Long-term treatment with lithium prevents the development of dopamine receptor supersensitivity.

Long-term treatment of rats with haloperidol produced an increased sensitivity to the locomotor and stereotypic effect of apomorphine. This behavioral dopaminergic supersensitivity was accompanied by increased binding of [3H] spiroperidol in the striatum. Rats treated concurrently with lithium and haloperidol failed to develop both behavioral sensitivity to apomorphine and increased striatal dopamine receptor binding. The ability of lighium to prevent recurrent manicdepressive episodes may be related, in part, to its ability to stabilize dopaminergic receptor sensitivity.

Cerebral ventricular enlargement in chronic schizophrenia. An association with poor response to treatment.

Response to neuroleptic drug treatment in ten chronic schizophrenic patients with enlarged cerebral ventricles was compared with ten similar patients with normal ventricles. The groups were closely matched for age, age at onset of illness, years of illness and hospitalization, drug dosage, and plasma neuroleptic concentration as measured by radioreceptor assay. Response was significantly worse in the patients with enlarged ventricles. This finding supports the notion that ventricular enlargement is clinically relevant in patients with chronic schizophrenia and that patients with this abnormality may have a biologically different illness than similar patients without it.

Clinical usefulness of susceptibility testing of anaerobes.

We have studied the clinical usefulness of antibiotic susceptibility testing of fresh clinical isolates of anaerobes (primarily from blood cultures). Analysis of 65 patients showed that susceptibility reports were used in only 13 instances (20%), representing mainly orothopedic and CNS infections. Of the 47 patients whose susceptibilities were not used, 20 received therapy (appropriate in each case) based on the culture report, and 27 were treated empirically. Only six patients in the empirically treated group received inappropriate treatment, but four of those six died, and patients in this group as a whole had a worse outcome than did patients in the other groups. However, these empirically treated patients also had a somewhat worse prognosis. We suggest that susceptibility testing of anaerobes be reserved for bacteremic patients and for managing severe, chronic anaerobic infections, such as septic arthritis, osteomyelitis, and brain abscesses.

Clinical characteristics of anaerobic bactibilia.

During a two-year period, 1,892 patients underwent biliary tract surgery at the Mayo Clinic. Both aerobic and anaerobic bile cultures were performed in 371 patients and 253 of these were positive. Anaerobes were isolated from 100 patients, although only twice in pure culture. Only aerobes grew from cultures from 153 patients. One hundred cases of biliary tract infections involving anaerobes and an equal number involving aerobes only were reviewed in order to determine their clinical characteristics. Prominent features of anaerobic bactibilia included (1) a history of complex, multiple, biliary tract surgeries often involving biliary-intestinal anastomoses and common bile duct manipulation, (2) severe symptoms, (3) high incidence of postoperative infectious complications, especially wound infections. Further analysis of anaerobic biliary infections suggested that Bacteroides fragilis was more often associated with serious pathologic conditions of the biliary tract than was Clostridium.

Prospective randomized comparison of mezlocillin therapy alone with combined ampicillin and gentamicin therapy for patients with cholangitis.

Forty-six patients with cholangitis were randomized to receive therapy with mezlocillin sodium (24 patients) or a combination of ampicillin sodium--gentamicin sulfate (22 patients). The biliary concentration of mezlocillin was 112 times higher than that of ampicillin and 778 times higher than that of gentamicin. The ratio of the concentration in serum or bile over the minimum inhibitory concentration against aerobic gram-negative bacilli (therapeutic index) was higher for mezlocillin than for either ampicillin or gentamicin. Twenty (83%) of 24 patients were cured following mezlocillin therapy compared with 9 (41%) of 22 patients after ampicillin-gentamicin therapy. The 3 patients with superinfection were in the ampicillin-gentamicin arm of the study. Fewer toxic or adverse effects occurred in association with mezlocillin treatment than with ampicillin-gentamicin treatment. Mezlocillin therapy was more effective, less toxic, and less expensive than treatment with ampicillin and gentamicin for patients with cholangitis.

Multilaboratory comparison of growth characteristics for anaerobes, using 5 different agar media.

