Inappropriate use of antibiotics and the risk for delayed admission and masked diagnosis of infectious diseases: a lesson from Taiwan.

BACKGROUND: Antibiotic resistance is a serious problem worldwide. It is particularly alarming in Taiwan and other countries of the Pacific Rim, where antimicrobial drugs are used excessively. OBJECTIVE: To determine whether use of antimicrobial drugs before coming to an emergency department was associated with delayed admission or masked or missed diagnoses at a large general hospital in Taiwan. METHODS: Antimicrobial activity in urine (AAU) was determined in all patients seen in the emergency department during a 3-month study. A physician, unaware of the results of the urine tests, reviewed the medical charts of patients who were admitted to the hospital to determine whether admission was delayed for at least 7 days or the diagnosis was masked or missed. RESULTS: Of the 1182 patients, 444 were admitted to the hospital. In 220 patients (49.5%), AAU was detected. There was no significant difference in AAU between patients with or without an infectious disease (53.0% vs 46.3%, respectively; P =.41). For patients with infection, 34.8% of those with AAU had a delayed admission, compared with only 21.6% without AAU (relative risk [RR], 1.61; 95% confidence interval [CI], 1.03-2.52; P =.03). For patients without infection, 36.2% of those with AAU had a delayed admission compared with 31.1% without AAU (RR, 1.16; 95% CI, 0.81-1.68; P =.64). For patients with infection, 48.7% of those with AAU had a masked or missed diagnosis, compared with 25.5% without AAU (RR, 1.91; 95% CI, 1.30-2.80; P<.001). For patients without infection, 27.6% of those with AAU had a masked or missed diagnosis compared with 14.8% without AAU (RR, 1.87; 95% CI, 1.11-3.17; P =.02). CONCLUSION: Use of antimicrobial drugs before coming to an emergency department was associated with a significantly increased risk for delayed and masked or missed diagnoses of infectious diseases and missed diagnosis of noninfectious diseases.

Eosinophilic meningitis caused by Angiostrongylus cantonensis: report of 17 cases.

PURPOSE: To describe two outbreaks of Angiostrongylus cantonensis infection that occurred in Kaohsiung, Taiwan, during 1998 and 1999, and to characterize the source of the outbreaks and the clinical manifestations of the disease. SUBJECTS AND METHODS: We performed a retrospective cohort study among Thai laborers with eosinophilic meningitis who ate raw snails (Ampullarium canaliculatus), as well as an environmental surveillance of larvae in snails. RESULTS: We enrolled 17 Thai laborers in whom severe headache and eosinophilia developed within 4 to 23 days after eating raw snails. Twelve (71%) developed eosinophilic meningitis. Third-stage larvae were found in the cerebrospinal fluids of 2 patients and in all 12 tested snails. Specific antibodies to A. cantonensis were detected in serum from 16 of the patients and in cerebrospinal fluid from 5 of the patients. Central nervous system manifestations included headache (n = 17 [100%]), fever (n = 11 [65%]), Brudzinski's sign/stiff neck (n = 11 [65%]), hyperesthesia (n = 3 [18%]), cranial nerve palsy (n = 2 [12%]), diplopia (n = 2 [12%]), and ataxia (n = 1 [6%]). Laboratory findings included peripheral eosinophilia (n = 15 [88%]) and cerebrospinal fluid eosinophilia (n = 12 [71%]); elevated immunoglobulin (Ig) E levels (n = 13 [100%]); and transient increases in white blood cell count (n = 7 [41%]) and in serum levels of creatine kinase (n = 7 [41%]), transaminase (n = 3 [18%]), and lactate dehydrogenase (n = 2 [12%]). The severity of illness and eosinophilia were correlated with the number of ingested snails. Meningeal and basal ganglion enhancement was noted on magnetic resonance imaging in several patients. Treatment with mebendazole combined with glucocorticosteroids appeared to shorten the course of the infection, but not the number of relapses. The eosinophil count fell to normal within 3 months, but IgE levels remained elevated for as long as 6 months. All patients recovered with minimal neurologic sequelae. CONCLUSION: Eosinophilic meningitis caused by A. cantonensis should be considered in patients who have headache or central nervous system manifestations after eating raw snails.

Novel screening method for urine cultures using a filter paper dilution system.

