zithromax and Acinetobacter-Infections

Antimicrobial susceptibility testing (AST) in RPMI 1640, a more physiologically relevant culture medium, revealed that a substantial proportion of carbapenem-resistant Acinetobacter baumannii isolates were susceptible to azithromycin, a macrolide antibiotic not currently considered effective against A. baumannii. Experiments using Galleria mellonella validated these

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Azithromycin; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Moths

To evaluate the effect of azithromycin (AZM) on biofilm formation and composition in multidrug resistant (MDR) Acinetobacter baumannii.. Ninety-six A. baumannii isolates were studied. Antimicrobial susceptibility and sub-minimum inhibitory concentration (sub-MIC) were determined by the broth microdilution method. Carbapenemase genes were detected by polymerase chain reaction and clonal diversity by pulsed-field gel electrophoresis (PFGE). Biofilm formation without AZM and AZM sub-MIC were determined by crystal violet staining. AZM-free biofilm composition and AZM sub-MIC were determined by detachment assays.. The selected A. baumannii were MDR; 93.8% were carbapenem-resistant and 24 were OXA-24-positive. PFGE showed predominance of clones A (53%), B (34.7%) and C (12.5%). Biofilm production at AZM sub-MICs decreased in 53.1%, increased in 34.7% and showed no differences in 12.5% of isolates, in comparison with biofilm production without AZM.. AZM sub-MIC can reduce biofilm production in A. baumannii MDR isolates with decreased protein and DNA in the biofilm. Our results may be useful in synergy studies for new therapeutic alternatives.. Evaluar el efecto de la azitromicina (AZM) en la formación y composición de biopelículas en Acinetobacter baumannii resistente a múltiples fármacos (MDR).. Se estudiaron 96 aislamientos de A. baumannii. La susceptibilidad antimicrobiana y la concentración inhibitoria submínima (sub-MIC) se determinaron por el método de microdilución del caldo. Los genes carbapenemasa fueron detectados por reacción en cadena de la polimerasa y la diversidad clonal por electroforesis en gel de campos pulsados (PFGE). La formación de biopelículas sin AZM y la sub-MIC de AZM por tinción de cristal violeta. La composición de la biopelícula sin AZM y la sub-MIC de AZM se determinaron mediante ensayos de desprendimiento.. Los A. baumannii seleccionados fueron MDR; el 93.8% resistentes al carbapenem y 24 OXA-24 positivos. El PFGE demostró predominancia en los clones A (53%), B (34.7%) y C (12.5%). La producción de biopelículas en sub-MIC de AZM disminuyó en un 53.1%, aumentó en un 34.7% y no mostró diferencias en un 12.5% de los aislamientos, comparado con la producción de biopelículas sin AZM.. La sub-MIC de AZM puede reducir la producción de biopelículas en aislamientos de A. baumannii MDR con disminución de proteínas y el ADN en la biopelícula. Nuestros resultados pueden ser útiles en estudios de sinergia para nuevas alternativas terapéuticas.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Azithromycin; Biofilms; Carbapenems; Humans

Topics: Acinetobacter Infections; Aged; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Azithromycin; Bacteremia; Candidemia; COVID-19 Drug Treatment; Enzyme Inhibitors; Female; Gram-Negative Bacterial Infections; Humans; Hydroxychloroquine; Italy; Klebsiella Infections; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Pneumonia, Ventilator-Associated; Protective Factors; Pseudomonas Infections; Respiration, Artificial; SARS-CoV-2; Staphylococcal Infections; Superinfection; Teicoplanin

