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PubMed1983

In-vitro susceptibility of Pseudomonas aeruginosa to old and new beta-lactam antibiotics and aminoglycosides.

In-vitro, activities of gentamicin, tobramycin, netilmicin, amikacin, cefsulodin, latamoxef (moxalactam), carbenicillin, ticarcillin and piperacillin were compared against 147 randomly selected strains of Pseudomonas aeruginosa. Tobramycin was the most active aminoglycoside (MIC 90:4 mg/l), complete cross resistance with gentamicin (MIC 90:8 mg/l) was observed. Amikacin was the best alternative aminoglycoside (MIC 90:12 mg/l) Netilmicin showed only moderate activity (MIC 90:16 mg/l). Cefsulodin was the most active beta-lactam antibiotic (MIC 90:8 mg/l) but significant cross-resistance was observed with ticarcillin (MIC 90:32 mg/l) and piperacillin (MIC 90:12 micrograms/ml). Carbenicillin was two dilutions less active than ticarcillin, latamoxef showed a good activity (MIC 90:64 mg/l). Having the highest ratio between serum achievable concentration and MIC 90, piperacillin could be the best alternative drug to the aminoglycosides, of the tested antibiotics.

Aminoglycosides↗
PubMed1985

Use of an in-vitro kinetic model to study antibiotic combinations.

A two compartment pharmacokinetic model was used to study combinations of piperacillin with N-formimidoyl thienamycin or amikacin, and azlocillin with netilmicin against strains of Pseudomonas aeruginosa. Antibiotic antagonism seen with in-vitro static tests of piperacillin and thienamycin did not occur with the kinetic model. Piperacillin plus amikacin showed enhanced activity, and azlocillin prevented bacterial regrowth seen with netilmicin alone during multiple dosing experiments at high bacterial inocula. This model is useful in the study of antibiotic combinations.

Anti-Bacterial Agents↗
PubMed1987

Antibiotic susceptibility of staphylococci from CAPD peritonitis in children.

Over a six year period to 1985, 64 episodes of bacterial peritonitis in children on CAPD yielded 59 Gram-positive and 15 Gram-negative isolates. The former included 27 strains of Staphylococcus epidermidis (45.8%) and 24 Staph. aureus (40.7%). Staph. epidermidis is now the commonest cause of infection in these patients and like Staph. aureus is spread by leaks and disconnections. It is also more resistant to antibiotics than Staph. aureus and this causes problems in the choice of antibiotics with failure to control peritonitis and subsequent complications such as diminished efficacy of therapy, peritoneal adhesions, recourse to haemodialysis and superinfection with fungi. Both species showed 100% sensitivity to vancomycin, rifampicin and netilmicin. Other sensitivity figures for Staph. epidermidis were methicillin 52%, benzylpenicillin 15%, cefamandole 52%, cefotaxime 52%, amoxycillin-clavulanic acid 52%, gentamicin 63%, co-trimoxazole 48%, fusidic acid 59% and erythromycin 52%. Apart from benzylpenicillin (8%), Staph. aureus was much more sensitive, the figures being 96% for methicillin and 92-100% for the others. Our initial choice of 'best-guess' therapy early in the series was cefamandole with the addition of gentamicin or tobramycin for Gram-negatives. This is now inappropriate, based on relatively poor clinical results and increasing resistance to antibiotics, and we would now use vancomycin as first choice, with netilmicin added to cover Gram-negatives.

Adolescent↗
PubMed1992

Antibacterial profile of flurithromycin, a new macrolide.

The in-vitro activity of flurithromycin against common respiratory tract Gram-positive (85 strains) and Gram-negative (44 strains) pathogens, and a collection of anaerobes (125 strains) was compared with that of erythromycin, cefixime, amoxycillin, co-amoxiclav, ciprofloxacin, netilmicin and clindamycin. Flurithromycin possessed the same spectrum and potency of antimicrobial activity as erythromycin. The presence of 50% human serum in the test media enhanced the activity of flurithromycin against all isolates, with the exception of Streptococcus pyogenes. Flurithromycin induced a post-antibiotic effect (PAE) that ranged from 0.25 h (Haemophilus influenzae) to 3.5 h (Streptococcus pneumoniae) for all strains tested. The presence of serum increased or diminished the duration of the PAE, depending on the strain being analysed. No interaction between flurithromycin and the other drugs tested was observed by the checkerboard technique, but when the time-kill system was used, 35 cases of synergy were noted out of 120 tests performed (29%), of which 15 (43%) were with Moraxella catarrhalis, 12 (34%) with Staphylococcus aureus, four (11%) with H. influenzae and the remainder with S. pneumoniae and S. pyogenes. Netilmicin produced most synergic interactions. Antagonism was not detected by either methods.