A multilaboratory study compared the growth of 30 fastidious anaerobes, using 5 different agar media: Wilkins-Chalgren (WC), WC with either whole or laked sheep blood, and Brucella supplemented with vitamin K(1) and hemin and either laked or whole sheep blood. The media were compared for quality and quantity of growth. Experiments were conducted either entirely in an anaerobic chamber or inoculated in ambient air with anaerobic incubation. The results showed that (1) any medium plus whole or laked blood was better than unsupplemented WC, (2) whole blood and laked blood additives gave similar results, (3) supplemented Brucella with whole or laked blood was superior to WC and WC with whole or laked blood, and (4) anaerobic and aerobic inoculation with anaerobic incubation gave similar results. Brucella agar supplemented with whole or laked blood supports the growth of fastidious anaerobic species better than the WC agars do.

Multilaboratory comparison of anaerobe susceptibility results using 3 different agar media.

A 5-laboratory study was performed that used the National Committee for Clinical Laboratory Standards (NCCLS) reference agar dilution method with 3 media formulations to determine whether the use of different media would affect minimum inhibitory concentration (MIC) results. Wilkins-Chalgren, Brucella-based blood agar (BRU), and Wilkins-Chalgren agar plus blood (WCB) and 6 antibiotics (clindamycin, cefoxitin, ceftizoxime, piperacillin, metronidazole, and trovafloxacin) were evaluated with 58 isolates. The MIC values were compared, and a significant correlation of >0.80 was demonstrated for all media and each antibiotic/organism group. The cumulative rate of errors for all antibiotics was 0.1%. These data indicate that a change in the NCCLS reference medium for testing of anaerobic bacteria susceptibility to either BRU or WCB will not affect the MIC results for the antibiotics and organisms evaluated.

Interaction of physostigmine and delta-9-tetrahydrocannabinol in man.

To investigate the hypothesis that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of marihuana, acts by interfering with cholinergic brain mechanisms, 0.75 to 1.25 mg of physostigmine, a centrally active cholinergic drug, was given intravenously to 5 normal volunteers who had ingested 20 to 40 mg of THC 2 hours earlier. Physostigmine decreased the degree of tachycardia and conjunctival injection produced by THC. The major psychologic effects of physostigmine were amplification of the lethargy and somnolence which occur late in the course of THC intoxication. We interpret the lack of physostigmine counteraction of the peak psychologic effects of THC as evidence against the hypothesis that THC acts predominantly by an anticholinergic mechanism.

d-Amphetamine-induced heterogeneous changes in psychotic behavior in schizophrenia.

In this placebo-paired, double-blind study, 13 of 45 schizophrenic patients showed an acute improvement in schizophrenic symptoms following d-amphetamine infusion (20 mg). The 18 patients who worsened tended to have higher CSF 3-methoxy-4-hydroxyphenylglycol levels than did those who improved. d-Amphetamine blood levels and clinical descriptors of schizophrenic subgroups did not differentiate patients who improved from those who worsened; however, patients who improved had been significantly more psychotic before the infusion. Patients who worsened had been more psychotic than those who did not change. The authors suggest that those who did not change. The authors suggest that sensitivity to dopamine stimulation in schizophrenia is state-dependent rather than trait-dependent and that the simple, undirectional hypothesis of schizophrenia needs to be reformulated.

Laboratory tests used to guide antimicrobial therapy.

Laboratory tests that are usually considered helpful in guiding antimicrobial therapy include antimicrobial agent susceptibility tests, determination of bacterial production of beta-lactamase, and assay of specific antimicrobial levels in serum and other body fluids. Susceptibility tests should be performed primarily on clinically significant isolates from critical specimens (such as blood or other normally sterile body fluids or tissues) with use of standardized methods established by the National Committee for Clinical Laboratory Standards. Reporting of results should be selective so that clinicians are encouraged to use the least expensive but useful agent in a group--for example, first-generation rather than third-generation cephalosporins. Because standardized methods are not available for assays of serum inhibitory and bactericidal activity, the accuracy and clinical utility of these tests are as yet undetermined. Determination of bacterial resistance to antimicrobial agents is the most important goal of susceptibility testing. Special methods are needed to detect methicillin-resistant staphylococci, high-level aminoglycoside- and glycopeptide-resistant enterococci, and antimicrobial-resistant strains of Neisseria gonorrhoeae, Streptococcus pneumoniae, and Haemophilus influenzae. Accurate measurement of serum concentrations of antimicrobial agents is important to ensure that therapeutic levels have been obtained and to avoid excessive levels of potentially toxic agents such as aminoglycosides and glycopeptides, especially when renal function is compromised.

