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The co-occurrence of aminoglycoside and β-lactam resistance was assessed in 3358 consecutive Escherichia coli clinical isolates collected in 2014 in the greater Zurich area, Switzerland. Non-susceptibility to at least one of the tested aminoglycosides was observed in 470/3358 E. coli strains (14%). In strains categorized as broad-spectrum β-lactamase (BSBL)-producers (1241/3358 isolates), extended-spectrum β-lactamase (ESBL)-producers (262/3358) and AmpC-producers (66/3358), resistance to aminoglycoside was found in 23%, 52% and 20% of the isolates, respectively. In contrast, aminoglycoside-susceptible strains were rarely resistant to β-lactams (33/1777, 1.9%). The genomes of 439 aminoglycoside-resistant E. coli were sequenced and aminoglycoside and β-lactam genotypes were analysed. The most prevalent aminoglycoside resistance genes were aph(3')-Ia (133 strains, 30.3%), aac(3)-IId (100 strains, 22.8%), and aac(6')-Ib-cr (52 strains, 11.8%). The most frequent associations with β-lactam resistance genes were aph(3')-Ia or aac(3)-IId with blaTEM-1 (94 and 72 strains, respectively), and aac(3)-IIa/aac(6')-Ib-cr with blaCTX-M-15/blaOXA-1 (23 strains). These results indicate a frequent association of aac(3) and aph(3') genotypes with BSBL production, and a frequent co-occurrence of aac(6') genes with ESBL production. The high rate of co-occurrence of aminoglycoside resistance and β-lactamase production must be considered in combination therapy.

International audience; Acute appendicitis in children requires early surgery and short-course antibiotics active against Enterobacteriaceae and anaerobes. Although an aminoglycoside-containing three-drug regimen has been used successfully for decades, simpler regimens with similar efficacy are increasingly used. This study evaluated the impact of a switch from the combination of cefotaxime, metronidazole and gentamicin (regimen 1) to piperacillin/tazobactam (regimen 2) as first-line regimen for complicated acute appendicitis in children. In total, 171 children were enrolled [median (IQR) age, 10 (6-13) years], treated with regimen 1 (n = 80) or regimen 2 (n = 91) following surgery for complicated acute appendicitis. The two groups were comparable except for surgical approach (through laparoscopy in 46% vs. 88% for regimens 1 and 2, respectively; P < 0.001). Post-operative complications and duration of hospital stay were similar. Deviations from antibacterial treatment protocol decreased from 36% (29/80) to 14% (13/91) (P < 0.001), with a dramatic reduction in antibacterial treatment duration from median (IQR) of 15 (12-16) days to 5 (5-8) days (P < 0.001). Post-operative intra-abdominal abscess developed in 32 children (18.7%). Female sex (OR = 2.76, 95% CI 1.18-6.48; P = 0.02) and sepsis/septic shock on admission (OR = 4.72, 95% CI 1.12-19.97; P = 0.035) were independently associated with post-operative intra-abdominal abscess, but not antibacterial regimen. This study shows that simplification of first-line antibacterial regimen for complicated appendicitis in children was associated with reduced protocol deviation, reduced duration of antibiotics, and similar outcomes (post-operative complications and duration of hospital stay).

Staphylococcus aureus is responsible for life-threatening and difficult-to-treat infections worldwide and antimicrobial resistance is an increasing concern. Whilst acquired resistance has been widely studied, little is known of the contributions from chromosomal determinants that upon inactivation may reduce the susceptibility of S. aureus to antibiotics. The aim of this study was to identify genetic determinants that upon inactivation reduce aminoglycoside susceptibility in S. aureus. The Nebraska Transposon Mutant Library of 1920 single-gene inactivations in S. aureus strain JE2 was screened for reduced susceptibility to gentamicin. Nine mutants were confirmed by Etest to display between 2- and 16-fold reduced susceptibility to this antibiotic. All of the identified genes were associated with the electron transport chain and energy metabolism. Four mutant strains (menD, hemB, aroC and SAUSA300_0355) conferred the largest decrease in gentamicin susceptibility and three exhibited a small colony variant phenotype, whereas the remaining mutants (qoxA, qoxB, qoxC, ndh and hemX) displayed colony morphology similar to the wild-type. All of the mutants, except hemX, displayed reduced membrane potential suggesting that reduced uptake of gentamicin is the predominant mechanism leading to reduced susceptibility. The results of this study demonstrate that S. aureus possesses multiple genes that upon inactivation by mutagenesis reduce the membrane potential and thereby reduce the lethal activity of gentamicin.

