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Trovafloxacin, a new fluoroquinolone, produced bactericidal activity (-0.33 +/- 0.13 delta log10 CFU/ml.h; intravenously [i.v.] administered dose, 15 mg/kg) comparable to that of vancomycin (-0.39 +/- 0.18 delta log10 CFU/ml.h; i.v. admininistered dose, 20 mg/kg) in the treatment of experimental meningitis in rabbits due to a pneumococcal strain highly resistant to penicillin (MIC of penicillin G, 4 micrograms/ml). The combination of both drugs significantly increased (P < 0.05) the killing rate (-0.60 +/- 0.23 delta log10 CFU/ml.h) compared to that produced by either monotherapy. These results were also confirmed in vitro.

In 3 divisions of internal medicine of teaching hospitals of the Comprehensive Hospital Drug Monitoring (CHDM) Foundation Bern/St Gallen, 42,920 patients consecutively admitted between 1974-1991 were investigated for adverse drug reactions. Of these 16,150 patients (38%) had received at least one systemically administered antibacterial drug during the hospital stay. Antibiotic-associated colitis included the following diagnoses: pseudomembranous colitis, hemorrhagic colitis and milder forms of colitis. We collected the data of these patients by searching for all diagnoses which might represent antibiotic-associated colitis (from the list of WHO adverse drug reaction terminology). 9 individual patients with one episode of probable antibiotic-associated colitis were found. In 5 of these cases, only one drug given during the hospital stay seemed to be implicated. An additional 32 patients were admitted with antibiotic-associated colitis in relation to treatment with the same groups of drugs before hospital admission. Based on the exposure pattern of the 9 patients with antibiotic-associated colitis compared to all patients exposed during hospital stay, we estimated the following frequencies related to the drug groups with at least 1,000 patients exposed: for all antibacterial chemotherapeutics 0.6/1000 (0.25-1.06); all penicillins 0.6/1000 (0.22-1.32), for benzyl-, phenoxy-, ureido-, isoxazolyl penicillins and methicillin 2.0/1000 (0.42-5.92) and aminopenicillin or analogues, with or without clavulanic acid 0.6/1000 (0.18-1.35). For cephalosporins the frequency is 1.4/1000 (0.17-5.12). Under sulfonamides combined with trimethoprim or related substances (5077 exposed patients) and fluoroquinolones (1043 exposed patients) no case was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the case of a 74-year-old patient with HLA-B27 negative spondylarthropathy presenting with acute disseminated vascular occlusions. The presence of livedo reticularis prompted a search for antiphospholipid antibodies which were found to be markedly elevated. Histopathological examination revealed noninflammatory vascular obstruction. The clinical evolution was rapidly fatal in spite of corticosteroid treatment. Livedo reticularis can be an important diagnostic clue to various types of underlying disease. Increased levels of antiphospholipid antibodies have been associated with thrombosis and thromboembolism, especially in the context of autoimmune diseases such as systemic lupus erythematosus. This paper reports antiphospholipid antibody-associated noninflammatory vascular occlusions in a patient with HLA-B27 negative spondylarthropathy. The pathogenetic mechanism of antiphospholipid antibody-mediated vascular occlusions is not completely understood and optimal therapy remains to be defined.