Bacteria, Anaerobic↗
PubMed1996

The effect of rifampicin on adaptive resistance of Pseudomonas aeruginosa to aminoglycosides.

Using the dynamic chequerboard technique, we confirmed that rifampicin produces a synergistic bactericidal effect when combined with amikacin or netilmicin. Adaptive resistance was suppressed when rifampicin was added to aminoglycoside after, but not during, first exposure to amikacin or netilmicin. The effect of rifampicin on adaptive resistance could account for the synergy between rifampicin and aminoglycosides.

Adaptation, Physiological↗
PubMed1999

Aminoglycoside resistance in Gram-negative blood isolates from various hospitals in Belgium and the Grand Duchy of Luxembourg. Aminoglycoside Resistance Study Group.

A total of 1102 consecutive clinical blood isolates, including 897 Enterobacteriaceae and 205 non-fermenting bacilli, were obtained from 13 university and university-affiliated hospitals, which were divided into a Northern and a Southern group. Resistance to gentamicin, tobramycin, netilmicin, amikacin and isepamicin was determined using a microdilution technique according to NCCLS procedures. The overall mean resistance level was 5.9% for gentamicin, 7.7% for tobramycin, 7.5% for netilmicin, 2.8% for amikacin and 1.2% for isepamicin. Resistance to amikacin and isepamicin was significantly higher in the Northern hospitals than in the Southern hospitals. In total, 157 isolates were found not to be susceptible to aminoglycosides. By PCR, 179 aminoglycoside resistance mechanisms, i.e. 150 genes encoding modifying enzymes and 29 permeability mechanisms, were detected in 148 isolates. A resistance mechanism could not be detected in nine isolates. Moreover, in a further 14 isolates the resistance profile was not fully explained by the detected genes. The aac(6')-I genes were found to be the most predominant resistance mechanism in both the Northern and Southern isolates, followed by aac(3) genes and permeability resistance. A total of 29 non-susceptible isolates harboured a combination of genes, 72.4% of which were a combination with the aac(6')-lb gene. The majority of these combinations were broad-spectrum combinations which represented 9.0% of the resistance mechanisms in non-susceptible Enterobacteriaceae and 19.3% in the non-fermenting bacilli.

Aminoglycosides↗
PubMed2003

Role of the acetyltransferase AAC(6')-Iz modifying enzyme in aminoglycoside resistance in Stenotrophomonas maltophilia.

Stenotrophomonas maltophilia is an emerging nosocomial pathogen that displays high-level intrinsic resistance to multiple antibiotics including aminoglycosides. A gene [aac(6')-Iz] encoding an aminoglycoside-modifying enzyme, AAC(6')-Iz acetyltransferase, was recently cloned and sequenced in S. maltophilia, but its importance with respect to aminoglycoside resistance in this organism was not determined. Using a homologous gene replacement approach, mutants carrying unmarked chromosomal deletions of the aac(6')-Iz gene were constructed in wild-type and in vitro-selected aminoglycoside-resistant S. maltophilia. AAC(6')-Iz-deficient mutants derived from both wild-type and aminoglycoside-resistant strains displayed an increase in susceptibility to amikacin, netilmicin, sisomicin and tobramycin (4- to 32-fold decrease in MICs), known substrates for AAC(6')-I enzymes. The cloned aac(6')-Iz gene restored the aminoglycoside resistance of the aac(6')-Iz mutants, and could also confer aminoglycoside resistance upon Escherichia coli. To assess the significance of the aac(6')-Iz gene with respect to the aminoglycoside resistance of clinical strains, its distribution was assessed in 65 clinical isolates from two hospitals. Using PCR, Southern hybridization, RT-PCR and/or nucleotide sequencing, the aac(6')-Iz gene was identified in 57% of the isolates. Susceptibility tests indicated a good correlation between the presence of the aac(6')-Iz gene and the resistance to tobramycin, netilmicin and sisomicin in these strains. These results indicate that the aac(6')-Iz gene is an important contributor to aminoglycoside resistance in clinical strains of S. maltophilia, particularly to tobramycin.

Acetyltransferases↗
PubMed1990

A clinical trial on efficacy and safety of teicoplanin in combination with beta-lactams and aminoglycosides in the treatment of severe sepsis of patients undergoing allogeneic/autologous bone marrow transplantation.