Background Combining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice. Objective To determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy. Methods A systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared β-lactam antibiotic monotherapy with combined β-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity. Results Four randomised controlled trials and five retrospective cohort studies were analysed. Compared with β-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with β-lactam antibiotics was not associated with reduced mortality compared with β-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63–1.08, P = 0.10, I2 42%). A subgroup analysis of cohort studies suggested reduced mortality with combination therapy (n = 3563, OR 0.79, 95% CI 0.64–0.99, P = 0.04, I2 32%). No increased risk of nephrotoxicity was identified (n = 1110, OR 1.31, 95% CI 0.83–2.09, P = 0.40, I2 0%). Conclusions The existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with β-lactam antibiotics.

The new aminoglycoside plazomicin shows in vitro potency against multidrug-resistant Enterobacteriales. The exposure–response relationship of plazomicin and the comparator aminoglycoside amikacin was determined for Escherichia coli, while for Klebsiella pneumoniae only plazomicin was tested. An in vitro pharmacokinetic model was used. Five E. coli strains (two meropenem-resistant) and five K. pneumoniae strains (two meropenem-resistant) with plazomicin MICs of 0.5–4 mg/L were used. Antibacterial effect was assessed by changes in bacterial load and bacterial population profile. The correlation between change in initial inoculum after 24 h of drug exposure and the AUC/MIC ratio was good (plazomicin R2 ≥ 0.8302; amikacin R2 ≥ 0.9520). Escherichia coli plazomicin AUC/MIC ratios for 24-h static, –1, –2 and –3 log drop were 36.1 ± 18.4, 39.3 ± 20.9, 41.2 ± 21.9 and 44.8 ± 24.3, respectively, and for amikacin were 49.5 ± 12.7, 55.7 ± 14.8, 64.1 ± 19.2 and 73.3 ± 25.3. Klebsiella pneumoniae plazomicin AUC/MIC ratios for 24-h static, –1, –2 and –3 log drop were 34.0 ± 15.2, 46.8 ± 27.8, 67.4 ± 46.5 and 144.3 ±129.8. Plazomicin AUC/MIC ratios >66 and amikacin AUC/MIC ratios >57.7 were associated with suppression of E. coli growth on 4 × or 8 × MIC recovery plates. The equivalent plazomicin AUC/MIC to suppress resistance emergence with K. pneumoniae was >132. The plazomicin AUC/MIC for 24-h static effect and –1 log reduction in E. coli and K. pneumoniae bacterial load was in the range 30–60. Plazomicin AUC/MIC targets aligned with those of amikacin for E. coli.

In addition to lipopolysaccharides (LPS), outer membrane proteins - Lpp, OmpA and peptidoglycan-associated lipoprotein (Pal) - are part of the outer membrane of Escherichia coli and are proposed to contribute to bacterial sepsis-related inflammation. This study showed that ampicillin (a β-lactam antibiotic) enhances Pal's release from Escherichia coli to a greater extent than gentamicin and levofloxacin (aminoglycoside and quinolone antibiotics, respectively). It is proposed that the majority of Pal is released in outer membrane vesicles (OMVs), which also contain LPS and other outer membrane and periplasmic proteins. The OMVs were purified by ultracentrifugation and characterised by transmission electron microscopy and nanoparticle tracking analysis, and Pal and other E. coli proteins were detected by Western blot. It also proposed that sepsis treatments using certain β-lactam antibiotics may further aggravate the over-exuberant inflammatory response by enhancing the release of Pal and LPS in OMVs.

Carbapenemase-producing Enterobacteriaceae (CPE) cause serious infections and are associated with high mortality in part due to limited treatment options. The in vitro activities of the new aminoglycoside plazomicin and comparators were evaluated against a collection of 164 CPE (VIM-1, n=125; KPC-2, n=34; OXA-48, n=4; and IMP-22, n=1). MIC90 values of gentamicin, tobramycin and amikacin were 256, 64 and 16 mg/L, respectively. Plazomicin exhibited an MIC range of 0.12-4 mg/L with MIC50 and MIC90 values of 0.25 and 1 mg/L. The MICs of plazomicin did not correlate with the other aminoglycoside MICs, with the resistance phenotype or with the carbapenemase harboured. Chequerboard experiments against 10 carbapenemase-producing Klebsiella pneumoniae isolates showed that combinations of plazomicin with colistin yielded synergy against 60% of the strains. Synergy of plazomicin with meropenem or fosfomycin was detected against 20% and 25% of the isolates, respectively. Using time-kill methodology, the interactions of plazomicin at 2×, 1× and 0.5× MIC with meropenem, colistin, fosfomycin or tigecycline at steady-state concentrations against two K. pneumoniae carrying the VIM-1 enzyme were investigated. Bactericidal activity was evident for both isolates at 2× MIC of plazomicin. Synergy was observed when plazomicin was combined with meropenem, colistin or fosfomycin against both isolates, whilst the combination with tigecycline resulted in indifference. Antagonism was not observed for any of the combinations tested. The results of this study suggest that plazomicin may address the need for new therapeutic options for the treatment of infections due to CPE.

