyticus KL122, and S. lugdunensis CRSN 850412). These probes were used for dot blot hybridization with genomic DNA of 58 reference and clinical isolates of Staphylococcus and non-Staphylococcus species. These six Staphylococcus species HSP60 probes correctly identified the entire set of staphylococcal isolates. The species specificity of these HSP60 probes was further demonstrated by dot blot hybridization with PCR-amplified DNA from mixed cultures of different Staphylococcus species and by the partial DNA sequences of these probes. In addition, sequence homology searches of the NCBI BLAST databases with these partial HSP60 DNA sequences yielded the highest matching scores for both S. epidermidis and S. aureus with the corresponding species-specified probes. Finally, the HSP60 degenerate primers were shown to amplify an anticipated 600-bp PCR product from all 29 Staphylococcus species and from all but 2 of 30 other microbial species, including various gram-positive and gram-negative bacteria, mycobacteria, and fungi. These preliminary data suggest the presence of species-specific sequence variation within the highly conserved HSP60 genes of staphylococci. Further work is required to determine whether these degenerate HSP60 primers may be exploited for species-specific microbic identification and phylogenetic investigation of staphylococci and perhaps other microorganisms in general.

Base Sequence↗
PubMed1994

Glycopeptides and nephrotoxicity.

Infections due to Gram-positive bacteria have become an increasing problem in the ICU. Furthermore, multidrug resistance among Gram-positive pathogens is increasingly recognized. Empirical therapy with antibiotic regimens that are effective against Gram-positive pathogens is often required in the ICU. Many critically ill patients in the ICU have multiorgan system failure, including acute renal failure, which further impedes optimal antimicrobial therapy. In this communication, the use of glycopeptides in the ICU is briefly reviewed, and the occurrence of associated nephrotoxicity during therapy with vancomycin or teicoplanin, alone or in combination with an aminoglycoside, is examined. Finally, existing recommendations regarding the dose regimens of these agents in patients with renal impairment are evaluated, and guide-lines for optimizing glycopeptide therapy through improved pharmacokinetic monitoring are presented.

Anti-Bacterial Agents↗
PubMed1994

In vitro synergism of ceftriaxone combined with aminoglycosides against Pseudomonas aeruginosa.

The antipseudomonal activities of ceftriaxone (CEF) or ceftazidime (CAZ), each combined with tobramycin (TOB) or netilmicin (NET), against 90 clinically significant Pseudomonas aeruginosa isolates were examined both by checkerboard and time-kill assays. As expected, susceptibility testing of single antibiotics by agar dilution demonstrated good activity for CAZ (89% susceptible), TOB (94%), and NET (58%), but poor activity for CEF (15%). Checkerboard studies revealed striking synergy (FIC indices < or = 0.5) for CEF, however, in combination with either TOB (72%) or NET (81%), compared with CAZ-TOB (44%) or CAZ-NET (60%) (P < 0.01, respectively). No antagonism (FIC indices > or = 4) was found in any of these combinations. The MIC90s of CEF, CAZ, or aminoglycosides in the combinations were reduced at least fourfold: CEF, from > 128 to 32 mg/liter; CAZ, from 16 to 4 mg/liter; TOB, from 4 to 0.5 mg/liter; and NET, from 32 to 4 mg/liter. With CEF and NET, the percentage of strains sensitive to < or = 8 mg/liter of both drugs alone and in combination increased from 9% to 69%. Results of the time-kill assay for CEF-NET agreed reasonably well with the checkerboard method (Spearman rank correlation coefficient, 0.40, P < or = 0.01), and generated a bactericidal outcome in 60% (24 of the 40 isolates), when tested with combinations at 1/4 MBC of either antibiotic alone. Importantly, concentrations of CEF and aminoglycoside combinations that demonstrated synergy by either checkerboard or time-kill assays were achievable in serum clinically. These data suggest a unique interaction of CEF-aminoglycoside combinations against P. aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Ceftazidime↗
PubMed1994

Toxic shock syndrome toxin 1-producing Staphylococcus aureus isolates contain the staphylococcal enterotoxin B genetic element but do not express staphylococcal enterotoxin B.

Toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxin B (SEB) are two examples of variable genetic traits produced by Staphylococcus aureus. Regarding phenotypes, most investigations have reported that SEB and TSST-1 are not coproduced in S. aureus. However, it is unclear whether genotypically SEB (entB) and TSST-1 (tst) genes are found within the same isolate. Gene probes specific for entB and tst showed that both genes were present within 8 TSST-1+ isolates analyzed. However, SEB was not produced by any of these isolates. In contrast, none of 9 SEB-producing S. aureus isolates contained the TSST-1 genetic element DNA. Hybridization of restriction fragments with TSST-1 and SEB genetic element probes and tryptophan auxotyping suggested that tst and entB are located in close proximity on the chromosome. The entB locus may be a preferred site of insertion for the TSST-1 genetic element, and such insertion may interfere with the expression of SEB.

