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As clinical persistence of Borrelia burgdorferi in patients with active Lyme borreliosis occurs despite obviously adequate antibiotic therapy, in vitro investigations of morphological variants and atypical forms of B. burgdorferi were undertaken. In an attempt to learn more about the variation of B. burgdorferi and the role of atypical forms in Lyme borreliosis, borreliae isolated from antibiotically treated and untreated patients with the clinical diagnosis of definite and probable Lyme borreliosis and from patient specimens contaminated with bacteria were investigated. Furthermore, the degeneration of the isolates during exposure to penicillin G in vitro was analysed. Morphological analysis by darkfield microscopy and scanning electron microscopy revealed diverse alterations. Persisters isolated from a great number of patients (60-80%) after treatment with antibiotics had an atypical form. The morphological alterations in culture with penicillin G developed gradually and increased with duration of incubation. Pleomorphism, the presence of elongated forms and spherical structures, the inability of cells to replicate, the long period of adaptation to growth in MKP-medium and the mycoplasma-like colonies after growth in solid medium (PMR agar) suggest that B. burgdorferi produce spheroplast-L-form variants. With regard to the polyphasic course of Lyme borreliosis, these forms without cell walls can be a possible reason why Borrelia survive in the organism for a long time (probably with all beta-lactam antibiotics) [corrected] and the cell-wall-dependent antibody titers disappear and emerge after reversion.

For a better understanding of the persistence of Borrelia burgdorferi sensu lato (s.l.) after antibiotic therapy the kinetics of killing B. burgdorferi s.l. under amoxicillin, doxycycline, cefotaxime, ceftriaxone, azithromycin and penicillin G were determined. The killing effect was investigated in MKP medium and human serum during a 72 h exposure to antibiotics. Twenty clinical isolates were used, including ten strains of Borrelia afzelii and ten strains of Borrelia garinii. The results show that the kinetics of killing borreliae differ from antibiotic to antibiotic. The killing rate of a given antibiotic is less dependent on the concentration of the antibiotic than on the reaction time. Furthermore, the data show that the strains of B. afzelii and B. garinii have a different reaction to antibiotics used in the treatment of Lyme borreliosis and that different reactions to given antibiotics also exist within one species. The B. garinii strains appear to be more sensitive to antibiotics used in therapy. Furthermore, the persistence of B. burgdorferi s.l. and clinical recurrences in patients despite seemingly adequate antibiotic treatment is described. The patients had clinical disease with or without diagnostic antibody titers to B. burgdorferi.

In both the early and the late phases of Lyme borreliosis, the aim of antibiotic therapy is to eliminate signs and symptoms of the disease and to eradicate Borrelia burgdorferi. Patients with early manifestations of the illness may develop subsequent signs and symptoms and a rise or persistent elevation of their antibody titers againstB. burgdorferi, despite treatment with antibiotics (Weber 1974; Steere et al. 1983a; Weber et al. 1986, 1990). Patients treated with antibiotics for late manifestations may experience persistence or recurrence of their signs and symptoms, and their IgG antibody titer against B. burgdorferi may decline more slowly, if at all, than in patients treated in the early phase of the disease (Weber et al. 1988; Hassler et al. 1990; Logigian et al. 1990). These possible or definite treatment failures might indicate that eradication of B. burgdorferi cannot be carried out as easily as the eradication of the causative agents of certain other bacterial infectious diseases.