We have developed a novel method for urine culture for office practice based on the use of filter paper as a solid-phase dilution device. Filtration dilutes and spreads the inoculum onto a solid culture surface. Experiments were conducted to determine the optimum inoculum size, microbial permeability through filter papers, and ability to exclude vaginal epithelial cells. The filter paper dilution system was compared to the standard streak method to detect bacteriuria in specimens submitted to the diagnostic laboratory. The sensitivity and specificity of the filter paper dilution system for detection of high-count (>/=10(4) CFU/ml) gram-negative bacteriuria in 487 urine specimens were 98.2 and 97.4%, respectively. The sensitivity and specificity for gram-positive bacteriuria in 404 urine specimens were 91.2 and 99.2%, respectively. Low-count gram-negative bacteriuria (<10(4) CFU/ml) was detected by the filter paper dilution system in five of nine specimens (55.6%). In addition, the filter paper dilution system was able to detect gram-negative bacteria in 12 of 41 (29.3%) mixed cultures. Lactobacillus and Gardnerella organisms in urine specimens were excluded by the filter paper dilution system. Only three of eight Candida sp. isolates were detected at counts of >/=10(4) CFU/ml. The system has good storage properties and can be inoculated at the point of source without the need for refrigeration or preservatives. It should be a useful screening method for office practice, where members of the family Enterobacteriaceae and staphylococci cause most infections. Standard culture methods are preferred for hospital diagnostic microbiology laboratories, where there is a need to detect yeasts and fastidious microorganisms and to isolate individual colonies from mixed cultures.

Antimicrobial activities of mefloquine and a series of related compounds.

Mefloquine was found to have bactericidal activity against methicillin- and fluoroquinolone-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis and gentamicin- and vancomycin-resistant strains of Enterococcus faecalis and Enterococcus faecium. The MICs were 16 microg/ml, and the minimal bactericidal concentrations (MBCs) were 16 to 32 microg/ml. These concentrations cannot be achieved in serum. Mefloquine was active at a more achievable concentration against penicillin-susceptible and -resistant Streptococcus pneumoniae, with MICs of 0.2 to 1.5 microg/ml. Mefloquine was not active against gram-negative bacteria and yeasts. In an attempt to find more active derivatives, 400 mefloquine-related compounds were selected from the chemical inventory of The Walter Reed Army Institute of Research. We identified a series of compounds containing a piperidine methanol group attached to pyridine, quinoline, and benzylquinoline ring systems. These had activities similar to that of mefloquine against S. pneumoniae but were far more active against other gram-positive bacteria (MICs for staphylococci, 0.8 to 6.3 microg/ml). They had activities similar to that of amphotericin B against Candida spp. and Cryptococcus neoformans. Combinations of the compounds with gentamicin and vancomycin were additive against staphylococci and pneumococci. The MIC and MBC of gentamicin were decreased by four- to eightfold when this drug was combined with limiting dilutions of the compounds. There was no antagonism with other antimicrobial drugs. The compounds were rapidly bactericidal. They appear to act by disrupting cell membranes. Combinations of the compounds with aminoglycoside antibiotics may have potential for therapeutic use.

Extent of antibiotic use in Taiwan shown by antimicrobial activity in urine.

Taiwan has high prevalence of antibiotic resistant, community-acquired respiratory pathogens. We investigated whether there was a high frequency of antibiotic use in the community. Antimicrobial activity in urine was detected in 55.2% of 1182 patients on arrival at an emergency department, 25.1% of 203 internal medicine out-patients, 7.6% of 471 high school students, and 7.4% of 202 people at a centre for senior citizens.

Detection of antimicrobial activity in urine for epidemiologic studies of antibiotic use.

Antibiotic resistance is the inevitable consequence of the selective pressure of antimicrobial drug use and the adaptive plasticity of the microorganisms. Excessive and irrational use of antimicrobial drugs is a problem in all countries. It is particularly troublesome in developing countries where there is a heavy burden of infectious diseases. This study was designed to determine whether detection of antimicrobial activity in the urine might be a useful tool for epidemiologic studies of the interaction between antibiotic use and resistance in developing countries. A laboratory marker is necessary because the history of antimicrobial drug use may be unreliable. Serial specimens or spontaneously voided urine were obtained from healthy volunteers given a single oral dose of commonly used antimicrobial drugs. Urine was also obtained from hospitalized patients the morning after the last dose of an antimicrobial drug and from untreated controls. Assays were performed with standard American Type Culture Collection (Rockville, MD) stains of Bacillus stearothermophilus, Escherichia coli, and Streptococcus pyogenes. Antimicrobial activity could not be detected in pretreatment urine. After a single oral dose, the beta lactam antibiotics and erythromycin could be detected for about 12 to 24 hours, whereas clindamycin, tetracycline, trimethoprim/sulfamethoxazole, and ciprofloxacin could be detected for 48 or more hours. In hospitalized patients, receiving multiple drugs, the following were the sensitivity and specificity for detection of antimicrobial activity: for B. stearothermophilus, 100.0% and 85.9%, respectively; for S. pyogenes, 94.9% and 94.9%, respectively; and for E. coli, 71.8% and 98.7%, respectively. The combination of E. coli and Streptococcus pyogenes exhibited a sensitivity of 97.4% and specificity of 94.9%. Detection of antimicrobial activity in urine is a promising method to determine antimicrobial drug use in epidemiologic studies, particularly in populations in which drug use history is unreliable.