International audience; Modifications of antibiotic pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We aimed to determine optimised amikacin (AMK), gentamicin (GEN) and tobramycin (TOB) intravenous dosing regimens in this patient population. Patients admitted to the medical ICU and treated with AMK, GEN or TOB were included. Analyses were performed using a parametric population approach. Monte Carlo simulations were performed and the probability of target attainment (PTA) was calculated using C-max/MIC >= 8 and trough concentrations as targets. A total of 117 critically ill hospitalised patients were studied. Median values (interindividual variability, omega(2)) of clearance were 3.51 (0.539), 3.53 (0.297), 2.70 (0.339) and 5.07 (0.339) L/h for AMK, GEN, TOB, and TOB in cystic fibrosis (CF), respectively. Median values (omega(2)) of central volume of distribution were 30.2 (0.215), 20.0 (0.109) and 25.6 (0.177) L for AMK, GEN and TOB, respectively. Simulations showed that doses should be adjusted to actual body weight and creatinine clearance (CLCR) for AMK and GEN, and according to CLCR and presence of CF for TOB. In conclusion, our recommendations for treating Pseudomonas aeruginosa infections in this population include using initial doses of 35 mg/kg for AMK or 10 mg/kg for TOB (CF and non-CF patients). GEN demonstrated the best rates of target attainment against Staphylococcus aureus infections with a dose of 5 mg/kg. As high aminoglycoside doses are required in this population, efficacy and safety targets are conflicting and therapeutic drug monitoring remains an important tool to manage this issue. (C) 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

This study aimed to assess the clinical impact and potential risk factors associated with polymyxin-resistant Enterobacteriaceae strains isolated from patients hospitalized in adult and neonatal intensive care units. A case-control study was conducted from September 2015 to January 2017. Antimicrobial susceptibility of polymyxin-resistant Enterobacteriaceae strains was determined by broth microdilution. The presence of resistance genes was evaluated by polymerase chain reaction and DNA sequencing. Renal failure [P=0.02, odds ratio (OR) 11.37, 95% confidence interval (CI) 1.0-128.63], use of a urinary catheter (P0.01, OR 4.16, 95% CI 38.82-366.07), transfer between hospital units (P=0.03, OR 9.98, 95% CI 1.01-98.42), carbapenem use (P0.01, OR 45.49, 95% CI 6.93-298.62) and surgical procedure (P0.01, OR 16.52, 95% CI 2.83-96.32) were found to be risk factors for the acquisition of polymyxin-resistant strains in adult patients. For neonatal patients, use of a central venous catheter (P0.01, OR 69.59, 95% CI 7.33-660.30) was the only risk factor associated with the acquisition of polymyxin-resistant strains. Analysis of the outcomes revealed that the mortality rate was significantly higher in adult (66.6%) and neonatal (23.5%) patients with polymyxin-resistant strains than in those with polymyxin-susceptible strains. In addition, carbapenem exposure (P0.01, OR 50.93, 95% CI 2.26-999.999) was strongly associated with mortality. On the other hand, aminoglycoside use (P0.03, OR 0.06, 95% CI 0.004-0.97) was a protective factor against mortality from polymyxin-resistant strains. Several risk factors were associated with polymyxin-resistant strains. The high mortality rates showed that acquisition of these strains is a predictor for unfavourable outcomes. Combination treatment with an aminoglycoside and polymyxin might be a better combination to improve patient outcomes.

Development of new antibiotics is costly and time-consuming, and therefore increasing the efficacy of conventional antibiotics is extremely attractive. For the human pathogen, Staphylococcus aureus, inactivation of the ATP synthase increases its susceptibility to gentamicin (an aminoglycoside) 16-fold. Aminoglycosides are rarely used as monotherapy against S. aureus due to the risk of development of resistance and toxic effects. This study explored the possibility of enhancing the efficacy of aminoglycosides against S. aureus and other Gram-positive pathogens by inhibiting the ATP synthase with resveratrol, a polyphenolic ATP synthase inhibitor that is commonly used as a dietary supplement. Co-administration of subinhibitory concentrations of resveratrol increased the activity of aminoglycosides, including gentamicin, kanamycin, neomycin, streptomycin and tobramycin, up to 32-fold against S. aureus, while the effect was lower (2-4-fold reduction in minimum inhibitory concentration) for other Gram-positive pathogens (i.e. Staphylococcus epidermidis, Enterococcus faecium and Enterococcus faecalis). The mechanism by which resveratrol increases the efficacy of aminoglycosides appears to be unrelated to membrane hyperpolarization and disruption of membrane integrity, which have been associated previously with increased aminoglycoside susceptibility. These results demonstrate that inhibition of the ATP synthase increases the efficacy of aminoglycosides against important Gram-positive pathogens, and the ATP synthase should be explored further as a target that may extend the clinical applicability of aminoglycosides.