Bacterial Toxins↗
PubMed1994

Identification of five Peptostreptococcus species isolated predominantly from the female genital tract by using the rapid ID32A system.

The rapid ID32A kit (bioMérieux Vitek, Inc., Hazelwood, Mo.) was evaluated for its ability to identify Peptostreptococcus species compared with conventional biochemical tests and gas-liquid chromatography (Virginia Polytechnic Institute), the current "gold standard" method. A total of 5 Peptostreptococcus American Type Culture Collection strains and 95 clinical isolates comprising Peptostreptococcus anaerobius, P. asaccharolyticus, P. magnus, P. micros, and P. prevotii isolates were included for analysis. Overall, the sensitivity and specificity of the rapid ID32A kit in the identification for five Peptostreptococcus species compared with the Virginia Polytechnic Institute method were 93 and 80%, respectively. All P. anaerobius (n = 20) and P. asaccharolyticus (n = 25) isolates were identified with 100% sensitivity and 100% specificity. For the identification of P. magnus (n = 24) and P. micros (n = 19), the rapid ID32A kit was 100% sensitive for both species; the specificity for P. magnus was 95.8% and that for P. micros was 57.9%. The sensitivity and specificity of the rapid ID32A kit for identification of P. prevotii (n = 12) were poor (41.7 and 8.3%, respectively). The rapid ID32A kit is a useful method for the rapid differentiation of P. anaerobius and P. asaccharolyticus from other Peptostreptococcus spp. Conventional methods should be used to identify to the species level isolates of P. magnus, P. micros, and P. prevotii.

Bacteriological Techniques↗
PubMed1994

Efficacy of microbial identification system for epidemiologic typing of coagulase-negative staphylococci.

The lack of an adequate typing system hampers our understanding of the epidemiology of infections caused by coagulase-negative staphylococci (CoNS). CoNS have become recognized as important nosocomial pathogens and the principal cause of infections associated with invasive devices. Sensitive, specific, and convenient methods are needed to evaluate whether implementing infection control guidelines reduces the risk of nosocomial infections from CoNS and other pathogens. The Microbial Identification System (MIDI) (Microbial ID Inc., Newark, Del.), a semiautomated system for fatty acid methyl ester analysis, shows considerable promise for clinical and epidemiologic applications. Its predictive accuracy and reliability were tested by using epidemiologically related and replicated CoNS isolates as well as CoNS from epidemiologically unrelated clinical infections, which were obtained from five established hospital culture collections in diverse geographic locations. Two hundred isolates were fully characterized in 5 days by one person using MIDI, and the results were similar to those produced by more expensive and time-consuming conventional typing methods. MIDI appears to be a useful screening tool that could be used before more expensive and labor-intensive molecular methods. It offers important advantages to hospital epidemiologists and clinical microbiologists who must identify and type CoNS isolates.

Bacterial Typing Techniques↗
PubMed1993

Clinical spectrum of nonmenstrual toxic shock syndrome (TSS): comparison with menstrual TSS by multivariate discriminant analyses.

To further characterize the clinical spectrum of nonmenstrual toxic shock syndrome (NMTSS), we constrasted and compared the clinical and laboratory features of 24 patients with NMTSS with those of 21 patients with menstrual TSS (MTSS), using univariate and stepwise discriminant analyses. In contrast to patients with MTSS, those with NMTSS comprised a heterogeneous group with varying host factors and clinical presentations. The NMTSS group differed from the MTSS group in terms of the frequency of prior antimicrobial treatment (46% vs. 16%; P = .05), the rate of nosocomial acquisition (65% vs. 0; P = .0001), and the time of onset of fever and rash in relation to the initial symptoms (P = .005 and .03, respectively, with earlier onset in the NMTSS group). In addition, NMTSS patients experienced more frequent renal and CNS complications and less frequent musculoskeletal involvement (P = .07 in all three cases). Stepwise discriminant analysis identified four variables (delayed onset of TSS symptoms after precipitating injury or event, more frequent CNS manifestations, less frequent musculoskeletal involvement, and higher degree of anemia) differentiating NMTSS patients from MTSS produced TSS toxin 1 (TSST-1) with comparable frequency (62% vs. 84%; P = .2), but production of staphylococcal enterotoxin A (SEA) was less common in NMTSS than in MTSS (33% vs. 74%; P = .01). Furthermore, MTSS-associated isolates more commonly coexpressed TSST-1 and SEA than did NMTSS-associated isolates (68% vs. 28%; P = .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Teicoplanin versus vancomycin in the empirical treatment of febrile neutropenic patients.

