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Biomedical subjects

D Milatovic

Publications and source records attributed to D Milatovic.

At least 19 recordsLinked to original sources
PubMed2000

Atypical effect of some spin trapping agents: reversible inhibition of acetylcholinesterase.

N-tert-butyl-alpha-phenylnitrone (PBN), a widely used nitrone-based free radical trap was recently shown to prevent acetylcholinesterase (AChE) inhibitors induced muscle fasciculations and brain seizures while being ineffective against glutamergic or cholinergic receptor agonist induced seizures. In the present study we compared the effects on AChE activity of four free radical spin traps PBN, alpha-(4-pyridil-1)-N-tert-butyl nitrone (POBN), N-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO). The kinetics of AChE inhibition were studied in vitro using a spectrophotometric kinetic assay with AChE from rat brain, diaphragm, electric eel and mouse brain. Spin trapping compounds S-PBN and DEPMPO, in concentrations up to 3 mM did not inhibit hydrolysis of ACh, while PBN and POBN inhibited hydrolysis of ACh in a reversible and concentration-dependent manner. Double reciprocal plots of the reaction velocity against varying ACh concentrations at each inhibitor concentration were linear and generally indicated mixed type inhibition. PBN was the most potent inhibitor of mouse AChE with Ki and Ki' of 0.58 and 2.99 mM, respectively, and the weakest inhibitor of electric eel AChE. In contrast, POBN showed the highest affinity for electric eel enzyme, with Ki and Ki' values of 1.065 and 3.15 mM, respectively. These findings suggest that the effect of PBN and POBN on AChE activity does not depend on trapping of damaging reactive oxygen and that in addition to their antioxidant action other pharmacological effects of these compounds should be considered when neuroprotective actions of PBN or POBN are investigated.

Acetylcholinesterase↗
PubMed2000

Spin trapping agent phenyl-N-tert-butylnitrone prevents diisopropylphosphorofluoridate-induced excitotoxicity in skeletal muscle of the rat.

Indirect evidence suggests that reactive oxygen species (ROS) may mediate muscle fiber necrosis following muscle hyperactivity induced by the anticholinesterase diisopropylphosphorofluoridate (DFP). Pronounced muscle fasciculations and muscle fiber necrosis were seen when acetylcholinesterase (AChE) activity was reduced to less than 30% of control. The spin trapping agent phenyl-N-tert-butylnitrone (PBN) was used in vivo to directly assess the formation of ROS during DFP (1.75 mg/kg, s.c.) induced muscle hyperactivity. Pretreatment with PBN (300 mg/kg, i.p.), the concentration necessary for in vivo spin trapping, prevented muscle hyperactivity as well as necrosis and attenuated the DFP induced AChE inhibition otherwise seen in DFP only treated rats. PBN had no effect when given after fasciculations were established. Muscle extracts from PBN and DFP treated rats subjected to electron spin resonance (ESR) spectroscopy tested negative for ROS. While the role of PBN as an antioxidant is well established, its prophylactic effect against excitotoxity induced by an AChE inhibitor are due to its protection of AChE, an unexpected non-antioxidant action.

Acetylcholinesterase↗
PubMed2000

Epidemiology of quinolone resistance of Klebsiella pneumoniae and Klebsiella oxytoca in Europe.

The epidemiology of quinolone resistance and the concomitant resistance to other antibiotic classes was investigated in 445 Klebsiella pneumoniae and 238 Klebsiella oxytoca isolates. Decreased susceptibility to ciprofloxacin was found in 7.2% and 3.4% of these two species, respectively. Ciprofloxacin resistance was significantly linked to ceftazidime resistance, the hallmark of extended-spectrum beta-lactamase production, as well as to resistance to all antibiotic classes tested. Using automated ribotyping, seven intrahospital- and interhospital-transmitted clones of ciprofloxacin-resistant isolates were found. The newer fluoroquinolones sitafloxacin and clinafloxacin may become increasingly valuable, since they proved to be active also against ciprofloxacin-resistant isolates.

Anti-Bacterial Agents↗
PubMed2000

In vitro potency of moxifloxacin, clinafloxacin and sitafloxacin against 248 genetically defined clinical isolates of Staphylococcus aureus.