Penicillins, cephalosporins and other betalactam antibiotics are widely used antibacterial drugs. Recently it was found that some of them also have effects on proliferating eukaryotic cells (Neftel, K.A. and Hübscher, U. (1987) Antimicrob. Agents Chemother. 31, 1657-1661), and one such effect was shown to be the inhibition of DNA polymerase alpha (Huynh Do,U., Neftel, K.A., Spadari, S. and Hübscher, U. (1987) Nucl. Acids Res. 15, 10495-10506). The data suggested that degradation products of betalactam antibiotics were responsible for the inhibitory effect on DNA polymerase alpha. There is some confirmation at the structural level, since we found that penicillin binding proteins, the natural target of the cephalosporins, share amino-acid homologies to DNA polymerases and also to reverse transcriptase from HIV1 (Hafkemeyer, P., Neftel, K.A. and Hübscher, U. Meth. Find. Exp. Clin. Pharmacol. 12, 43-46, 1990). We have purified and determined the structure of one product from the cephalosporin Ceftazidim and found one molecule (HP 0.35) that did not interfere with eukaryotic cell proliferation but rather had a specific inhibitory effect on the RNase H activity of human immunodeficiency virus 1 (HIV1) and feline immunodeficiency virus (FIV) reverse transcriptases, while the DNA polymerising activity of these enzymes was not affected. RNases H from HeLa cells, calf thymus and Escherichia coli on the other hand were much less affected by HP 0.35. The inhibitory concentration of 50% (IC50) was more than 10 times lower compared to those of all cellular RNases H. We therefore tested the effect of HP 0.35 on in vitro lentivirus infection as exemplified by FIV-infection of CD(4+)-cat lymphocytes in cell culture. Under conditions where cell proliferation was absolutely unaffected, HP 0.35 was able to inhibit FIV-infection in CD(4+)-cat lymphocytes. Moreover, preincubation of these lymphocytes with HP 0.35 rendered the cells completely unsusceptible to FIV-infection. These data suggest that a degradation product of a clinically used betalactam antibiotic might represent an effective inhibitor class for lentiviral RNase H.

Heat induced radial segmentation of leukocyte nuclei is an in vitro phenomenon accompanying inflammatory diseases. We studied 62 patients with suspected polymyalgia rheumatica (PMR) to determine, whether heat induced radial segmentation can help in discriminating PMR from other conditions. At the initial presentation patients with PMR had more radial segmentation formation than patients with other inflammatory conditions. Prednisone induced a rapid and marked decrease in radial segmentation formation in patients with PMR. This latter finding was much less marked in patients with other inflammatory conditions. We conclude that heat induced radial segmentation at the initial presentation and during prednisone treatment can help in discriminating PMR from other inflammatory conditions.

Penicillin-binding proteins are the specific targets for the beta-lactam antibiotics. Recently it was observed that beta-lactam antibiotics also have targets in proliferating eukaryotic cells (1), one of which most likely is the replicative DNA polymerase alpha. Here we show that HIV-reverse transcriptase and human DNA polymerase alpha share amino acid sequence homologies to five bacterial penicillin-binding proteins.

Several episodes of acute intravascular immune hemolysis in a 68 year old patient induced by (+)-cyanidanol-3 (Catergan) are reported. Clinical and serological criteria of the so-called immune-complex mechanism of immune drug-induced hemolysis were realised. The meaning of the additional marked affinity of the drug to the erythrocytic surface remains unclear. The patient's serum was cross-reactive with rutine but not with troxerutine.

This is a case report on a nulliparous women, who developed the HELLP syndrome following intravenous tocolysis. Contrary to our expectations, neither schistocytes nor signs of intravasal coagulation were apparent; however, we found Fenoterol-associated anti-erythrocyte antibodies. However, the low titre of these antibodies does not explain the massive haemolysis. It is suggested, that these antibodies represent a causal factor in developing the HELLP syndrome.

Intravenous administration of a total dose of more than 200 million IU of penicillin-G led to sensitisation of lymphocytes and formation of specific anti-penicilloyl antibodies of the IgG class. These effects were prevented when the penicillin solution used was freshly prepared and given as a bolus rather than as a slow infusion. The causative antigens seem to be related not to penicilloylated high molecular weight impurities in the penicillin preparations, but to the degradation and/or transformation products of penicillin-G that form when the drug is in solution even if only for a few hours, and not only at room temperature but also at 4 degrees C. Thus penicillin solutions should be freshly prepared and administered from vials containing less than 10 million IU so that bolus doses can be given.

38% of penicillin-G in solution decays at 20 degrees C within 24 h, 50% at 37 degrees C and 66% within 3 h at 56 degrees C. These degraded penicillin-G solutions strongly inhibit growth and maturation of granulocytic stem cells in vitro. Inhibitory concentrations are in the range obtainable with high dose penicillin therapy in vivo. No cytotoxicity of degraded penicillin solutions on bone marrow cells was seen over 24 h. It is suggested that penicillin-G degradation products are responsible for severe granulocytopenia observed after high dose penicillin-G therapy.