Early institution of empiric therapy with a broad-spectrum antibiotic has markedly reduced the morbidity and mortality from infections complicating severe or prolonged cytopenia in patients receiving either an allogeneic or autologous bone marrow transplant. Ceftazidime in combination with an aminoglycoside, i.e. netilmicin, has been established as a combination schedule offering low or even avoiding therapy-related toxicity. We evaluated teicoplanin for suspected Gram-positive infections after inadequate response to initial beta-lactam and aminoglycoside combination therapy. All 11 patients so far included in this study received either an allogeneic (five patients) or an autologous (six patients) bone marrow transplant for acute myeloid leukaemia (AML), non-Hodgkin lymphoma (NHL, high grade) or other malignant diseases. All patients developing a primary septicaemia of unknown origin (10 patients) or a catheter related septicaemia (one patient) were treated with 400 mg teicoplanin, administered i.v. once daily in combination with a cephalosporin and an aminoglycoside (ceftazidime 2 g, i.v., t.i.d., netilmicin 400 mg once daily). All 11 patients responded to therapy, 10 patients were clinically cured, one patient improved under therapy. The therapeutic regimen was well tolerated and adverse drug reactions did not occur. We have not observed any delayed take of prolonged neutropenia or thrombocytopenia with this therapeutic regimen when compared to other bone marrow transplant patients who did not receive this antimicrobial therapy. Our preliminary results suggest that teicoplanin is a potentially effective and well-tolerated antimicrobial agent in bone marrow transplant patients with infections not responding primarily to beta-lactams and aminoglycosides.

Adolescent↗
PubMed1989

Septicaemia with coagulase negative staphylococci in a neonatal intensive care unit. Risk factors for infection, and antimicrobial susceptibility of the bacterial strains.

Septicaemia caused by coagulase negative staphylococci is a problem in the neonatal intensive care units (NICU). The very low birthweight (VLBW) infants are at a special high risk because of their immature host defense. In this study the potential risk factors were compared between the VLBW septicaemia patients and the VLBW infants who had not contracted septicaemia in the NICU. The factor most clearly related with septicaemia was the use of umbilical artery catheters. The strategy against neonatal septicaemia includes restriction of the use of intravascular catheters. Also enhancement of the host defense by immunoglobulin therapy is considered. The coagulase negative staphylococci were multiresistant to antibiotics. The combination of netilmicin and benzylpenicillin covered the bacteria found in septicaemia cases in the NICU, and is now the standard treatment in suspected cases. Coagulase negative staphylococci are treated with vancomycin or netilmicin.

Anti-Bacterial Agents↗
PubMed1984

Norfloxacin: in vitro activity compared with that of seven other antibacterial agents against urinary tract pathogens.

The minimal inhibitory concentrations (MICs) of norfloxacin, nalidixic acid, ampicillin, amoxycillin/clavulanic acid (4:1), mecillinam, cefaclor , sulphamethoxazole/trimethoprim (20:1) and netilmicin against 435 clinical isolates of bacterial urinary tract pathogens have been determined. An agar dilution method was employed. Norfloxacin was the most active agent in the study on a weight-for-weight basis. The drug was highly active against Enterobacteriaceae. Norfloxacin was more active than netilmicin against Pseudomonas aeruginosa (MICs less than or equal to 2 mg/l and less than or equal to 4 mg/l, respectively). Norfloxacin was also active against Gram-positive bacteria including enterococci and Staphylococcus saprophyticus (MICs less than or equal to 4 mg/l). Norfloxacin may well become a useful agent for the oral treatment of urinary tract infection, particularly as a drug for the treatment of infections caused by multiresistant organisms.

Anti-Bacterial Agents↗
PubMed1978

Outbreak of multiply drug-resistant Proteus mirabilis originating in a surgical intensive care unit: in vitro susceptibility pattern.

A multiply drug-resistant strain of Proteus mirabilis was isolated from 14 patients on a surgical service. Antimicrobial susceptibility studies demonstrated that the organism was highly resistant to numerous antibiotics, including gentamicin, tobramycin, and sisomicin. The organism was susceptible in vitro to amikacin but had low-level resistance to netilmicin. In vitro susceptibility studies with combinations of cephalothin with netilmicin and trimethoprim with sulfamethoxazole showed these drugs to be synergistic. Other drug combinations failed to act synergistically.

Cross Infection↗
PubMed1978

Synergy of azlocillin and mezlocillin combined with aminoglycoside antibiotics and cephalosporins.