The in vitro potency of three newer fluoroquinolones, moxifloxacin, clinafloxacin and sitafloxacin was tested against 248 genetically defined Staphylococcus aureus isolates, comprising 116 unrelated S. aureus, seven heterogeneous intermediate vancomycin-resistant S. aureus strains as well as 125 clonally related methicillin-resistant S. aureus. All strains were susceptible to clinafloxacin and sitafloxacin based on an investigational breakpoint of 1 mg/L and were less influenced by mutations within the grl and gyr gene loci. In one-quarter to one-third of the strains tested, reserpine decreased slightly the MICs of moxifloxacin, clinafloxacin and sitafloxacin. Compared with moxifloxacin, clinafloxacin and sitafloxacin showed a significantly increased anti-staphylococcal potency.

Anti-Infective Agents↗
PubMed2000

Molecular epidemiology of penicillin-resistant Streptococcus pneumoniae colonizing children with community-acquired pneumonia and children attending day-care centres in Fortaleza, Brazil.

To study clonal diversity of penicillin-resistant Streptococcus pneumoniae, 161 randomly selected isolates with reduced susceptibility to penicillin, collected from the nasopharynx of children under 5 years of age with community-acquired pneumonia and healthy controls from public day-care and immunization centres in Fortaleza, Brazil, were characterized by microbiological and serological techniques and automated ribotyping. Also included were 44 randomly selected penicillin-susceptible strains and three international reference strains. With automated ribotyping 75 ribopatterns were observed: 50 ribogroups were unique and 25 ribogroups were represented by two or more isolates. Genetic diversity was extensive but some degree of genetic homogeneity was found in strains from children with pneumonia, strains from children in day-care centres, isolates with reduced susceptibility to penicillin and isolates expressing 'paediatric' serogroups. Fourteen (56%) clusters contained both isolates with reduced penicillin susceptibility and penicillin-susceptible isolates, suggesting emergence of penicillin resistance. In general, there was a good correlation between ribogroups and serogroups, but 12 (48%) clusters contained isolates with alternative serogroups. Isolates with such alternative serogroups were more often encountered in penicillin-susceptible strains (41%) than in strains with reduced susceptibility to penicillin (7%). Thirty-eight (19%) isolates (including seven penicillin-susceptible strains) showed ribotypes indistinguishable from those of two international epidemic clones of S. pneumoniae: ribogroup 54-S-1 (15 isolates) with a ribopattern characteristic of the 23F multiresistant 'Spanish/USA' clone and ribogroup 74-S-3 (23 isolates) with a pattern similar to that of the 6B multiresistant 'Spanish' clone.

Analysis of Variance↗
PubMed2000

In vitro activities of sitafloxacin (DU-6859a) and six other fluoroquinolones against 8,796 clinical bacterial isolates.

The in vitro activities of sitafloxacin, ciprofloxacin, trovafloxacin, levofloxacin, clinafloxacin, gatifloxacin, and moxifloxacin against 5,046 gram-negative bacteria, 3,344 gram-positive cocci, and 406 anaerobes were determined. Sitafloxacin was the most active agent against gram-positive cocci and anaerobes. Against Enterobacteriaceae and nonfermenters, its activity was either equivalent to or better than that of clinafloxacin.

Anti-Infective Agents↗
PubMed2000

Molecular surveillance of European quinolone-resistant clinical isolates of Pseudomonas aeruginosa and Acinetobacter spp. using automated ribotyping.

Nosocomial isolates of Pseudomonas aeruginosa and Acinetobacter spp. exhibit high rates of resistance to antibiotics and are often multidrug resistant. In a previous study (D. Milatovic, A. Fluit, S. Brisse, J. Verhoef, and F. J. Schmitz, Antimicrob. Agents Chemother. 44:1102-1107, 2000), isolates of these species that were resistant to sitafloxacin, a new advanced-generation fluoroquinolone with a high potency and a broad spectrum of antimicrobial activity, were found in high proportion in 23 European hospitals. Here, we investigate the clonal diversity of the 155 P. aeruginosa and 145 Acinetobacter spp. sitafloxacin-resistant isolates from that study by automated ribotyping. Numerous ribogroups (sets of isolates with indistinguishable ribotypes) were found among isolates of P. aeruginosa (n = 34) and Acinetobacter spp. (n = 16), but the majority of the isolates belonged to a limited number of major ribogroups. Sitafloxacin-resistant isolates (MICs > 2 mg/liter, used as a provisional breakpoint) showed increased concomitant resistance to piperacillin, piperacillin-tazobactam, ceftriaxone, ceftazidime, amikacin, gentamicin, and imipenem. The major ribogroups were repeatedly found in isolates from several European hospitals; these isolates showed higher levels of resistance to gentamicin and imipenem, and some of them appeared to correspond to previously described multidrug-resistant international clones of P. aeruginosa (serotype O:12) and Acinetobacter baumannii (clones I and II). Automated ribotyping, when used in combination with more discriminatory typing methods, may be a convenient library typing system for monitoring future epidemiological dynamics of geographically widespread multidrug-resistant bacterial clones.