Derivatives of beta-lactam antibiotics of the cephalosporin type at 0.02-1 mM concentrations interfered with in vitro replication of two DNA-containing viruses, herpes simplex I and vaccinia, but showed no effects on two RNA-viruses, lymphocytic choriomeningitis virus and vesicular stomatitis virus, or on cell viability. The exact structure of the active compounds remains unknown, but opening of the beta-lactam ring appears to be a prerequisite for their formation. Whereas cephalosporin derivatives were most active, no active products were obtained from penicillins and monobactams. The potential of these unexpected antiviral effects of widely used beta-lactam antibiotics remains subject of further study.

Based on the radioallergosorbent test (RAST), the authors have developed a series of assays to detect IgE and IgG antibodies against a number of frequently used drugs. In this system drugs bound covalently to cellulose paper are incubated with serum and washed; the hapten-specific IgE and IgG antibodies are then qualified and quantified by means of 125I-labelled anti-human IgE and IgG respectively. Thus far the sera of 1,228 patients have been analyzed following therapy with betalactam antibiotics, co-trimoxazole, salicylates, pyrazolones, flavonoids and tetrahydroisoquinoline. The induction of IgG antibodies is a frequent occurrence and that of IgE rare. Isolated high titers of IgE are associated mainly with anaphylactic reactions; in the presence of simultaneously raised IgG titers such side reactions are often absent. Highest IgG titers were found in patients with immune hemolysis after betalactam antibiotics, flavonoids and tetrahydroisoquinoline. In the other types of side reaction specific IgG titers were not significantly higher than in patients without side reactions. The estimation of circulating antibodies against drugs cannot yet be utilized diagnostically except in the rare cases of anaphylactic side reactions. However, the method described permits specific and sensitive detection of sensitization and is suited for scientific purposes.

Pretreatment blood smears of adult patients with acute lymphoblastic leukemia were examined for neoplastic cells showing nuclear radial segmentation (RS). RS was present in 6 of 7 patients with immunologically proven T-cell leukemia, but not in 11 patients whose leukemic cells lacked T-cell markers. Electron microscopic studies of neoplastic cells showed multiple nuclear indentations and abundant cytoplasmic microfilaments and microtubuli in connection with pericentriolar dense material. RS formation was decreased in 1 patient after chemotherapy with a vincristine-containing regimen, while the white cell count remained unchanged. Radial segmentation (RS) of leukocyte nuclei is a well-known phenomenon, which is observed ex vivo (Rieder cells), and can be induced in vitro. Convoluted or multilobulated nuclei in lymphoid neoplasms are similar to RS nuclei both with regard to their structure and their sensitivity to spindle-blocking drugs. We propose that the nuclear alterations observed in a variety of different T-cell neoplasms are identical with RS, and suggest that RS might be a morphological marker for subsets of lymphoproliferative disorders of T-cell origin.

Angiotensin I converting enzyme inhibition by captopril and enalapril may influence sodium and potassium homeostasis. In patients without cardiac failure and with normal renal function significant electrolyte disturbances rarely occur. We report on four patients who developed life-threatening electrolyte disturbances following treatment with enalapril for severe cardiac failure (NYHA-class II-IV). There were important concomitant factors in all four cases: in one case under additional medication with a thiazide diuretic and a nonsteroidal antiinflammatory, hyponatremia of 107 mmol/l occurred. In two further cases severe hyperkalemia of 7.4 and 7.3 mmol/l was observed in the presence of acute renal failure due to enalapril-induced hypotension and concomitant therapy with a nonsteroidal antiinflammatory drug respectively. In a fourth case the combination of enalapril with a potassium-sparing diuretic provoked severe hyperkalemia of 7.9 mmol/l.

During treatment with flavonoid drugs a number of patients developed adverse reactions such as fever, various skin eruptions and intravascular hemolysis. The appearance of flavonoid-specific IgE and IgG antibodies and its possible relation to the observed side effects was studied on a total of 168 individuals treated with flavonoid drugs: 71 patients received troxerutin (Venoruton) parenterally to improve tolerance of radiation therapy, 12 patients were treated intravenously with silymarin (Legalon) for amanita intoxication and 77 patients received various flavonoid drugs for other indications. Flavonoid treatment often induced specific IgG antibodies and less frequently IgE antibodies. After short treatment IgE antibodies were more frequently detected than after treatment of longer duration which nearly always induced IgG antibodies. Patients with hemolysis had the highest IgG titers. In cases with fever and skin eruptions no correlation with antibody titers became evident. Antibody production in patients undergoing radiation therapy appeared to be lower than in non-irradiated patients. Both the IgE and IgG antibody test show a remarkable cross-reactivity between four different flavonoids. Prospective studies will be necessary to decide whether or not this method for the detection of anti-flavonoid antibodies will be suitable for recognizing increased risk of side reactions upon reexposure to flavonoid drugs.