Gram-positive infections have become prevalent among neutropenic patients with cancer. A prospective, randomized, double-blind trial of teicoplanin, 6 mg/kg every 12 h for three doses then every 24 h, versus vancomycin hydrochloride, 15 mg/kg every 12 h, in the empirical treatment of febrile neutropenic patients was undertaken among 50 consecutive patients with haematological malignancy. The patients also received piperacillin sodium, 3 g every 4 h, and tobramycin sulphate, 1.5-2 mg/kg every 8 h. Both groups (25 teicoplanin and 25 vancomycin) were comparable in age, sex, renal function, underlying disease and concurrent therapy. Among 22 patients (44%) with culture-proven infection, Gram-positive organisms were isolated in 15 (9 with bacteraemia) and Gram-negative in 11 (4 with bacteraemia). Mixed or polymicrobial infection occurred in 8 patients. Serum 1-h peak and trough levels at steady state were 41 +/- 15 and 12 +/- 3 mg/l for teicoplanin (at 14 +/- 4 days), and 40 +/- 10 and 8 +/- 5 mg/l for vancomycin (at 0.9 +/- 0.6 days). Mean elimination half-life and apparent volume of distribution at steady state were 80.5 +/- 21.5 h and 1.4 +/- 0.8 l/kg for teicoplanin, and 5.6 +/- 1.8 h and 0.6 +/- 0.2 l/kg for vancomycin. Empirical antimicrobial therapy was successful in 23 teicoplanin and 21 vancomycin patients, respectively (p = 0.67; two-tailed Fisher's exact test). Nephrotoxicity (serum creatinine > 110 mmol/l), however, was more common among vancomycin patients (10 versus 2; p = 0.02), while termination of treatment due to adverse effects was also more common among vancomycin patients (10 versus 2; p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Characterization of Neisseria meningitidis by polymerase chain reaction and restriction endonuclease digestion of the porA gene.

Subtype classification based on the use of monoclonal antibodies to the class 1 outer membrane protein combined with techniques such as multilocus enzyme electrophoresis remains the standard method of characterizing isolates during outbreaks of invasive meningococcal disease. We developed a rapid typing method based on the restriction fragment length polymorphisms (RFLPs) within the polymerase chain reaction (PCR) product of the porA gene, which encodes the class 1 outer membrane protein, reflecting genotypic rather than phenotypic variability between strains. Forty-five isolates of invasive Neisseria meningitidis obtained from October 1990 to April 1992 were studied after randomization and coding. Included among these were isolates from a local outbreak that resulted in a mass vaccination program. PCR amplification for each isolate was followed by restriction digestion with the following enzymes in the indicated sequence: HaeIII, RsaI, HinfI, HpaII, and AluI. Eighteen different patterns were demonstrated on the basis of RFLPs, whereas only seven groups were identified after standard subtyping. The most common isolate identified by serosubtyping was serogroup C, serotype 2a, subtype P1.2 (C:2a:P1.2) (38%). Thirteen (76%) of these group C isolates shared a common RFLP pattern after digestion with the five restriction enzymes. We were able to further differentiate strains of C:2a:P1.2 with electrophoretic type 5 from electrophoretic types 1, 9, and 15 that occurred during an apparent outbreak. We were also able to characterize 15 isolates (33%) which could not be subtyped with monoclonal antibodies. Our method offers a convenient alternative to standard subtyping procedures and is particularly useful in outbreak situations in which rapid characterization of N. meningitidis is essential so that rational public health policy regarding preventative measures can be formulated.

Bacterial Outer Membrane Proteins↗
PubMed1993

Improved purification and biologic activities of staphylococcal toxic shock syndrome toxin 1.

An improved method for producing highly purified toxic shock syndrome toxin 1 (TSST-1) by preparative isoelectric focusing in a Bio-Rad Rotofor cell and then chromatofocusing is described. Purification to homogeneity was confirmed by silver staining after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE; 50 micrograms of protein was loaded), by immunoblotting with polyclonal rabbit antiserum raised against the crude culture supernatant used for purification, and by autoradiography after iodination and SDS-PAGE. Biologic activity was demonstrated by mitogenicity and cytokine induction (tumor necrosis factor alpha [TNF-alpha], interleukin 1-beta [IL-1 beta], and IL-6) of human peripheral blood mononuclear cells (PBMCs) and by lethality in New Zealand White rabbits following subcutaneous infusion. In contrast to commercial TSST-1 preparations, our TSST-1 preparation required the presence of both monocytes and T cells for the induction of TNF-alpha and IL-1 beta from human PBMCs. A 46-kDa contaminating protein in the commercial TSST-1 preparation, identified as staphylococcal lipase, was likely responsible for the induction of TNF-alpha and IL-1 beta from human monocytes in the absence of T cells, a biologic activity falsely attributed to purified TSST-1. Our improved purification procedure for TSST-1 provides a high yield and is both more rapid and less labor intensive than previously reported methods. Furthermore, our studies clearly demonstrate the need for stringent methods of purity assessment of TSST-1 preparations before ascribing to them their potent biologic activities.