4-Quinolones↗
PubMed2000

Distinguishing species of the Burkholderia cepacia complex and Burkholderia gladioli by automated ribotyping.

Several species belonging to the genus Burkholderia are clinically relevant, opportunistic pathogens that inhabit major environmental reservoirs. Consequently, the availability of means for adequate identification and epidemiological characterization of individual environmental or clinical isolates is mandatory. In the present communication we describe the use of the Riboprinter microbial characterization system (Qualicon, Warwick, United Kingdom) for automated ribotyping of 104 strains of Burkholderia species from diverse sources, including several publicly accessible collections. The main outcome of this analysis was that all strains were typeable and that strains of Burkholderia gladioli and of each species of the B. cepacia complex, including B. multivorans, B. stabilis, and B. vietnamiensis, were effectively discriminated. Furthermore, different ribotypes were discerned within each species. Ribotyping results were in general agreement with strain classification based on restriction fragment analysis of 16S ribosomal amplicons, but the resolution of ribotyping was much higher. This enabled automated molecular typing below the species level. Cluster analysis of the patterns obtained by ribotyping (riboprints) showed that within B. gladioli, B. multivorans, and B. cepacia genomovar VI, the different riboprints identified always clustered together. Riboprints of B. cepacia genomovars I and III, B. stabilis, and B. vietnamiensis did not show distinct clustering but rather exhibited the formation of loose assemblages within which several smaller, genomovar-specific clusters were delineated. Therefore, ribotyping proved useful for genomovar identification. Analysis of serial isolates from individual patients demonstrated that infection with a single ribotype had occurred, despite minor genetic differences that were detected by pulsed-field gel electrophoresis of DNA macrorestriction fragments. The automated approach allows very rapid and reliable identification and epidemiological characterization of strains and generates an easily manageable database suited for expansion with information on additional bacterial isolates.

Automation↗
PubMed2000

Cholinergic and noncholinergic brain biomarkers of insecticide exposure and effects.

The objective of this investigation was to determine the distribution of cholinergic and noncholinergic biomarkers in discrete brain regions (cortex, stem, striatum, hippocampus, and cerebellum) of rats treated with dimethyl sulfoxide (DMSO, controls), and insecticides such as carbofuran (CARB, 1.5 mg/kg, sc), or methyl parathion (MPTH, 5 mg/kg, ip). Both insecticides produced characteristic signs of anticholinesterase nature within 5-7 min after injection. In controls, analyses of the brain regions revealed a wide variability in the values of cholinergic (acetylcholinesterase, AChE) and noncholinergic (creatine kinase, CK; and lactic dehydrogenase, LDH, and their isoenzymes) biomarkers. The highest activities of AChE and LDH were found in the striatum (1661+/-23 micromol/g/h and 57,720+/-478 IU/l, respectively) and lowest in the cerebellum (118+/-6 micromol/g/h) and 39,480+/-918 IU/l, respectively). However, the activity of CK was found highest in the cerebellum (742,560+/-798 IU/l) and lowest in the hippocampus (353,400+/-11,696 IU/l). Each brain region showed a characteristic profile of CK and LDH isoenzymes. Among the CK isoenzymes, activity of CK-BB was highest (77.5-89.3%), followed by CK-MM (6.7-15.6%), and least CK-MB (0-6.9%). The cerebellum had no CK-MB activity. In all brain regions, CK-MM isoenzyme had only the CK-MM3 subform. Among the LDH isoenzymes, activity of LDH-4 was highest in all brain regions (23-40%), except the cerebellum in which LDH-1 was highest (29%). Compared to the brain, control serum contained very little CK and LDH activity, but serum had three distinct CK and five distinct LDH isoenzymes. Unlike brain regions, serum had three CK-MM subforms. Each insecticide induced characteristic alterations in brain biomarkers. AChE activity was maximally inactivated in cortex (90. 6%) with CARB, and in cerebellum (95.3%) with MPTH. With either insecticide, the least inhibition of AChE occurred in the striatum. Unlike AChE, carboxylesterase (CarbE) did not show brain regional variability in controls, and its activity was uniformly inhibited in all brain regions by CARB and comparatively greater by MPTH. CARB- or MPTH-induced characteristic alterations in CK, LDH, and their isoenzymes in the brain, which were also reflected in serum, as a result of their leakage from the brain by increased permeability due to depletion of ATP (38-57% and 33-47%, respectively) and phosphocreatine (PCr, 23-42% and 56-65%, respectively).