Serum samples from 41 patients who developed adverse reactions during therapy with nomifensine were screened by RAST-based immunoassay for specific IgE and IgG antibodies against nomifensine and three of its metabolites. The results were compared with those of 10 patients without side effects and with 8 non-treated controls. Nomifensine-specific IgE antibodies were found in none of the subjects. However, all patients treated with nomifensine (with and without side effects) had specific IgG antibodies. The antibody cross-reacted in all cases with the metabolites. The titers did not discriminate clearly between the different side reactions and only partially between the presence or absence of a side reaction. The finding of specific anti-drug IgG antibodies warrants more detailed investigation of immunological mechanisms, to determine the clinical relevance of these antibodies and identify patients at risk for serious side effects.

Benzodiazepines are the most frequently prescribed drugs in the Western world. About 3% of the adult Swiss population regularly use benzodiazepines for the treatment of anxiety states or for induction of sleep. All benzodiazepine agonists available exert qualitatively similar pharmacodynamic actions. They commonly activate central GABAergic neuroinhibition, thereby inducing anxiolysis, sedation/hypnosis, anticonvulsion and muscle relaxation. However, various derivatives differ in their physicochemical and pharmacokinetic properties such as lipophilicity, rate of gastrointestinal absorption, hepatic biotransformation and elimination half life. These differences among individual substances can be used clinically to optimize therapy for the individual patient. For example, the elimination half life greatly influences the frequency, intensity and type of adverse reactions such as hangover, rebound insomnia, development of tolerance and dependence as well as withdrawal symptoms. It is estimated that "low-dose dependency" develops in as many as 30 to 45% of chronically treated patients. Low-dose dependency is mainly characterized by the appearance of withdrawal symptoms after cessation of therapy. Since management of the withdrawal state is difficult and especially troublesome for the patient it is best to prevent the development of benzodiazepine dependence by prescribing these drugs less and restricting them to short-term use (7-14 days).

beta-Lactam antibiotics can induce severe neutropenia by a hitherto unknown mechanism. Fifty cases of beta-lactam antibiotic-induced neutropenia (less than 1,000 neutrophils/mm3) from 17 hospitals were analyzed and compared with 140 literature cases. The incidence of neutropenia was 5%-greater than 15% in patients treated for greater than or equal to 10 days with large doses of any beta-lactam antibiotic but less than 0.1% with shorter duration of therapy. In greater than 95% of cases recovery occurred between one to seven days after withdrawal of beta-lactam antibiotics. Bone marrow aspirates were characterized by a lack of well-differentiated myeloid elements in the presence of numerous immature granulocyte precursors. Nine penicillins and eight cephalosporins inhibited in vitro granulopoiesis in a dose-dependent manner. There was a good correlation between the inhibitory capacity of beta-lactam antibiotics in vitro and the doses inducing neutropenia in vivo. These observations may be relevant for therapy in the granulocytopenic patient.

Clinical and serological data in 5 cases of autoimmune hemolysis following therapy with Catergen are reported and compared to the data in similar literature reports. The main argument in favour of Catergen as causative agent in our 5 cases was rapid remission of hemolysis within 2 1/2 to 10 weeks of withdrawing Catergen treatment. Besides causing hemolysis mediated by drug dependent antibodies, long term treatment with Catergen may induce formation of IgG autoantibodies against red blood cells with or without overt hemolysis.

Radial segmentation (RS) of leukocyte nuclei has been observed, for example, in leukemias (Rieder cells). In 6 of 8 patients with T-ALL, RS of neoplastic cells was found in the peripheral blood, whereas in 14 patients with non-T-ALL no RS cells were present. RS may be a morphologic marker for certain T-cell neoplasms, and with regard to ultrastructure it seems to be identical to heat-induced RS of non-neoplastic cells.