The activity of eight aminoglycosides (amikacin, apramycin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin and tobramycin) against a collection of 257 amoxicillin/clavulanic acid (AMC)-resistant Escherichia coli isolates was determined by microdilution. Aminoglycoside resistance rates, the prevalence of aminoglycoside-modifying enzyme (AME) genes, the relationship between AME gene detection and resistance phenotype to aminoglycosides, and the association of AME genes with mechanisms of AMC resistance in E. coli isolates in Spain were investigated. Aminoglycoside-resistant isolates were screened for the presence of genes encoding common AMEs [aac(3)-Ia, aac(3)-IIa, aac(3)-IVa, aac(6')-Ib, ant(2")-Ia, ant(4')-IIa and aph(3')-Ia] or 16S rRNA methylases (armA, rmtB, rmtC and npmA). In total, 105 isolates (40.9%) were resistant to at least one of the aminoglycosides tested. Amikacin, apramycin and arbekacin showed better activity, with MIC90 values of 2 mg/L (arbekacin) and 8 mg/L (amikacin and apramycin). Kanamycin presented the highest MIC90 (128 mg/L). The most common AME gene was aac(6')-Ib (36 strains; 34.3%), followed by aph(3')-Ia (31 strains; 29.5%), ant(2")-Ia (29 strains; 27.6%) and aac(3)-IIa (23 strains; 21.9%). aac(3)-Ia, aac(3)-IVa, ant(4')-IIa and the four methylases were not detected. The ant(2")-Ia gene was usually associated with OXA-1 [21/30; 70%], whilst 23/25 (92%) strains producing CTX-M-15 had the aac(6')-Ib gene. The most prevalent AME gene was aac(6')-Ib (18/41; 44%) in nosocomial isolates, whilst ant(2")-Ia and aph(3')-Ia genes (20/64; 31%) were more frequent in strains of community origin. In 64.6% isolates the phenotypic profile correlated with the presence of commonly encountered AMEs. (C) 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Gram-negative bacilli are the causative organisms in a significant proportion of patients with severe community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU). Clinical guidelines recommend broad-spectrum antimicrobials for empirical treatment despite alarming global trends in antimicrobial resistance. In this study, we aimed to assess the safety and efficacy of gentamicin, an aminoglycoside with potent bactericidal activity, for empirical Gram-negative coverage of severe CAP in patients admitted to the ICU. A retrospective cohort study was performed at a university teaching hospital where the severe CAP guideline recommends penicillin, azithromycin and gentamicin as empirical cover. Ceftriaxone plus azithromycin is used as an alternative. Adults with radiologically-confirmed severe CAP were included, comparing those who received gentamicin in the first 72 h of admission with those who did not. Participants were identified using ICD-10 codes for bacterial pneumonia and data manually extracted from electronic medical records. Of 148 patients admitted with severe pneumonia, 117 were given at least one dose of gentamicin whereas the remaining 31 were not. The two groups were well matched in terms of demographics, co-morbidities and disease severity. There were no significant differences between the gentamicin and no-gentamicin groups in the incidence of acute kidney injury [60/117 (51%) vs. 16/31 (52%), respectively], hospital mortality [20/117 (17%) vs. 7/31 (23%)] and secondary outcomes including relapse and length of hospital stay. In conclusion, gentamicin is safe and has similar outcomes to alternative Gram-negative antimicrobial regimens for empirical coverage in severe CAP patients admitted to the ICU.

Candida spp. are the primary opportunistic pathogens of nosocomial fungal infections, causing both superficial and life-threatening systemic infections. Combination therapy for fungal infections has attracted considerable attention, especially for those caused by drug-resistant fungi. Gentamicin (GM), an aminoglycoside antibiotic, has weak antifungal activity against Fusarium spp. The aim of this study was to investigate the interactions of GM with azoles against Candida spp. and the underlying mechanisms. In a chequerboard assay, GM was found not only to work synergistically with azoles against planktonic cells of drug-resistant Candida albicans with a fractional inhibitory concentration index (FICI) of 0.13-0.14, but also synergised with fluconazole (FLC) against C. albicans biofilms pre-formed in

Plazomicin is a next-generation aminoglycoside with a potentially unique set of clinical characteristics compared with other aminoglycosides. This study assessed the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of plazomicin against 15 clinical isolates as well as three reference strains representing Brucella abortus, Brucella melitensis and Brucella suis. These data were compared with those obtained for six other aminoglycosides and two aminocyclitols. Plazomicin and gentamicin were the only drugs demonstrating bactericidal activity towards two of the three Brucella spp., whilst plazomicin was the only drug exhibiting bactericidal activity against B. suis. This is the first study to assess the bactericidal nature of plazomicin against Brucella spp. in vitro.