Laboratory tests used to guide antimicrobial therapy.

Laboratory tests that can be helpful in guiding antimicrobial therapy include antimicrobial susceptibility testing, determination of bacterial beta-lactamase activity, assay of serum inhibitory and bactericidal activity, and assay of specific antibiotic levels in serum. When any microorganism is isolated from a normally sterile body fluid in a patient with clinical evidence of infection, susceptibility studies should be performed. The standardized disk test provides results that should be comparable from laboratory to laboratory but has the disadvantage of yielding results expressed only as susceptible, intermediate, or resistant. In contrast, dilution methods allow determination of the minimal inhibitory concentration of an agent, which can be correlated with blood, urine, and other body fluid levels of the antimicrobial agent. Accurate measurement of serum concentrations of antimicrobial agents is important when the margin between therapeutic and toxic levels is narrow, such as for aminoglycosides or vancomycin, and when a patient has renal failure and may have accumulation of high levels of antimicrobial agents that would normally be excreted by the kidneys.

Antiparasitic agents.

In recent years, introduction of new and more effective agents has improved the overall therapy for parasitic infections. This field, however, is still plagued by numerous problems, including the development of resistance to antimicrobial agents (especially with malaria), unavailability of agents in the United States or lack of approval by the Food and Drug Administration, and major toxicities or lack of experience in pregnant women and children, which limits use in these groups of patients. Widespread resistance of Plasmodium falciparum to chloroquine and other agents has complicated the treatment and prophylaxis of this type of malaria. A combination of quinine and Fansidar is usually effective oral therapy for falciparum malaria; quinidine may be administered if intravenous therapy is needed. Mefloquine, which is currently recommended for prophylaxis against chloroquine-resistant P. falciparum, is also effective for single-dose oral treatment, although this regimen has not yet been approved by the Food and Drug Administration. Metronidazole has been widely used for treatment of gastroenteritis due to Entamoeba histolytica and Giardia lamblia (not approved by the Food and Drug Administration for the latter) and is considered safe and effective. A new macrolide, azithromycin, has been reported to be effective for cryptosporidiosis in experimental animals; currently, no effective therapy is available for human infections. Combinations of sulfonamides with other antifolates, trimethoprim or pyrimethamine, are recommended therapy for Pneumocystis carinii pneumonia or toxoplasmosis, respectively. Therapies for the various types of leishmaniasis and trypanosomiasis are complex, often toxic, and often of limited efficacy. The benzimidazoles are effective for roundworm infections, although thiabendazole has severe toxic effects. The recent introduction of ivermectin has revolutionized the treatment and control of onchocerciasis. Another relatively new agent, praziquantel, is a true broad-spectrum anthelmintic agent that is effective against most trematodes, many adult cestodes, and larval cestodes as well (especially cysticerci of Taenia solium).

Laboratory tests used to guide antimicrobial therapy.

Laboratory tests that can be helpful in guiding antimicrobial therapy include antimicrobial susceptibility testing, determination of bacterial beta-lactamase production, assay of serum inhibitory and bactericidal activity, and assay of specific antibiotic levels in serum. Susceptibility studies should be performed on any microorganism that is isolated from normally sterile body fluid in the presence of clinical evidence of infection. The standardized disk test provides results that should be comparable from laboratory to laboratory. Dilution methods, however, allow determination of the minimal concentration of an agent which inhibits growth, and this value can be correlated with blood, urine, and other body fluid levels of the antimicrobial agent. Determination of serum bactericidal activity is, in effect, an assay of the activity of antimicrobial-containing serum; it indirectly measures the combined effects of susceptibility of the test organism and serum concentration of the antimicrobial agent. Accurate measurement of serum concentrations of antimicrobial agents may be important when treatment includes agents that have a narrow margin between therapeutic and toxic levels such as the aminoglycosides (especially gentamicin) or in patients with renal failure, who may accumulate unusually high levels of antimicrobial agents normally excreted by the kidneys.