Es werden die Behandlungsergebnisse von 31 Kindern aus vier Kliniken in Europa und Sudamerika, die an einer eitrigen Meningitis litten und mit Cefotaxim behandelt wurden, vorgelegt. Unter anderem wurden Meningitiden mitEscherichia coli (3 Falle),Pseudomonas aeruginosa (2 Falle), Salmonellen (1 Fall), Klebsiellen (2 Falle) undSerratia (1 Fall) erfolgreich behandelt. Versager gab es bei funf Patienten (1mal mitHaemophilus influenzae, 1mal Salmonellen, 1mal Streptokokken der Gruppe A, 1malE. coli, 1malStaphylococcus aureus). Die aufgrund pharmakokinetischer Untersuchungen fur die Behandlung einer Sepsis mit 100 mg/kg/Tag bereits reichliche Neugeborenen-Dosierung wurde bei der Meningitisbehandlung auf 150–200 mg/Tag erhoht. Die Pharmakokinetik dieser Substanz im Neugeborenen-Alter ergab, das die Halbwertszeit im Durchschnitt bei 2–3 Std. liegt (Extreme 1,5–12 Std.); das Verteilungsvolumen und die Clearance von Cefotaxim fur das Neugeborenen-Alter wurde bestimmt (Computerberechnung bei acht Sepsisfallen). Die gemessenen Liquorkonzentrationen von Cefotaxim waren fur die meisten Erreger ausreichend. Die bisherigen Erfahrungen lassen vermuten, das mit Cefotaxim ein wirksames Praparat fur ein breites Erregerspektrum von eitrigen Meningitiden zur Verfugung steht.

Efficacy of Oral Ofloxacin and Ciprofloxacin. Cross-over Study. The efficacy of the 4-quinolones ciprofloxacin (CPX) and ofloxacin (OFX) was studied in a cross-over study. Twenty out-patients with cystic fibrosis and chronic colonization of the respiratory tract with Pseudomonas aeruginosa were treated for ten days with OFX, then another ten days with CPX, and vice versa. Drug concentrations in serum and sputum were assayed. The patients' clinical and laboratory parameters were monitored. The side-effects that appeared did not require interrupting treatment. The serum and sputum concentrations were found to be above the minimal inhibitory concentration. Although P. aeruginosa was not eliminated by the therapy, two-thirds of the patients showed improvement during the infection that could be observed clinically and in laboratory measurements. Oral treatment with OFX and CPX is efficacious.

The chemotherapy of septicaemia in newborns differs fundamentally from that in older children or adults because, although newborns have a fully developed immunological system, the system has not yet "learned" to operate completely. Ultimately, optimal chemotherapy can only be found empirically. In this respect a few basic guidelines can be given however: 1. The initial therapy must bring the pathogen under control with a high degree of certainty, since a correction in therapy following pathogen indentification is usually too late. 2. Since the pharmacokinetics of antibiotics in newborns vary considerably, the minimal peak serum concentration observed should exceed the MIC of the pathogen. 3. In rapidly maturing newborns and premature babies the pharmacokinetics of each antibiotic must be known precisely. 4. Since in the individual case there can never be absolute certainty with respect to the three above-mentioned problems, combination therapy should be given at all times.

A retrospective analysis was carried out in 225 newborns treated for septicemia at the University Children's Hospital, Munich, from 1969 to 1978. The mortality rate was almost double in patients with septicemia caused by pathogens resistant to one partner of the antibiotic combination therapy (61%) compared to infants treated with an antibiotic regimen where the pathogen was susceptible to both chemotherapeutic agents (31%). Without taking possible synergism into consideration, we conclude that at present a combination therapy with cephalosporins and aminoglycosides, together with exchange transfusion, is indicated in neonatal septicemia and meningitis.

Mit dem passiven Hamolysetest wurde das Auftreten von Lipoid A-Antikorpern beim Menschen untersucht. Parallel dazu wurden die O-Antikorpertiter gegen E. coli, Klebsiella, Proteus und Ps. aeruginosa mit der Methode der indirekten Hamagglutination bestimmt. Es wurden 62 Kinder im Alter von 3 bis 14 Jahren erfast, die wegen nicht obstruktiver rezidivierender Harnwegsinfektionen schon uber einen langeren Zeitraum in unserer Klinik behandelt wurden. Die serologischen Ergebnisse wurden den radiologischen Befunden bei diesen Kindern gegenubergestellt. Vergleichende Untersuchungen wurden bei 50 gesunden Kindern unter 3 Jahren, bei 50 gesunden Erwachsenen, bei 50 Erwachsenen mit nicht obstruktiven Harnwegsinfektionen und bei 50 Kindern unter 3 Jahren mit bakteriellen Infektionen ohne Beteiligung der Harnwege durchgefuhrt. Das Auftreten von Lipoid A-Antikorpern ist bei Kindern mit Pyelonephritis statistisch signifikant haufiger als bei den ubrigen Gruppen. Bei annahernd 8/9 aller Kinder mit Pyelonephritis konnten Lipoid A-Antikorper nachgewiesen werden. Die Ergebnisse lassen vermuten, das Lipoid A bei der Pyelonephritis von pathogenetischer Bedeutung sein kann. Die Bestimmung der Lipoid A-Antikorpertiter scheint eine geeignete Methode zu sein, um bei Kindern mit Harnwegsinfektionen eine Beteiligung der oberen Harnwege und des Nierenparenchyms zu erfassen.