Severe hemolysis occurred in a 51-year-old female after a 17-day course of intravenous amoxicillin. A strongly positive direct antiglobulin test (anti-IgG titer 1:2,000) ensued which disappeared after withdrawal of the drug. Both the patient's serum and eluate obtained from the patient's red cells contained an IgG antibody which reacted with red blood cells coated in vitro with amoxicillin, but not with uncoated cells. In addition, high-titer antipenicillin, antiampicillin and antiamoxicillin IgG antibodies could be demonstrated in her serum by a RAST-based solid-phase radioimmunoassay. The patient's hemolysis gradually subsided within 1 week after discontinuing the drug. This is the first report of amoxicillin-induced immune hemolytic anemia.

High dose penicillin-G has been found empirically to be effective against liver cell damage in amanita mushroom poisoning. We have recently found that betalactam antibiotics inhibit eukaryotic DNA polymerase-alpha, penicillins being more active than cephalosporins, and this may explain the antagonistic effect of penicillin-G against amanitin toxicity. Preliminary experiments in liver cell cultures and in mice are summarized, as well as first clinical experience pointing to the possibility that cephalosporins may be more effective against amanita mushroom toxicity than penicillin-G.

The last five years have produced an explosive development of new beta-lactam compounds with extended bacterial spectra to include most of the gram-positive cocci as well as the gram-negative bacilli. With the exception of activity against enterococci, there are now third-generation cephalosporins with a spectrum of activity similar to that of the aminoglycosides. In addition, beta-lactams retain a high level of activity against anaerobes and against aerobes surviving in anaerobic conditions, a capacity that is lacking with the aminoglycoside group of antibiotics. The beta-lactams in general and some specific compounds in particular (moxalactam, ceftriazone) have a good penetration into the cerebrospinal fluid, a capacity that is also lacking with the aminoglycosides. Since there is a wide range of different spectra of activity among penicillins and cephalosporins, it is also possible to choose an antibiotic with a spectrum restricted to the offending microorganisms. Finally, because the potential toxicity of beta-lactams is less than that of the aminoglycosides (with the possible exception of myelotoxicity), the first choice of antibiotic in a patient with suspected severe infection should be a beta-lactam. The addition of an aminoglycoside should be reserved for those situations in which a synergistic action between the beta-lactam and the aminoglycoside antibiotics is expected to increase the efficacy of the beta-lactam alone, e.g., enterococcal infections, Pseudomonas aeruginosa infections, infections in severely neutropenic patients, or bacterial endocarditis.

Sera from 125 patients receiving mean total doses of beta-lactam therapy of 215 g over a mean of 14 days were assayed by radioimmunoassay. Titres of anti-penicilloyl antibodies, expressed in arbitrary units of specific IgG per microliter of serum (u/microliter), ranged from undetectable (less than 3 u/microliter) to 1,650 u/microliter. There was a higher prevalence of elevated IgG levels in patients who developed haemolytic anaemia or neutropenia compared with patients with no adverse reactions but only in those patients who developed haemolytic anaemia were the antibody titres significantly higher. A subsidiary finding was that a correlation was established between mean total dose and prevalence of positive IgG titres, on a patient group basis (r = 0.87).

Oral beta-blockade with atenolol and pindolol was found to increase urinary 5-hydroxyindoleacetic acid (5-HIAA). In addition pindolol and perhaps some of its metabolites but not atenolol do interfere with chemical analysis of 5-HIAA. This may be due to structural similarities.

The in vitro effect of several compounds containing the B-lactam structure (including 6-aminopenicillanic acid, piperacillin, 7-aminocephalosporanic acid, ceftazidime and clavulanic acid) on the generation of cytotoxic lymphocytes was investigated in two different in vitro systems: (1) generation of virus specific cytotoxic T-cells and (2) proliferation of lymphocytes were assessed in secondary in vitro anti-viral immune responses. Both activities were suppressed by B-lactams in a dose-dependent manner. In these experiments, as found previously with human in vitro granulopoesis and proliferation of the human erythroleukaemic cell line K-562, cephalosporins and clavulanic acid were five to twenty times more suppressive than penicillins. Since concentrations that were effective in vitro are being achieved, particularly with cephalosporins, in the serum of patients, the possible clinical consequences of our findings may have to be taken into consideration.