Synergistic activity between both azlocillin and mezlocillin and aminoglycosides or cefazolin could be demonstrated by checkerboard dilution, isobologram, and killing curve techniques. Azlocillin and mezlocillin combined with gentamicin, netilmicin, or amikacin were synergistic against Escherichia coli, Klebsiella, Citrobacter, Enterobacter, Serratia, and indole-positive Proteus. Synergy was observed with isolates that were susceptible or resistant to azlocillin or mezlocillin. Synergy was seen most often when azlocillin or mezlocillin were combined with amikacin, gentamicin, or netilmicin against Pseudomonas aeruginosa. The combination of mezlocillin and an aminoglycoside produced synergy more often than did carbenicillin plus an aminoglycoside. No antagonism was seen when aminoglycoside antibiotics were combined with azlocillin or mezlocillin. Cefazolin was synergistic against Pseudomonas, Providencia, P. mirabilis, indole-positive Proteus, Citrobacter, Klebsiella, and Escherichia coli, when combined with azlocillin or mezlocillin. However, the combination of either agent with cefazolin was antagonistic when tested against selected indole-positive Proteus and Enterobacter isolates.

Aminoglycosides↗
PubMed1978

Activity of 5-episisomicin compared with that of other aminoglycosides.

5-Episisomicin, a semisynthetic aminoglycoside, has been shown to inhibit many members of the Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. At a concentration of 3.1 mug/ml, more than 90% of Escherichia coli, Klebsiella pneumoniae, Enterobacter, Citrobacter, indole-positive Proteus, and Providencia were inhibited. 5-Episisomicin had activity against S. aureus, E. coli, Klebsiella, Enterobacter, and Citrobacter similar to gentamicin and netilmicin. It had activity similar to amikacin and netilmicin against many gentamicin-resistant bacteria. The activity of 5-episisomicin was greatest at an alkaline pH and in medium of low magnesium content. Synergy of 5-episisomicin and carbenicillin was found to occur most often against Pseudomonas.

Aminoglycosides↗
PubMed1980

Comparative susceptibilities of clinical isolates of Serratia marcescens to newer cephalosporins, alone and in combination with various aminoglycosides.

We examined 100 clinically significant isolates of Serratia marcescens for susceptibility to newer cephalosporin and cephamycin antibiotics, alone and in combination with various aminoglycosides. Moxalactam and cefotaxime were the most effective agents; all isolates were inhibited by 25 and 50 micrograms/ml, respectively. All strains were susceptible to amikacin at concentrations safely achievable in serum, whereas gentamicin, netilmicin, and tobramycin inhibited 63, 63, and 16% of the isolates, respectively. Moxalactam, cefotaxime, and amikacin were active against gentamicin-susceptible and gentamicin-resistant strains. Studies of synergy revealed that moxalactam and cefotaxime, in combination with netilmicin or amikacin, were often synergistic and infrequently antagonistic against cephalothin- and gentamicin-resistant strains. These results suggest that moxalactam and cefotaxime, alone or in combination, may be efficacious in treating infections due to multiply antibiotic-resistant S. marcescens.

Aminoglycosides↗
PubMed1999

Use of pharmacodynamic indices to predict efficacy of combination therapy in vivo.

Although combination therapy with antimicrobial agents is often used, no available method explains or predicts the efficacies of these combinations satisfactorily. Since the efficacies of antimicrobial agents can be described by pharmacodynamic indices (PDIs), such as area under the concentration-time curve (AUC), peak level, and the time that the concentration is above the MIC (time>MIC), it was hypothesized that the same PDIs would be valid in explaining efficacy during combination therapy. Twenty-four-hour efficacy data (numbers of CFU) for Pseudomonas aeruginosa in a neutropenic mouse thigh model were determined for various combination regimens: ticarcillin-tobramycin (n = 41 different regimens), ceftazidime-netilmicin (n = 60), ciprofloxacin-ceftazidime (n = 59), netilmicin-ciprofloxacin (n = 38) and for each of these agents given singly. Multiple regression analysis was used to determine the importance of various PDIs (time>MIC, time>0.25 x the MIC, time>4 x the MIC, peak level, AUC, AUC/MIC, and their logarithmically transformed values) during monotherapy and combination therapy. The PDIs that best explained the efficacies of single-agent regimens were time>0.25 x the MIC for beta-lactams and log AUC/MIC for ciprofloxacin and the aminoglycosides. For the combination regimens, regression analysis showed that efficacy could best be explained by the combination of the two PDIs that each best explained the response for the respective agents given singly. A regression model for the efficacy of combination therapy was developed by use of a linear combination of the regression models of the PDI with the highest R(2) for each agent given singly. The model values for the single-agent therapies were then used in that equation, and the predicted values that were obtained were compared with the experimental values. The responses of the combination regimens could best be predicted by the sum of the responses of the single-agent regimens as functions of their respective PDIs (e.g., time>0.25 x the MIC for ticarcillin and log AUC/MIC for tobramycin). The relationship between the predicted response and the observed response for the combination regimens may be useful for determination of the presence of synergism. We conclude that the PDIs for the individual drugs used in this study are class dependent and predictive of outcome not only when the drugs are given as single agents but also when they are given in combination. When given in combination, there appears to be a degree of synergism independent of the dosing regimen applied.