Nowadays, Acinetobacter baumannii is resistant to almost all available antibiotics. The evaluation of synergistic effects between the antibiotics against this pathogen is among the efforts to counteract its antimicrobial resistance. This study aimed to evaluate possible synergistic effect of colistin and ampicillin/sulbactam (separately) with several antibiotics against clinical isolates of multi-drug resistant (MDR) A. baumannii.. Acinetobacter baumannii strains were isolated from biological samples of hospitalized patients with any type of nosocomial infection related to this pathogen. Only MDR strains (resistance to at least three classes of antibiotics including cephalosporins, fluoroquinolones, and aminoglycosides) were included in the study. After determining the minimum inhibitory concentration (MIC) of antibiotics against the isolates by broth microdilution test, the checkerboard method was used for evaluation of any possible synergistic effect of both colistin and ampicillin/sulbactam with several other antibiotics.. Twenty isolates underwent synergy test for colistin and 20 isolates for ampicillin/sulbacatam. Doxycycline (55%), azithromycin (35%), and co-trimoxazole (35%) had the most frequency of synergistic effect with colistin. On the other hand, amikacin and gentamicin (55%), doxycycline (50%), co-trimoxazole (45%), azithromycin (40%), and cefepime (40%) had the most frequency of synergistic effect with ampicillin/sulbactam. No antagonistic effect was observed for both antibiotics.. Colistin and ampicillin/sulbactam have substantial synergistic effect with several antibiotics especially doxycycline, co-trimoxazole, azithromycin, and amikacin (with ampicillin/sulbactam) against MDR strains of Acinetobacter baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Amikacin; Ampicillin; Anti-Bacterial Agents; Azithromycin; Colistin; Doxycycline; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Microbial Sensitivity Tests; Sulbactam; Trimethoprim, Sulfamethoxazole Drug Combination

Recently, opportunistic nosocomial infections caused by Acinetobacter baumannii have become increasingly prevalent worldwide. The pathogen often establishes biofilms that adhere to medical devices, causing chronic infections refractory to antimicrobial therapy. Clinical reports have indicated that some macrolide antibiotics are effective against chronic biofilm-related infections. In this study, we examined the direct anti-biofilm effects of seven macrolides (azithromycin, clarithromycin, erythromycin, josamycin, spiramycin, fidaxomicin, and ivermectin) on A. baumannii using a simple and newly established in vitro assay system for the swift and serial spectrophotometric determinations of two biofilm-amount indexes of viability and biomass. These macrolides were found to possess direct anti-biofilm effects exerting specific anti-biofilm effects not exclusively depending on their bacteriostatic/bactericidal effects. The anti-biofilm effect of azithromycin was found to be the strongest, while those of fidaxomicin and ivermectin were weak and limited. These results provide insights into possible adjunctive chemotherapy with macrolides for A. baumannii infection. Common five macrolides also interfered with the Agrobacterium tumefaciens NTL(pCF218) (pCF372) bioassay system of N-acyl homoserine lactones, providing insights into sample preparation for the bioassay, and putatively suggesting the actions of macrolides as remote signals in bacterial quorum sensing systems.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Acyl-Butyrolactones; Agrobacterium tumefaciens; Anti-Bacterial Agents; Azithromycin; Biofilms; Biological Assay; Clarithromycin; Erythromycin; Fidaxomicin; Humans; Ivermectin; Josamycin; Microbial Sensitivity Tests; Microbial Viability; Quorum Sensing; Spiramycin

Multidrug-resistant (MDR) Acinetobacter baumannii infections have high mortality rates and few treatment options. Synergistic drug combinations may improve clinical outcome and reduce further emergence of resistance in MDR pathogens. Here we show an unexpected potent synergy of two translation inhibitors against the pathogen: commonly prescribed macrolide antibiotic azithromycin (AZM), widely ignored as a treatment alternative for invasive Gram-negative pathogens, and minocycline, among the current standard-of-care agents used for A. baumannii.. Media-dependent activities of AZM and MIN were evaluated in minimum inhibitory concentration assays and kinetic killing curves, alone or in combination, both in standard bacteriologic media (cation-adjusted Mueller-Hinton Broth) and more physiologic tissue culture media (RPMI), with variations of bicarbonate as a physiologic buffer. Synergy was calculated by fractional inhibitory concentration index (FICI). Therapeutic benefit of combining AZM and MIN was tested in a murine model of A. baumannii pneumonia. AZM + MIN synergism was probed mechanistically by bacterial cytological profiling (BCP), a quantitative fluorescence microscopy technique that identifies disrupted bacterial cellular pathways on a single cell level, and real-time kinetic measurement of translation inhibition via quantitative luminescence. AZM + MIN synergism was further evaluated vs. other contemporary high priority MDR bacterial pathogens.. Although two translation inhibitors are not expected to synergize, each drug complemented kinetic deficiencies of the other, speeding the initiation and extending the duration of translation inhibition as verified by FICI, BCP and kinetic luminescence markers. In an MDR A. baumannii pneumonia model, AZM + MIN combination therapy decreased lung bacterial burden and enhanced survival rates. Synergy between AZM and MIN was also detected vs. MDR strains of Gram-negative Klebsiella pneumoniae and Pseudomonas aeruginosa, and the leading Gram-positive pathogen methicillin-resistant Staphylococcus aureus.. As both agents are FDA approved with excellent safety profiles, clinical investigation of AZM and MIN combination regimens may immediately be contemplated for optimal treatment of A. baumannii and other MDR bacterial infections in humans. FUND: National Institutes of Health U01 AI124326 (JP, GS, VN) and U54 HD090259 (GS, VN). IC was supported by the UCSD Research Training Program for Veterinarians T32 OD017863.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Azithromycin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Drug Synergism; Mice; Microbial Sensitivity Tests; Protein Biosynthesis