We tested the hypothesis that (1) beta 1-selective and nonselective beta adrenoceptor blockades have a different influence on stress-induced catecholamine overshoot, and (2) beta 1-selective blockade shifts the epinephrine/norepinephrine ratio in favor of norepinephrine. Seven violinists were investigated; each performed four times in public after ingesting different beta blockers. A significantly greater urinary norepinephrine/creatinine excretion was found with selective beta blockade than with nonselective. In addition during selective beta blockade creatinine excretion decreased significantly in comparison with nonselective blockade. This might be due to a higher concentration of circulating norepinephrine, stimulating alpha receptors in the renal vasculature.

A patient is presented who developed agranulocytosis while taking amodiaquine for suppressive therapy of malaria. An amodiaquine-dependent granulocytotoxic antibody could be demonstrated in the patient's serum on day 1 after stopping amodiaquine medication. Granulocyte transfusion was ineffective on days 6 and 7, possibly due to the slow elimination of the drug.

We report a case of constant microcytosis which could not be related to any of the usual, known causes. The biochemical and functional investigations showed - apart from the small volume - no difference compared with normal erythrocytes. There was no evidence for a hereditary defect. It is concluded that the condition may represent a variant of the normal.

The authors report a case of total detachment of a Starr-Edwards aortic valve prosthesis occurring eleven years after implantation. The detached valve had embolized into the descending thoracic aorta. The prosthetic valve was projected into an apparently normal position on a supine chest X-ray. The correct diagnosis was thus delayed. The authors stress the importance of obtaining lateral views or performing fluoroscopy and/or echocardiography in the emergency room in patients with acute chest symptoms after heart valve replacement.

Betalactam antibiotics (BLA) are the most widely used antibacterial drugs in practical medicine. Recent experiments suggested that BLA, especially after "aging" in aqueous solutions, have an inhibitory effect on the growth of a variety of cultured human cells by interfering with DNA synthesis (Neftel et al. Cell Biol. Toxicol. 2, 513-521, 1986). Our initial observation that the replicative DNA polymerase alpha might be the target of the action of betalactam compounds (Hübscher et al. Cell Biol Toxicol. 2, 541-548, 1986) is now substantiated due to the following experimental data: (i) extractable DNA polymerase alpha is greatly reduced in cells that had been treated with BLA; (ii) the relative cellular distribution of thymidine and of its phosphorylated derivatives is not affected by BLA; (iii) BLA inhibit crude and highly purified mammalian DNA polymerase alpha; (iv) the inhibitory effect appears to be of the mixed type with a slight deviation from purely non-competitive behaviour towards the four deoxyribonucleoside triphosphates and; (v) the inhibition is evident in aphidicolin sensitive DNA polymerases from mammalian tissues and in DNA polymerases from DNA viruses such as Herpes simplex and Vaccinia. In sum, the results suggest that one of the most commonly used class of drugs has a target within eukaryotic cells being most likely the replicative DNA polymerase alpha.

Penicillin-G degradation products have been shown to inhibit in vitro myelopoiesis in a dose-dependent manner. Similar inhibition was seen with 6 semisynthetic penicillins and 2 cephalosporins. 50% inhibitory doses in vitro well matched total and daily doses given in vivo before neutropenia developed. These findings suggest a toxic rather than an immune-mediated pathogenesis for betalactam-induced neutropenia.

The relationship between nonsteroidal antiinflammatory drugs (NSAID) and peptic lesions in the upper gastrointestinal tract remains unclear in many respects. Nevertheless, there is increasing evidence that the risk in patients over 65 years of age and particularly in women is higher than in younger individuals. Data suggest that compounds with long elimination half life increase the risk further. In patients at risk it is therefore advisable to start treatment with the lowest potentially effective dosage and to avoid compounds with long half lives as first line treatment. NSAID are today the most frequent cause of drug induced renal damage. The renal function disturbances induced by NSAID are largely due to inhibition of renal prostaglandin synthesis. In patients with underlying risk factors NSAID can cause acute renal failure, salt and water retention and hyperkalemia. Because of a progressive decline in renal function and alterations in water and electrolyte homeostasis with aging, elderly patients taking NSAID are particularly at risk of developing renal disease.