Exchange transfusion of fresh heparinised whole blood was evaluated as a means of supplying “opsonins” and blood cells and lessening the high mortality of bacterial septicaemia in neonates. Pre-transfusion, post-transfusion, donor, and adult control sera were examined for the presence of “opsonic” activity againstStaphylococcus aureus (A 502 strain) in a standardized bactericidal in vitro assay. In all 23 neonates opsonic activity rose significantly following exchange transfusion. The results are discussed in the light of immuno-therapeutic trials in systemic bacterial infections as a supportive measure of antimicrobial therapy.

A microbiological method was developed for measuring cefoxitin serum levels in newborns with septicemia who were being treated with a combination of cefoxitin, amikacin and penicillin G. Serum specimens were taken at random intervals during treatment and basic pharmacokinetic data such as volume of distribution, clearance and rate constant of elimination were calculated using a computer based programme. A dosage of 100 mg/kg cefoxitin three times daily yielded effective blood levels without accumulation of the drug in the serum during a ten day treatment period. The volume of distribution by far exceeded the intravascular volume so it can be assumed that effective tissue concentrations were achieved.

Trends in relative susceptibility of clinical isolates, mostly from newborns with nosocomial infections, to the aminoglycosides in use in a hospital for children are described and related to practical therapeutic aspects. Currently, amikacin is the most effective of the available antibiotics against many gram-negative bacterial species, and its administration appears to be as complicated as that of other aminoglycosides. With 5 mug/ml taken as the cut-off point for susceptibility in vitro, 90% of 211 clinical isolates (Pseudomonas aeruginosa, Escherichia coli, Klebsiella, Serratia, and other species) could be considered sensitive to amikacin; the respective figures for sensitivity to sisomicin, gentamicin, and tobramycin were 80.5%, 66%, and 70%. Cross-resistance of microorganisms to amikacin and gentamicin, sisomicin, or tobramycin has not been demonstrated. Treatment with amikacin was successful in 13 of 15 children (premature and normal newborns with primarily septicemia); death of two patients was attributable to the underlying disease. For neonatal infections we recommend 12 mg of amikacin/kg per day; determination of the minimal inhibitory concentration for the causative pathogen and monitoring of serum concentrations are desirable.

Anhand der aktuellen bakteriellen Resistenzsituation in einer Kinderklinik wird die Indikation von Cefamandol fur die Behandlung der Neugeborenenperiode analysiert. Bei einer Dosierung von 100 mg/kg/Tag ist kein bedrohlicher kumulativer Effekt zu erwarten. Die tiefsten Spiegel wahrend der Behandlung mit einer 3maligen Dosis pro Tag liegen zwischen 0 und 35µg/ml (Fruhgeborene!), die Spitzenkonzentrationen um 100 µg/ml. Trotz der erheblichen Variationsbreite ahnelt die Halbwertszeit derjenigen bei Erwachsenen. Die gunstigen MHK's bei dem haufigsten gramnegativen Erreger des Neugeborenenalters —Escherichia coli — und die Staphylokokkenempfindlichkeit gegen Cefamandol (die zwar bei Cephalotin in vitro graduell hoher ist, aber in vivo aufgrund der gunstigeren pharmakokinetischen Verhaltnisse zumindest ausgeglichen wird), lassen Cefamandol fur das Neugeborenenalter als besonders geeignet erscheinen.