Antimicrobial activity of rifabutin.

Rifabutin is a spiro-piperidyl-rifamycin derived from rifamycin-S. It is structurally related to rifampin and shares many of its properties. Rifabutin has a broad spectrum of antimicrobial activity. It is considerably more active than rifampin in vitro against the Mycobacterium avium complex (MAC), Mycobacterium tuberculosis, and Mycobacterium leprae. It also is active against most atypical mycobacteria, including Mycobacterium kansasii, but Mycobacterium chelonae is relatively resistant. Rifabutin also is active against staphylococci, group A streptococci, Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Haemophilus ducreyi, Campylobacter jejuni, Helicobacter pylori, Chlamydia trachomatis, and Toxoplasma gondii. It has poor activity against Enterobacteriaceae and Pseudomonas species. This review focuses on the antimicrobial profile of rifabutin in relation to its pharmacological properties. Special emphasis is placed on its in vitro activity against MAC and other mycobacteria, its efficacy in cell culture and animal models, and its potential as a component of multidrug therapy for mycobacterial and other infectious diseases.

Effect of salicylate on expression of flagella by Escherichia coli and Proteus, Providencia, and Pseudomonas spp.

Osmotic stress, salicylate, and Mar (multiple antibiotic resistance) mutation are known to block the expression of the OmpF porin. Since these conditions have also been shown to inhibit the expression of P and CFA fimbriae in Escherichia coli, we speculated that they might affect the expression of flagella as well. Hyperosmotic conditions have been shown to block the synthesis of flagellin and expression of flagella in E. coli (C. Li, C. J. Louise, W. Shi, and J. Adler, J. Bacteriol. 175:2229-2235, 1993). In the current study, sodium salicylate was found to inhibit the motility of E. coli, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, and Providencia stuartii in a reversible, concentration-dependent manner. Swarming did not occur at 20 mM sodium salicylate. Salicylate also blocked the synthesis of flagellin in E. coli. Phenotypic Mar mutants of E. coli derived from motile strains were amotile. Flagella were markedly reduced as determined by scanning electron microscopy when P. mirabilis was grown in broth containing 20 mM salicylate. Salicylate had no apparent effect, however, on expression of a 40-kDa porin protein in P. mirabilis. This finding suggests that the noted effect of salicylate on Proteus spp. may be mediated through a mechanism other than porin production or that the Proteus porin may not be analogous to OmpF in E. coli. Salicylate decreased the motility of Pseudomonas cepacia but had no effect on Pseudomonas aeruginosa. The exact mechanism by which salicylate exerts its effect is not known, but it appears to be related to osmoregulation.

Use of antimicrobial drugs in developing countries.

The era of antimicrobial therapy is now in its seventh decade. The major scientific discoveries made during this period have saved of countless lives and markedly reduced the morbidity of infectious diseases. These achievements are now threatened by the global emergence of resistant strains. The process is fostered by the remarkable genetic diversity and transfer of resistance among microbes, the selective forces of antibiotic use, and powerful socioeconomic and marketing forces. It is doubtful that development of new drugs will adequately address the problem. The only measures which might slow the development and transmission of resistant microorganisms are those that decrease the global burden of infectious diseases. This requires improved sanitation, nutrition and immunization, hospital infection control and strategies that will diminish the inappropriate and excessive promotion and use of antibiotics. Physicians, pharmacists and consumers need to be better informed about how to use antibiotics and the dangers of inappropriate use. The multinational and local pharmaceutical companies must become more responsible for their products and promotional practices. The current situation is bleak. It will undoubtedly will get worse as the burden of resistant microorganisms continues to increase.