The main objectives in childhood urinary tract infections are rapid recovery from complaints, prevention of urosepsis and infection-related complications as well as the prevention of renal parenchymal damage. Calculated antibiotic therapy should take the local resistance rates of uropathogens into consideration. The current situation of bacterial resistances differs from region to region. In Escherichia coli, resistance rates against cephalosporins, aminoglycosides, nitrofurantoin und chinolones have been relatively low. In contrast, resistance rates against ampicillin have increased over the last 20 years. A similar trend has been observed for TMP/SMX. The choice of appropriate antibiotics, the duration of therapy and the form of application depend on age, severity of clinical symptoms and the presence of complicating factors. In early infancy, a combination of aminoglycoside/ampicillin or ceftazidime/ampicillin is commonly recommended as first-line treatment in pyelonephritis. Pyelonephritis in young infants should always be treated in a paediatric clinic. In later infancy and childhood, an oral third-generation cephalosporin can be used.

Adaptive resistance is an autoregulated phenomenon characterised by induction of resistance in the presence of drug and reversal to the sensitive phenotype in its absence. This type of resistance is well documented for polycationic antibiotics, including aminoglycosides and polymyxins, in Pseudomonas aeruginosa and other aerobic Gram-negative bacilli. It is not caused by selection of resistant mutants but rather by phenotypic alterations in order to survive the lethal drug effect. Adaptive resistance to aminoglycosides is mainly mediated by the MexXY-OprM efflux pump that is rapidly upregulated in bacteria surviving the first exposure to aminoglycosides and is downregulated when bacteria are no longer in contact with the drug. A two-component regulatory system designated ParR-ParS plays a major role in adaptive resistance induced by cationic peptides. In the presence of cationic peptides, ParR-ParS activates the lipopolysaccharide modification operon (arnBCADTEF) leading to increased resistance in polymyxins and aminoglycosides. The bactericidal kinetics related to adaptive resistance have important clinical implications and provide a rationale for administering cationic antibiotics in larger initial and longer interval bolus dosing. A better understanding of this phenomenon and the molecular mechanisms responsible will be essential not only for optimum use of cationic antibiotics but also for developing new agents with ability to counteract the detrimental effects of adaptive resistance and thus enhance the therapeutic efficacy of polycationic compounds.

Pseudomonas aeruginosa colonisation and chronic lung infection associated with biofilm formation is a major cause of morbidity and mortality in cystic fibrosis (CF) patients. There is thus an urgent need to develop alternative ways to treat biofilm-associated clinical infections. A kinetic study of twice-daily co-administration of the antibiotics tobramycin and clarithromycin was performed over 28 days on 12-day-old mature P. aeruginosa biofilms formed on microplate pegs for 23 clinical isolates of various phenotypes and genotypes to simulate the treatment of CF patients with inhaled tobramycin through aerosolisation (TOBI). Drug activity was assessed by enumeration of persistent bacteria before, during and after treatment. A mature (12-day-old) biofilm model was chosen because a previous study suggested that such a biofilm was a more realistic in vitro model than a 24-h-old biofilm. Synergistic activity of the drug combination was confirmed on biofilms of 9/23 P. aeruginosa isolates. Of these nine isolates, total destruction of the biofilm was observed for five of them. Combination treatment was superior or equivalent to treatment with tobramycin alone, as activity was observed on 47.8% of the isolates with the combination versus 26.1% with tobramycin alone. No correlation was observed between drug susceptibility profiles and the phenotype or genotype of the isolates.

Cystic fibrosis (CF) is a common and lethal genetic disorder with a carrier frequency of 1 in 29 Caucasians. Chronic respiratory infections with Pseudomonas aeruginosa are the leading cause of morbidity and mortality in individuals with CF. Aminoglycoside antibiotics, including gentamicin, are highly effective against P. aeruginosa, but severe toxicity limits their use. One potential strategy for avoiding this problem is to encapsulate aminoglycosides in liposomes. In this study, we compared the bactericidal capacity of liposome-encapsulated gentamicin with that of free antibiotic against clinical isolates of P. aeruginosa. Liposome size, encapsulation efficiency and minimal inhibitory concentrations (MICs) of the free and liposomal gentamicin against gentamicin-sensitive and -resistant strains of P. aeruginosa were determined. In vitro time-kill studies were performed using free and liposomal gentamicin at 1, 2 or 4 times the MICs. The average liposomal size was 426.25 +/- 13.56 nm, with a gentamicin encapsulation efficiency of 4.51 +/- 0.54%. The MICs for liposomal gentamicin were significantly lower than those of corresponding free gentamicin. In addition, the time-kill values for liposomal gentamicin were either equivalent to or better than those of the free antibiotic. In conclusion, our liposomal gentamicin formulation is a more potent antipseudomonal drug with an improved killing time and prolonged antimicrobial activity.