Acetylcholinesterase↗
PubMed2000

Seizure-induced changes in energy metabolites and effects of N-tert-butyl-alpha-phenylnitrone (PNB) and vitamin E in rats.

Impaired energy metabolism may play a critical role in the neuronal injury caused by kainic acid (KA) induced status epilepticus (SE). Following an acute dose of KA (15 mg/kg, s.c.) rats developed SE within 1 h. Rats were sacrificed 1 or 72 h after the onset of SE using a head focused microwave technique and the brain regions (pyriform cortex, amygdala, and hippocampus) were assayed for energy metabolites: ATP, ADP, AMP, phosphocreatine (PCr) and creatine (Cr) using reversed-phase HPLC (RP-HPLC). Control values were significantly higher in cortex (23-32%) than in other brain regions. Within 1 h, SE caused a marked decline in ATP (44-56%), PCr (49-64%), total adenine nucleotides (TAN, 45-50%) and total creatine compounds (TCC, 32-51%). Within three days, the hippocampus showed the greatest recovery, as the reduced values returned to normal. Pretreatment of rats with an antioxidant (PBN, 200 mg/kg, i.p., 30 min prior to KA; or vitamin E (Vit-E), 100 mg/kg, i.p./day for 3 days), which did not prevent seizure activity, attenuated depletion of high-energy phosphates caused by KA. These findings suggest that the depletion of energy metabolites caused by KA-induced seizures may be linked to oxidative stress mediated toxicity.

Animals↗
PubMed1999

Nitrone spin trapping compound N-tert-butyl-alpha-phenylnitrone prevents seizures induced by anticholinesterases.

The neuroprotection afforded by spin trapping agents such as N-tert-butyl-alpha-phenylnitrone (PBN) has lent support to the hypothesis that increased production of reactive oxygen species (ROS) is a major contributing factor to excitotoxicity, aging and cognitive decline. Little is known, however, about the pharmacological properties of PBN. We have compared the acute effects of PBN on the development of seizures induced by the irreversible acetylcholinesterase (AChE) inhibitor diisopropylphosphorofluoridate (DFP), the reversible AChE inhibitor physostigmine (PHY), the muscarinic cholinergic receptor agonist pilocarpine (PIL) and the glutamatergic receptor agonist kainic acid (KA). Rats were sacrificed 90 min after the injection of seizure-inducing agents. In situ hybridization was used to detect the induction of immediate early gene (IEG) c-fos and c-jun mRNA's and the levels of AChE mRNA. The activity of AChE was visualized by AChE staining and quantified using an in vitro AChE assay. The seizures correlated with the induction of IEG mRNA's with all agents used. The pre-treatment with 150 mg/kg of PBN prevented DFP- and PHY-induced seizures and the related expression of IEG mRNA's, but had no effect on PIL- or KA-induced seizures and associated IEG mRNA's changes. PBN prevented seizures and significantly protected AChE activity against DFP inhibition when given before, but not when given after DFP. This study shows that PBN specifically protects against anticholinesterase-induced seizures by reversible protection of AChE activity and not by the blockade of muscarinic or glutamate receptors, reactivation of AChE or scavenging of ROS. The anticholinesterase properties should be considered when using PBN in studies of cholinergic dysfunction.

Acetylcholinesterase↗
PubMed1999

Different role of carboxylesterases in toxicity and tolerance to paraoxon and DFP.