Effect of salicylate, bismuth, osmolytes, and tetracycline resistance on expression of fimbriae by Escherichia coli.

Adherence of Escherichia coli is facilitated by fimbriae and several outer membrane proteins (OMPs). Hypertonic conditions, salicylate, and Mar mutations are known to reduce OmpF expression. We speculated that OMPs involved in export or assembly of fimbrial subunits might be similarly affected. To explore this hypothesis, E. coli expressing P, type 1, S, colonization factor antigen I (CFA/I), or CFA/II fimbriae was grown in the presence of salicylate, bismuth salts, NaCl, and nonfermented sugars. Tetracycline-resistant clones were derived from several P-fimbriated strains. The bacteria were tested for the ability to agglutinate erythrocytes, yeast cells, and alpha-D-Gal(-4)-beta-D-Gal-bonded latex (Gal-Gal) beads and were examined for fimbriae by electron microscopy. Hyperosmolar conditions decreased fimbrial expression for all strains. Expression of P fimbriae by pyelonephritic strains, all of which were OmpF+, was reversibly repressed by salicylate and bismuth salts. CFA strains were similarly affected. Tetracycline-resistant P-fimbriated strains were OmpF deficient, were unable to agglutinate erythrocytes and Gal-Gal beads, and lacked fimbriae as observed by electron microscopy. Strains with plasmid-encoded P-fimbrial genes did not demonstrate OmpF on polyacrylamide gel electrophoresis profiles and were not affected by salicylate. The type 1-fimbriated phenotype was not affected by salicylate or bismuth unless the strains also expressed P fimbriae. S-fimbriated strains were not affected. The mechanism by which salicylates, bismuth salts, and tetracycline resistance inhibit or modulate the expression of P fimbriae may be mediated through OmpF and other OMPs.

Chemoprophylaxis and suppressive therapy in the management of urinary tract infections.

Urinary tract infections are among the most common infectious diseases encountered in domiciliary and hospital practice. The ease of treatment and prophylaxis depends on host factors and the nature of invading microbe. Prophylaxis is often effective in preventing infection from exogenous or endogenous sources. It is useful in females with frequent, recurrent infections, in males with a persistent prostatic focus, in renal transplant recipients, and following instrumentation of the urinary tract. It is often useful in children with vesico-ureteral reflux and in patients undergoing urological operations. It is ineffective in patients with long-term indwelling catheters. A wide variety of prophylactic tactics is available. These are designed to meet the special needs of individual patients. Patient counselling is a key feature of a good prophylactic regimen. Desirable features of antimicrobial drugs used for prophylaxis include good oral absorption, minimum toxicity, high concentrations in the urine, minimum potential for development of resistance and low cost. Suppressive therapy is often ineffective and cannot substitute for corrective surgical procedures. It is important to recognize microbial failure and to avoid unnecessary therapy.

The use of antimicrobial drugs in Nagpur, India. A window on medical care in a developing country.

The objective of the study was to determine the patterns of use of antimicrobial drugs in the general population of the large, industrial city of Nagpur, India. Interviews of pharmacists and clients were carried out in a stratified, random sample of 34 pharmacies to determine beliefs and practices in prescribing and self-prescribing of antibiotics by complaint, choice of drug, dose, duration, cost, age and sex of the consumers. The study showed that drugs were dispensed without prescription despite prohibition by the Indian Pharmaceutical Act. Sales of antimicrobial drugs accounted for 17.5% of 511 purchases and 23.3% of expenditures for drugs. Proprietary brands of penicillins, co-trimoxazole and tetracyclines were dispensed most often (64.8%). The most common indications were upper respiratory, gastrointestinal and nonspecific complaints. The median number of units obtained was 5.0 (95% range 1-20), at a median cost of $0.50 per purchase, usually taken for less than five days. Repeat purchases were made without consulting a physician. Almost two thirds of purchases (63.9%) were for males, mainly under the age of ten years. Clients had poor knowledge of the indications, side effects, adverse reactions and appropriate duration of therapy. The dispenser viewed himself as a businessman rather than a professional and rarely offered unsolicited advice. Co-prescribing of 'tonics' added to costs and decreased the purchasing power for antimicrobial drugs. Most purchases of antimicrobial drugs in community pharmacies in Nagpur were for minor indications and were limited by the purchasing power of the consumers. It is doubtful that the choice of drug and the short duration of therapy would be effective for serious infections.(ABSTRACT TRUNCATED AT 250 WORDS)