A retrospective survey of the isolation rate of Enterococcus avium during the period March 1994–February 2000 conducted in Laikon General Hospital using the whonet software, revealed a peak in the isolation rates of this species during March 1995–February 1996. The ten strains isolated during this time were studied further. No glycopeptide resistance was detected but resistance to ampicillin, ciprofloxacin, erythromycin, gentamicin (high-level) and streptomycin (high-level) was present in nine, ten, nine, three and seven of the isolates, respectively. The genes aac(6′)-Ie+aph(2′′)-Ia and ant(6)-I , encoding for high-level gentamicin and streptomycin resistance, respectively, were detected only in the isolates with the corresponding phenotypes. Beta-lactamase production and haemolysis were not detected. There was evidence of ward-, floor- and building-specific distribution among the different aminoglycoside resistance phenotypes. DNA fingerprinting by PFGE grouped six of the ten isolates in a single cluster with 83% similarity, even though they expressed various resistance phenotypes. These results suggest dissemination of resistance genes among both genetically related and unrelated strains.

Extended-interval aminoglycoside dosing (EIAD), while a relatively recent concept in mainstream clinical practice, actually has its roots in the mid 1970s. Early trial and error approaches of manipulating the dosage regimen to avoid toxicity and improve efficacy have helped to characterize the pharmacodynamic properties of these drugs. The increasing successful use of EIAD and improved understanding of pharmacodynamics has helped this dosing regimen gain acceptance into routine clinical practice. A 1998 United States survey demonstrated that approximately 75% of hospitals have adopted EIAD into routine patient care. However, controversy still exists regarding some aspects of infrequent aminoglycoside administration, such as length of the drug-free interval and patient exclusion criteria. After more than 50 years of experience with the aminoglycosides we continue to learn how to most appropriately use these drugs.

The worldwide emergence of Streptococcus pneumoniae with decreased susceptibility to penicillin has led to the suggestion that drug combinations might be used. The aim of this study was to determine possible synergy using a combination of penicillin with sub-inhibitory doses of gentamicin against 26 clinical isolates of S. pneumoniae with decreased susceptibility to penicillin, using half-chequerboards and killing curves. Synergy was demonstrated for ten of the 26 isolates with the combination of penicillin with gentamicin at 1 mg/l and for 22 isolates with penicillin and gentamicin at 2 mg/l. Killing curves on three isolates showed synergy and confirmed the chequerboard results. Further synergy studies using penicillin or cefotaxime/ceftriaxone, plus low dose gentamicin against penicillin-resistant pneumococci are indicated.

The activity of ACHN-490 was evaluated against 493 meticillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2009–2010 from 23 US hospitals. The MIC 50 and MIC 90 values (minimal inhibitory concentrations for 50% and 90% of the organisms, respectively) for ACHN-490 were 1 and 2 μg/mL compared with 8 and 32 μg/mL for amikacin, 0.5 and 1 μg/mL for gentamicin and 2 and >16 μg/mL for tobramycin. The gene encoding the aminoglycoside-modifying enzyme APH(2″)-Ia/AAC(6′)-Ie was present in 12% of the subset of 84 isolates examined by polymerase chain reaction (PCR), whilst the gene encoding ANT(4′)-Ia was present in 89% of isolates. ACHN-490 activity was not affected by either enzyme.

The in-vitro activities of various antibiotics, either alone or in combination with amikacin were assessed using clinical isolates of Pseudomonas aeruginosa . The minimum inhibitory concentrations (MIC) of these antibiotics were determined by microbroth dilution method against 50 clinical strains. The MIC values showed that 96, 94, and 74% of the isolates were susceptible or moderately susceptible to amikacin, meropenem and ceftazidime, respectively. The in vitro activities of ceftazidime and meropenem in combination with amikacin were determined by microbroth chequerboard technique and results were interpreted using the fractional inhibitory concentration (FIC) index. With a FIC index of ≤0.5 as borderline, synergistic interactions were more frequent with ceftazidime (70.8%) than with meropenem (40%). No antagonism was observed.