Adult↗
PubMed1993

Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial.

To evaluate the clinical efficacy of interferon-alpha in hepatocellular carcinoma, 71 adult Chinese patients with histologically proven inoperable hepatocellular carcinoma were randomized to receive recombinant interferon-alpha 2a (50 x 10(6) IU/m2) intramuscularly three times a week (n = 35) or no antitumor therapy (n = 36). The survival of interferon-alpha-treated patients was significantly better than that of patients who received no antitumor therapy (p = 0.0471); median lengths of survival were 14.5 and 7.5 wk, respectively. Objective tumor regression greater than 50% was observed in 31.4% (11 of 35) of patients receiving interferon-alpha. Interferon-alpha induced tumor regression greater than 50% in 11 (31.4%) patients. Compared with the group receiving no antitumor therapy, the interferon-alpha therapy group had more tumor regression (p < 0.0001) and less tumor progression (p = 0.001). This high-dose interferon-alpha therapy was relatively well tolerated; only 34.3% of patients required reduction of dosage by one third or one half because of persistent fatigue. Two patients with diabetes mellitus (one also had tabes dorsalis) exhibited mental deterioration that might have been partially attributable to interferon-alpha therapy. We conclude that interferon-alpha is useful in a proportion of Chinese patients with inoperable hepatocellular carcinoma, both in prolonging survival and in inducing tumor regression.

Adult↗
PubMed1993

Prosthetic valve endocarditis. Experience with porcine bioprostheses.

Prosthetic valve endocarditis remains an infrequent but serious complication of cardiac valvular replacement. Prosthetic valve endocarditis was diagnosed in 56 (1.8%) of 3200 patients in whom one or more porcine bioprostheses were implanted between 1975 and 1988. Of the 56 patients with prosthetic valve endocarditis, there were 40 men and 16 women, with a mean age at initial implantation of 57 years (27 to 81 years). Of the 56 patients, 6 were initially treated for native valve endocarditis. There were 8 cases of early prosthetic valve endocarditis (defined as occurring less than 60 days after initial surgical intervention) and 48 cases of late prosthetic valve endocarditis (occurring after 60 days). The overall mortality rate of the 56 patients was 32% (18 patients). Of the 8 patients with early prosthetic valve endocarditis, 6 (75%) died. Of the 48 patients with late prosthetic valve endocarditis, 12 (25%) died. The predominant organisms were Staphylococcus epidermidis (12 cases), Streptococcus viridans (8 cases) and Staphylococcus aureus (7 cases). The presence of hemodynamic compromise, including congestive heart failure, septic embolism, persistent sepsis, and echocardiographic evidence of vegetations, dictated the mode and timing of the addition of surgical intervention to medical therapy. The survival rate for medically and surgically treated patients with late prosthetic valve endocarditis was 91% (20 patients); none of the patients with early prosthetic valve endocarditis survived (all had severe hemodynamic compromise). We analyzed 18 factors for the prediction of early and late death. The predictors of death by univariate analysis for both early and late prosthetic valve endocarditis were age, diagnosis time, renal status, sepsis, management mode, fever, dental procedures, and dental prophylaxis. The predictors by multivariate analysis were age, diagnosis time, renal status, and management mode for early prosthetic valve endocarditis, and only diagnosis time for late prosthetic valve endocarditis. Annular abscess formation occurred in 27% of the patients. There were no complex aortic or mitral reconstructions. There was one reoperation for recurrent and residual endocarditis. There was one late death as a result of recurrent prosthetic valve endocarditis. We advocate early diagnosis and aggressive combined medical and surgical treatment before the development of hemodynamic compromise and other characteristic signs when the culprit organisms are Staphylococcus aureus, gram-negative organisms, and Candida albicans.

Adult↗
PubMed1992

Evaluation of new anti-infective drugs for the treatment of respiratory tract infections. Infectious Diseases Society of America and the Food and Drug Administration.

These guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. Five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. A wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. Inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. Microbiologic evaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. Alternatively, surrogate markers may be used to identify the etiologic agent. The efficacy of new drugs is evaluated with reference to anticipated response rates. Establishment of the microbial etiology of respiratory tract infections is hampered by the presence of "normal flora" of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. This issue is addressed for each category of infection described. For example, it is suggested that for initial phase 2 trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collect exudate for culture. Acute exacerbations of chronic bronchitis also present difficulties in the establishment of microbial etiology. These guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. For pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. For each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. Clinical improvement is not acceptable unless quantitative response measures can be applied.

Anti-Bacterial Agents↗