Antiparasitic agents.

Several important developments have occurred in recent years in the chemotherapy for and prophylaxis of parasitic infections. Although mefloquine is clearly the most effective agent for prevention of chloroquine-resistant falciparum malaria, its use has been compromised by side effects, both real and imagined. Well-designed studies have shown that side effects occur no more frequently with low-dose mefloquine than with chloroquine. Use of mefloquine in pregnant women has not been associated with birth defects, but the incidence of stillbirths may be increased. Malarone is a new agent that combines atovaquone and proguanil, and it may be as effective as mefloquine; however, it is not yet available in the United States. Several newer agents have appeared in response to the development of multidrug resistant Plasmodium falciparum, especially in Southeast Asia. Halofantrine is available for the treatment of mild to moderate malaria due to P. falciparum and for P. vivax infections. Because of severe toxic effects, use of halofantrine should be restricted to only those unusual and rare situations in which other agents cannot be used. Artemisinin (an extract of the Chinese herbal remedy qinghaosu) and two derivatives, artesunate and artemether, are active against multidrug resistant P. falciparum and are widely used in Asia in oral, parenteral, and rectal forms. The antibacterial azithromycin in combination with atovaquone or quinine has now been reported to treat babesiosis effectively in experimental animals and in a few patients. Azithromycin in combination with paromomycin has also shown promise in the treatment of cryptosporidiosis (and toxoplasmosis when combined with pyrimethamine) in patients with the acquired immunodeficiency syndrome (AIDS). Albendazole is currently the only systemic agent available for treatment of microsporidiosis, an infection primarily of patients with AIDS. In addition, albendazole and ivermectin have emerged as effective broad-spectrum antihelminthics, with albendazole becoming the drug of choice for hydatid disease (echinococcosis), neurocysticercosis, and most intestinal nematode infections (except strongyloidiasis and trichuriasis). Liposomal amphotericin B is the first drug approved by the Food and Drug Administration for the treatment of visceral leishmaniasis.

Laboratory tests used to guide antimicrobial therapy.

Laboratory tests that can be helpful in guiding antimicrobial therapy include antimicrobial susceptibility testing, determination of bacterial beta-lactamase production, assay of serum inhibitory and bactericidal activity, and assay of specific antibiotic levels in serum. Susceptibility studies should be performed on any microorganism that is isolated from normally sterile body fluid (blood, cerebrospinal fluid, pleural fluid, synovial fluid) in the presence of clinical evidence of infection. The standardized disk test provides results that should be comparable from laboratory to laboratory. Dilution methods, however, allow determination of the minimum concentration of an agent which inhibits growth (MIC), and this value can be correlated with blood, urine, and other body fluid levels of the antimicrobial agent. Determination of serum bactericidal activity is, in effect, an assay of the activity of antimicrobial-containing serum; it indirectly measures the combined effects of susceptibility of the test organism and serum concentration of the antimicrobial agent. Accurate measurement of serum concentrations of antimicrobials may be important when treatment includes agents that have a narrow margin between their therapeutic and their toxic levels such as the aminoglycosides (especially gentamicin) or in patients with renal failure, who may accumulate unusually high levels of antimicrobials normally excreted by the kidneys.

Symposium on antimicrobial agents. Metronidazole.