Klebsiella aerogenes K41, resistant to third generation cephalosporins and aminoglycosides, was isolated from clinical samples of 153 in-patients. Blood cultures accounted for 24 (15.7%) of isolates. The MIC 90 of ceftazidime for the isolates of 84 patients was >512 mg/l and was reduced to 2.0 by 4 mg/l of clavulanic acid, but only to 64 by 4 mg/l of sulbactam. Isolates of K. aerogenes K41 produced extended-spectrum β-lactamase (ESBL) SHV-5 and TEM-1, identified by isoelectric focusing. Plasmid profiles showed that co-dissemination of cephalosporin and aminoglycoside resistance, plus ESBL production, coincided with the acquisition of a 116-kb plasmid. This plasmid was transferable in vitro from K. aerogenes K41 to other serotypes and genera of the Enterobacteriaceae.

Increasing antibiotic resistance and the development of multidrug-resistance in the enterococci has complicated the treatment of serious enterococcal infections. It has been demonstrated in vitro that interferon-gamma (IFN-gamma) significantly augments the activities of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The present study was aimed at determining whether this beneficial effect of IFN-gamma on antienterococcal antibiotic activity can be validated in vivo. Following intraperitoneal inoculation in mice with a gentamicin- and vancomycin-resistant E. faecalis clinical isolate, the animals received IFN-gamma, antibiotic or a combination of both agents, subcutaneously, at determined dosing regimens. Treatment with IFN-gamma alone significantly improved survival of infected animals in a dose-dependent manner. High dose IFN-gamma was not beneficial and the level of enterococcal infectious burden influenced the effectiveness of the cytokine. The addition of IFN-gamma to therapy with gentamicin or vancomycin, or a combination of both antibiotics was associated with a marked increase in survival of infected non-neutropenic mice compared to treatments with the agents alone. However, the same treatments made in infected neutropenic mice did not show an enhancement effect by IFN-gamma after a combination therapy with antibiotics. In a study to examine pharmacokinetic interactions, concurrent administration with IFN-gamma significantly modified the disposition of gentamicin but not that of vancomycin. The results of this study suggest that the use of IFN-gamma in combination with vancomycin or gentamicin is a new treatment option that might improve the outcome of therapy of multidrug-resistant E. faecalis infections.

Teicoplanin have different safety profiles which can affect choice. Nephrotoxicity is significantly less likely to occur during treatment with teicoplanin than vancomycin when an aminoglycoside is being given concurrently. 'Red man' syndrome is a troublesome effect of vancomycin infusion which is extremely uncommon with teicoplanin use. Rash and fever can be dose-related phenomena but patients reacting to one glycopeptide may not react to both. Although thrombocytopenia is more frequent with teicoplanin, it is reversible and seldom seen at standard doses.

Over the past 20 years, antibiotic resistance has increased in virtually every species of bacteria examined. In this paper, the main mechanisms of antibiotic resistance currently known for antibiotics used for treatment of disease caused by oral and upper respiratory bacteria will be reviewed, with an emphasis on the most commonly used antibiotics. The possible role that mercury, which is released from silver amalgams, plays in the oral/respiratory bacterial ecology is also discussed, as it relates to possible selection of antibiotic resistant bacteria.

Antibiotic resistance in Gram-negative bacteria, especially Enterobacteriaceae, can be conferred by a large number of different acquired resistance genes, although it appears that relatively few dominate. A previous survey of Escherichia coli and Klebsiella pneumoniae isolates from Sydney, Australia, revealed that a limited set of genes could reliably predict resistance to third-generation cephalosporins (3GCs) and aminoglycosides. Here we tested E. coli and K. pneumoniae isolates with a cefotaxime, ceftriaxone and/or ceftazidime minimum inhibitory concentration of ≥ 2 μg/mL from China and Singapore, with significantly higher resistance rates than Australia, as well as the USA. Few targets were needed to predict non-susceptibility to 3GCs (95/95; 100%) and gentamicin (47/51; 92%). The gene types detected here are consistent with previous surveys in similar countries with similar resistance rates, where the majority of 3GC resistance can be explained by blaCTX-M genes. This study identified a limited set of genes capable of predicting resistance to 3GC and aminoglycoside antibiotics and implies a restriction in the global resistance gene pool that can be exploited for diagnostic purposes.