Animals↗
PubMed2000

In vitro activities of nontraditional antimicrobials against multiresistant Acinetobacter baumannii strains isolated in an intensive care unit outbreak.

Fifteen multiresistant Acinetobacter baumannii isolates from patients in intensive care units and 14 nonoutbreak strains were tested to determine in vitro activities of nontraditional antimicrobials, including cefepime, meropenem, netilmicin, azithromycin, doxycycline, rifampin, sulbactam, and trovafloxacin. The latter five drugs were further tested against four of the strains for bactericidal or bacteriostatic activity by performing kill-curve studies at 0.5, 1, 2, and 4 times their MICs. In addition, novel combinations of drugs with sulbactam were examined for synergistic interactions by using a checkerboard configuration. MICs at which 90% of the isolates tested were inhibited for antimicrobials showing activity against the multiresistant A. baumannii strains were as follows (in parentheses): doxycycline (1 microg/ml), azithromycin (4 microg/ml), netilmicin (1 microg/ml), rifampin (8 microg/ml), polymyxin (0.8 U/ml), meropenem (4 microg/ml), trovafloxacin (4 microg/ml), and sulbactam (8 microg/ml). In the kill-curve studies, azithromycin and rifampin were rapidly bactericidal while sulbactam was more slowly bactericidal. Trovafloxacin and doxycycline were bacteriostatic. None of the antimicrobials tested were bactericidal against all strains tested. The synergy studies demonstrated that the combinations of sulbactam with azithromycin, rifampin, doxycycline, or trovafloxacin were generally additive or indifferent.

Acinetobacter↗
PubMed2003

Aminoglycoside resistance resulting from tight drug binding to an altered aminoglycoside acetyltransferase.

The aacA29b gene, which confers an atypical aminoglycoside resistance pattern to Escherichia coli, was identified on a class 1 integron from a multidrug-resistant isolate of Pseudomonas aeruginosa. On the basis of amino acid sequence homology, it was proposed that the gene encoded a 6'-N-acetyltransferase. The resistance gene was cloned into the pET23a(+) vector, and overexpression conferred high-level resistance to the usual substrates of the aminoglycoside N-acetyltransferase AAC(6')-I, except netilmicin. The level of resistance conferred by aacA29b correlated perfectly with the level of expression of the gene. The corresponding C-terminal six-His-tagged AAC(6')-29b protein was purified and found to exist as a dimer in solution. With a spectrophotometric assay, an extremely feeble AAC activity was detected with acetyl coenzyme A (acetyl-CoA) as an acetyl donor. Fluorescence titrations of the protein with aminoglycosides demonstrated the very tight binding of tobramycin, dibekacin, kanamycin A, sisomicin (K(d), </=1 micro M) and a weaker affinity for amikacin (K(d), approximately 60 micro M). The binding of netilmicin and acetyl-CoA could not be detected by either fluorescence spectroscopy or isothermal titration calorimetry. The inability of AAC(6')-29b to efficiently bind acetyl-CoA is supported by an alignment analysis of its amino acid sequence compared with those of other AAC(6')-I family members. AAC(6')-29b lacks a number of residues involved in acetyl-CoA binding. These results lead to the conclusion that AAC(6')-29b is able to confer aminoglycoside resistance by sequestering the drug as a result of tight binding.

Acetyltransferases↗
PubMed1985

Radioenzymatic assays for aminoglycosides with kanamycin 6'-acetyltransferase.

To facilitate the rapid and accurate quantitation of parenterally administered aminoglycosides, we defined the optimum conditions (pH, duration of incubation, and cofactor concentrations) to permit radioenzymatic assays with kanamycin acetyltransferase. The accuracy in quantitating tobramycin, netilmicin, kanamycin, and amikacin at concentrations in the therapeutic range was greater than 90%, with a mean recovery of 102.8%. The mean of the interassay coefficient of variation was 7.8%. Typical standard curves at six different concentrations resulted in a correlation coefficient (r value) of greater than 0.99 for each aminoglycoside. The radioenzymatic assay correlates well with the bioassay (tobramycin and netilmicin) and radioimmunoassay (amikacin and kanamycin); the correlation coefficient is greater than 0.90 for all. We conclude that the radioenzymatic assay utilizing kanamycin 6'-acetyltransferase is feasible for all commercially available parenterally administered aminoglycosides.

Acetyl Coenzyme A↗