Metronidazole, a nitroimidazole derivative, is a unique antimicrobial agent that is active against both bacterial and parasitic organisms, although only the anaerobic members of these groups are susceptible. It has been used for the treatment of trichomoniasis for almost 30 years and is also effective in amebiasis and giardiasis. More recently, metronidazole has emerged as a principal agent for the treatment of anaerobic infections. It is highly effective against all species of anaerobes except certain non-spore-forming gram-positive bacilli and cocci and is the only agent rapidly bactericidal against the Bacteroides fragilis group. The hydroxy metabolite is 65% as effective as metronidazole and may play a major therapeutic role. Clinical studies have substantiated its efficacy for prophylaxis during elective colorectal surgical procedures and the treatment of deep abdominal sepsis (usually in combination with another agent such as an aminoglycoside). Metronidazole is the treatment of choice for bacterial vaginosis and seems to be as effective as vancomycin for treatment of Clostridium difficile-related diarrhea and colitis. Good blood levels are produced after both oral and intravenous administration, and side effects are infrequent and minimal. Metronidazole should not be taken during the first trimester of pregnancy because of concerns about mutagenicity. Tinidazole and ornidazole are recently developed nitroimidazole derivatives that have even greater antimicrobial activity than metronidazole.

Antimicrobial susceptibilities of anaerobic bacteria isolated at the Mayo Clinic during 1982 through 1987: comparison with results from 1977 through 1981.

Results of antimicrobial susceptibility testing of anaerobic bacteria isolated at the Mayo Clinic were reviewed for 1982 through 1987 and compared with a previous survey during 1977 through 1981 at this institution. Between the earlier and the later period, clindamycin resistance increased in the Bacteroides fragilis group (from 4% of isolates to 8%). We noted continuing penicillin resistance among Bacteroides species other than B. fragilis and rare penicillin resistance among Fusobacterium organisms, with four isolates during the 1982 through 1987 period being beta-lactamase producers. The high levels of resistance to some agents seen in certain Clostridium species in 1977 through 1981 were not as great in the current survey. No major changes were noted in the susceptibilities of C. perfringens, anaerobic non-spore-forming gram-positive bacilli, and anaerobic gram-positive cocci.

Metronidazole.

Metronidazole, a nitroimidazole derivative, is a unique antimicrobial agent that is active against both bacterial and parasitic organisms, although only the anaerobic members of these groups are susceptible. It has been used for the treatment of trichomoniasis for about 20 years and is also effective against amebiasis and giardiasis. More recently, metronidazole has emerged as a principal agent for the treatment of anaerobic bacterial infections. It is highly effective against all species of anaerobes except certain non-spore-forming gram-positive bacilli and cocci and is the only agent rapidly bactericidal against the Bacteroides fragilis group. Clinical studies have proved its efficacy in prophylaxis for elective colorectal surgical procedures and in the treatment of deep abdominal sepsis (usually in combination with another agent, such as an aminoglycoside). Metronidazole is the treatment of choice for nonspecific vaginitis that seems to be a mixed infection due to anaerobes and Gardnerella vaginalis. Adequate concentrations in the blood are produced after both oral and intravenous administration, and the side effects are infrequent and minimal.

Assessment of Campylobacter-like organisms in the postoperative stomach, iatrogenic gastritis, and chronic gastroduodenal diseases: preliminary observations.

Campylobacter-like organisms (provisionally named C. pyloridis) were demonstrated in gastric biopsy specimens by histopathologic analysis and bacterial culture. C. pyloridis organisms were found in 12 of 26 patients (46%) with gastric or duodenal ulcer but in none of 10 healthy volunteers without histologic evidence of gastritis. Iatrogenic antral gastritis, induced by 7 days of treatment with nonsteroidal anti-inflammatory drugs, was not associated with the presence of C. pyloridis. Organisms were found in 6 of 24 patients who had undergone gastric operations, but the prevalence of C. pyloridis was not higher in those with symptoms of alkaline reflux gastritis than in asymptomatic postgastrectomy control patients. We conclude that C. pyloridis is less common in patients with drug-induced and postoperative gastritis than in patients with peptic ulcer.

Isolated antral narrowing associated with gastrointestinal cryptosporidiosis in acquired immunodeficiency syndrome.

A 33-year-old man with human immunodeficiency virus infection had severe protracted diarrhea. Radiologic assessment disclosed narrowing of the gastric antrum. Biopsy specimens revealed diffuse Cryptosporidium infection of the antral mucosa. Isolated antral narrowing due to Cryptosporidium gastritis should be added to the list of gastrointestinal complications associated with acquired immunodeficiency syndrome (AIDS).