Administration of either amikacin (1985) or gentamicin (1984, 1986–1991) as first-choice aminoglycoside did not decrease the high incidence of amikacin-resistant Serratia marcescens (AR Sm ) isolates responsible for nosocomial infections at the J.A. Fernandez Hospital of Buenos Aires (42% in 1984, 31% in 1985 and 41% in 1987, differences not significant). In addition, a significant peak ( P = 0.003) was detected in 1986, with an AR Sm incidence of 70%. The incidence of AR Sm decreased by 1988–1991 for reasons not related to aminoglycoside use. In the period 1984–1987 all S. marcescens isolates carried the 6′-aminoglycoside-acetyltransferase-Ic [ aac(6′)-Ic ] gene, while in addition 20% of the isolates contained the plasmid-encoded 3′-aminoglycoside-phosphotransferase-VIa[ aph(3′)-VIa ] and 2% the 6′-aminoglycoside-acetyltransferase-Ib [ aac(6′)-Ib ] genes. From 1988 to 1992 resistance to amikacin was associated with only 4 ARSm isolates and correlated with the appearance of Tn 1331 -related sequences in these isolates. This transposon or related sequences, however, was not widely spread in the S. marcescens population under investigation. Combined use of restriction fragment length polymorphism (RFLP), ribotyping and plasmid profile analysis revealed that S. marcescens strains of the same genotype, including isolates either expressing or not the aac(6′)-Ic gene, were involved in outbreaks occurring in May 1984, May 1985 and May 1986. Furthermore, these epidemiological tools permitted discrimination of different S. marcescens clones, each bearing a particular amikacin-resistance marker.

The most common problems limiting the medical use of aminoglycosides have been the nephro- and oto-toxicities and the increasing bacterial resistance. It has been shown that encapsulation of drugs into liposomes enhances their efficacy while reducing their toxicities. The present in vitro study was designed to evaluate the antimicrobial activities of free and liposomal amikacin, netilmicin and tobramycin. We, therefore, encapsulated these drugs into liposomes prepared by sonication. The drug contained in liposomes was measured by enzyme multiplied immunoassay technique (EMIT) after lysis of the vesicles by 0.2% Triton X-100. The comparative encapsulation efficiency of the three antibiotic preparations was assessed. Aminoglycosides kinetic release from liposomes in presence of normal human sera was also studied in vitro over a 48 h period at 37°C under 5% CO 2 . The MICs of these encapsulated drugs to Pseudomonas aeruginosa, Xanthomonas maltophilia, Escherichia coli, Streptococcus faecalis and Staphylococcus aureus were determined and compared to those of respective free drugs using an agar dilution method. The amikacin and tobramycin encapsulation efficiencies were significantly ( P ≤ 0.05) higher (5.36% ± 0.17 and 5.06% ± 0.10) than those of netilmicin (3% ± 0.18). However, in presence of sera, liposomal retention of netilmicin was significantly ( P ≤ 0.05) lower (61.88 ± 0.14%) than that of amikacin (81.45 ± 0.64%) and tobramycin (94.07 ± 0.18%) after 1 h of incubation and then remained nearly constant over an 48 h period of the study. The MICs of liposomal netilmicin against all bacterial strains tested were reduced, compared to those of free netilmicin. However, liposomal amikacin and tobramycin MICs were nearly similar to those of free respective drugs. Overall, liposomal netilmicin appears to be a promising approach in the management of Gram-positive and Gram-negative bacterial infections and should be further evaluated in in vivo experiments.

The objective of this review was to compare the effectiveness and safety of β-lactam combined with aminoglycoside or fluoroquinolone with that of β-lactam monotherapy for the treatment of Pseudomonas aeruginosa infections. We searched Scopus and PubMed databases and synthesised the outcomes of the individual studies in a meta-analysis. Both non-randomised studies and randomised controlled trials (RCTs) that evaluated outcomes of patients with P. aeruginosa infections receiving treatment with β-lactams alone or in combination with an aminoglycoside or a fluoroquinolone were included. Studies including patients with cystic fibrosis were excluded. Nineteen articles (eight RCTs) were included (1721 patients with P. aeruginosa infections). Patients receiving combination therapy had no difference in mortality compared with patients receiving β-lactam monotherapy either as definitive (risk ratio=0.97, 95% confidence interval 0.77-1.22) or as empirical treatment (1.02, 0.78-1.34). In the definitive treatment group, no difference in mortality was found between combination therapy and monotherapy for patients with bacteraemia (0.95, 0.67-1.34) or severe infections (0.96, 0.75-1.24). Patients receiving definitive combination therapy had non-significantly higher clinical cure compared with patients receiving β-lactam monotherapy (1.36, 0.99-1.86). A higher clinical cure rate was observed for patients receiving empirical treatment with combination therapy (1.23, 1.05-1.43). There was no difference in clinical cure either for RCTs (1.29, 0.91-1.83) or for non-randomised studies (1.18, 0.97-1.45). In conclusion, no benefit in mortality was observed in patients receiving combination therapy for P. aeruginosa infections. A well-designed multicentre RCT is warranted to address this important issue.