LpxC inhibitors have generally shown poor in vitro activity against Acinetobacter baumannii We show that the LpxC inhibitor PF-5081090 inhibits lipid A biosynthesis, as determined by silver staining and measurements of endotoxin levels, and significantly increases cell permeability. The presence of PF-5081090 at 32 mg/liter increased susceptibility to rifampin, vancomycin, azithromycin, imipenem, and amikacin but had no effect on susceptibility to ciprofloxacin and tigecycline. Potentiating existing antibiotics with LpxC inhibitors may represent an alternative treatment strategy for multidrug-resistant A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Amidohydrolases; Amikacin; Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Carbapenems; Drug Resistance, Multiple, Bacterial; Imipenem; Microbial Sensitivity Tests; Minocycline; Rifampin; Tigecycline; Vancomycin

Treatment options for multidrug-resistant (MDR) strains of Acinetobacter baumannii that acquire resistance to colistin are limited. Acinetobacter baumannii can become highly resistant to colistin through complete loss of lipopolysaccharide (LPS) owing to mutations in the genes encoding the first three enzymes involved in lipid A biosynthesis (lpxA, lpxC and lpxD). The objective of this study was to characterise the susceptibility to 15 clinically relevant antibiotics and 6 antimicrobial peptides (AMPs) of MDR A. baumannii clinical isolates that acquired colistin resistance due to mutations in lpxA, lpxC and lpxD as well as their colistin-susceptible counterparts. A dramatic increase in antibiotic susceptibility (≥16-fold increase) was observed upon LPS loss for azithromycin, rifampicin and vancomycin, whereas a moderate increase in susceptibility was seen for amikacin, ceftazidime, imipenem, cefepime and meropenem. Importantly, concentrations ranging from 8 mg/L to 32 mg/L of the six AMPs were able to reduce bacterial viability by ≥3 log10 in growth curve assays. We also demonstrate that colistin resistance results in partial colistin dependence for growth in LPS-deficient strains containing mutations in lpxA, lpxC and lpxD, but not when colistin resistance occurs via LPS modification due to mutations in the PmrA/B two-component system. The results of this study indicate that loss of LPS expression results in collateral sensitivity to azithromycin, rifampicin and vancomycin, and that the six AMPs tested retain activity against LPS-deficient strains, indicating that these antibiotics may be viable treatment options for infections caused by these strains.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Azithromycin; Bacterial Proteins; Colistin; Drug Resistance, Multiple, Bacterial; Humans; Lipid A; Lipopolysaccharides; Microbial Sensitivity Tests; Microbial Viability; Rifampin; Vancomycin