The serum titres of IgG and IgM antibodies to lipid A were measured in 24 children with chronic pyelonephritis (PN), 55 with recurrent lower urinary tract infections (LUTI), 13 with gram-negative sepsis (S), and in 50 control children using an enzyme-linked immunosorbent assay (ELISA). Children ranged in age from 1 month-17 years. Patients with PN were differentiated by the presence or absence of an acute infectious episode and/or vesico-ureteric reflux (VUR). During an acute episode in PN and LUTI, IgG titres were significantly higher than in controls, but only PN patients with an acute infectious episode also had significantly elevated IgM titres. Overall, children with LUTI showed a significantly lower frequency of detectable IgG lipid A antibodies (27%) than in PN (63%). In PN children with VUR not accompanied by an infectious episode, lipid A antibody was found at relatively low titres, while an episode not accompanied by VUR displayed significantly elevated IgG titres, and an episode accompanied by VUR showed elevation of both IgG and IgM anti-lipid A antibody titres.

Von 14 Patienten mit schwerer kombinierter Immundefizienz (SCID) wurde ein Mangel an Adenosindesaminase (ADA) in den Erythrozyten berichtet. Die unzureichende Entwicklung des lymphatischen Systems ist moglicherweise Folge des Enzymmangels. ADA kann spektralphotometrisch und elektrophoretisch in verschiedenen Geweben nachgewiesen werden. Der Genort fur ADA liegt auf Chromosom 20. Untersuchungen des Enzymdefekts bei verschiedenen Formen primarer Immundefizienzen erlauben die Abgrenzung einer genetisch definierten Krankheitseinheit. Fur die Klinik ergeben sich neue Aspekte in der Pathogeneseforschung, pranatalen Diagnostik, genetischen Beratung und moglicherweise kausalen Behandlung der SCID mit ADA-Mangel.

Die A-Gammaglobulinamie eines 7 Jahre alten Jungen wurde mit i.m. Injektionen von Gammaglobulinpraparaten behandelt. Es kamen dabei erstmals Gammaglobulinpraparationen (Behring-Werke, Marburg) zur Anwendung, die neben einem 80%igen Anteil IgG (7s) entweder einen 20%igen Anteil IgM (IgG 6 g/100 ml, IgM 1,5–2,0 g/100 ml) oder IgA (IgG 6 g/100 ml, IgA 2,0 g/100 ml) enthielten. Das Verhalten dieser i.m. injizierten Ig im Organismus wurde untersucht. Wir bestimmten quantitativ den Gehalt der Ig im peripheren Blut nach wiederholten i.m. Injektionen und Seruminfusionen uber einen Zeitraum von 14 Tagen mit folgenden Methoden: 1. einfache radiale Immundiffusion, 2. Elektroimmundiffusion, 3. quantitative Pracipitation, 4. Immunoelektrophorese.

Indikationsfehler einer Chemotherapie bei Operationen Neugeborener bedeutet entweder 1. falsche praventive Anwendung oder 2. falsche Wahl des Medikaments.

The action of gentamicin on penicillin G-induced spheroplasts was studied in 4 Proteus strains (1 Proteus mirabilis , 2 P. rettgeri , 1 P. vulgaris

A semiautomatic microdilution method is described, which requires 44 μl of blood for each determination of antibacterial activity. The test strain used was Staphylococcus aureus SG 511; the medium was Standard I nutrient broth. The end point was determined after 14–16 incubation by the changing color of the indicator (phenol red). The dilution factor was alternated, 1:1.33 and 1:1.5; the standard was performed in triplicate, both leading to a lower deviation as compared with the twofold dilution methods. In a study of clindamycin pharmacokinetics in children, almost identical blood levels were obtained when comparing the microdilution method with a previously used microdisc diffusion method; however, the microtube dilution method was easier to perform.