Acinetobacter baumannii is one of the main pathogens that cause ventilator-associated pneumonia (VAP). Hypersecretion of mucin in the airway is associated with the onset of VAP. Furthermore, macrolides are known to accelerate the resolution of VAP. However, this mechanism has not been elucidated. We examined whether macrolides inhibit MUC5AC production that is induced by multidrug-resistant A. baumannii (MDRAB). MUC5AC production in bronchial cells after MDRAB stimulation was analyzed by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction. For the inhibition study, cells were treated with azithromycin (AZM) or clarithromycin (CAM) simultaneously along with MDRAB stimulation. Western blotting was performed was performed to determine potential rules for signal modules. MDRAB induced MUC5AC production and gene expression. The EGFR-ERK/JNK-NF-κB pathway was involved in MDRAB-induced MUC5AC production. AZM but not CAM inhibited MUC5AC production. AZM suppressed the phosphorylation of ERK/JNK and the nuclear translocation of NF-κB. Our results suggest that the efficacy of macrolides against VAP may be due to the inhibition of mucin production.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Azithromycin; Blotting, Western; Bronchi; Cells, Cultured; Clarithromycin; Drug Resistance, Multiple, Bacterial; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Gene Expression Regulation; Humans; Mucin 5AC; Pneumonia, Ventilator-Associated; Reverse Transcriptase Polymerase Chain Reaction

Acinetobacter baumannii is one of the main pathogens that cause ventilator-associated pneumonia (VAP) and is associated with a high rate of mortality. Little is known about the efficacy of macrolides against A. baumannii. In order to confirm the efficacy of azithromycin (AZM) against VAP caused by multidrug-resistant A. baumannii (MDRAB), we used a mouse model that mimics VAP by placement of a plastic tube in the bronchus. AZM (10 and 100 mg/kg of body weight) was administered subcutaneously every 24 h beginning at 3 h after inoculation. Phosphate-buffered saline was administered as the control. Survival was evaluated over 7 days. At 48 h postinfection, mice were sacrificed and the numbers of viable bacteria in lungs and bronchoalveolar lavage fluid were compared. Histopathological analysis of lung specimens was also performed. The treatment groups displayed significantly longer survival than the control group (P < 0.05). AZM did not have an antimicrobial effect. Histopathological examination of lung specimens indicated that the progression of lung inflammation was prevented in the AZM-treated groups. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in bronchoalveolar lavage fluid were significantly decreased (P < 0.05) in the AZM-treated groups. AZM may have a role for the treatment of VAP with MDRAB because of its anti-inflammatory effects.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bacterial Load; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Lung; Male; Mice; Microbial Viability; Pneumonia; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Survival Analysis

Based on imipenem resistance in an Acinetobacter genospecies 3 clinical isolate, we were able to identify, for the first time in this genomic species, a plasmid-encoded bla(OXA-58) gene that was 100% homologous to the same gene in Acinetobacter baumannii.

Topics: Acinetobacter; Acinetobacter Infections; Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; beta-Lactamases; Carbapenems; Humans; Imipenem; Microbial Sensitivity Tests; Molecular Sequence Data; Plasmids; Sequence Analysis, DNA

The susceptibilities of 142 Acinetobacter baumannii-calcoaceticus complex isolates (95 from wounded U.S. soldiers deployed overseas) to 13 antimicrobial agents were determined by broth microdilution. The most active antimicrobial agents (> or =95% of isolates susceptible) were colistin, polymyxin B, and minocycline.

Topics: Acinetobacter; Acinetobacter Infections; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Military Personnel; Minocycline; Polymyxin B; United States; Warfare

The activity of azithromycin against 225 clinical strains of Acinetobacter baumannii isolated consecutively from 26 Spanish hospitals in November 2000 was studied. The MICs of azithromycin were determined by microdilution, according to the NCCLS guidelines. The bactericidal activity of azithromycin against 15 clonally unrelated A. baumannii strains with different antimicrobial susceptibility patterns was tested using the subculture method. The killing-curves method was also performed against five strains with different susceptibility to azithromycin. The MIC(50) and MIC(90) of azithromycin were 32 and 64 mg/l, respectively. Moderate bactericidal activity was observed in 14 out of the 15 strains evaluated by the subculture method (MBCs from 1 to 4 dilution steps higher than the MICs) and by the killing-curve method. For three strains the number of CFU/ml was reduced 1 to 1.4 log by concentrations of azithromycin equivalent to 1 and 4 times their MICs. lt is concluded that azithromycin has moderate bactericidal activity against the strains of A. baumannii evaluated.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Azithromycin; Drug Resistance; Humans; Microbial Sensitivity Tests