The contribution of carboxylesterase (CarbE) to toxicity and tolerance to the organophosphorus anticholinesterases (OP-antiChE) paraoxon (diethyl p-nitrophenyl phosphate) and DFP (diisopropylphosphorofluoridate) was investigated in rats. Daily injections (20 days) of paraoxon (0.33 micromol/kg) or DFP (2.72 micromol/kg) reduced AChE activity in brain to 29 or 16% and in diaphragm to 58 or 54%, respectively. The animals tolerated an accumulated 6-fold LD50 dose and survived an LD90 dose of carbachol, indicating tolerance to this cholinergic agonist. A single dose of paraoxon or DFP significantly reduced CarbE activity of plasma, lung and liver. After paraoxon, rapid recovery was seen of plasma and liver CarbE while recovery after DFP was much slower. Daily pretreatment with the CarbE inhibitors CBDP (2-[o-cresyl]-4H-1,2,3-benzodioxa- phosphorin-2-oxide) (7.22 micromol/kg, s.c.) or iso-OMPA (tetraisopropylpyrophosphoramide) (8.76 micromol/kg, i.p.), followed by paraoxon (0.33 micromol/kg, s.c.) 30 min later, prevented the development of tolerance to paraoxon and potentiated its toxicity. Rats died on day four of the combined treatment. The CarbE inhibitors neither potentiated the DFP toxicity, nor prevented tolerance development to DFP. We conclude that rat plasma CarbE provides a significant protection against paraoxon toxicity because its rapid reactivation can reduce the toxicity of repeated paraoxon applications and thus contribute to tolerance development. This same mechanism does not apply to DFP toxicity, as inhibition of CarbE of plasma, liver and lung neither potentiated its toxicity, nor prevented tolerance development. These findings confirm previous observations that CarbE detoxification is of greater importance for highly toxic OP-antiChEs such as nerve agents and paraoxon than for less toxic ones such as DFP.

Acetylcholinesterase↗
PubMed1999

Hydrogen peroxide for prevention of bacterial growth on polymer biomaterials.

BACKGROUND: Despite widespread use of potent antibiotics, infections of artificial implants and catheters are of increasing concern. We tested whether local treatment with 3% hydrogen peroxide (H2O2), long known as an inexpensive wound disinfectant, could prevent or reduce bacterial growth on polymer biomaterials. METHODS: Two-centimeter-long pieces of polyurethane and silicone tubing were contaminated with a standardized solution of Staphylococcus epidermidis (10(5)/mL) and then rinsed and wiped with saline (0.9%) solution. Bacterial growth was assessed after incubation at 37 degrees C for 24 hours. Bacterial colonies were compared for the following treatments: wiping only with saline; wiping with 1.5%, 2%, or 3% H2O2; pretreating biomaterials with 3% H2O2 and subsequent contamination for 2 and 4 hours without treatment after contamination; and contamination of tubings 1 month after pretreatment with 3% H2O2. The effect of 3% H2O2 was also assessed on contamination with Escherichia coli. RESULTS: Bacterial growth was reduced by more than 99% when the contaminated tubes were treated with 3% H2O2 compared with saline control (p < 0.001). Lower concentrations of H2O2 were less effective. The length of the contamination period had no influence on the effectiveness of H2O2 when used on polyurethane but did with silicone tubings. Pretreatment with H2O2 1 month before contamination still reduced bacterial growth rate by 90% on polyurethane and by 75% on silicone tubings. Comparable effects on bacterial growth rate were observed for staphylococci (-90%, p < 0.001) and escherichiae (-90%, p < 0.001). CONCLUSIONS: Local treatment with 3% H2O2 significantly reduced bacterial growth on polymer biomaterials even for 1 month after treatment. This finding might influence clinical strategies of prevention of foreign body infection.

Anti-Infective Agents, Local↗
PubMed1999

Molecular epidemiology of quinolone resistance and comparative in vitro activities of new quinolones against European Staphylococcus aureus isolates.

UNLABELLED: New fluoroquinolones (FQ) may possibly be used as alternative therapeutic options for Staphylococcus aureus infections. Our objectives were: (1) to define the in vitro activities of seven FQs in a collection of 434 methicillin-susceptible and 457 methicillin-resistant S. aureus from 23 European university hospitals; (2) to characterise the prevalence of mutations in the grlA and gyrA genes in all ciprofloxacin-resistant (n=433) isolates of S. aureus; (3) to determine the percentage of ciprofloxacin-resistant S. aureus strains with measurable quinolone efflux. METHODS: (1) The in vitro activities of different FQs were determined by microdilution tests. (2) PCR-amplified DNA was sequenced. (3) Ciprofloxacin minimum inhibitory concentrations (MIC) were determined in the presence and absence of reserpine, which inhibits efflux pumps. RESULTS: (1) Irrespective of the methicillin resistance of the isolates, sitafloxacin and clinafloxacin showed the best in vitro activities. (2) All ciprofloxacin-resistant isolates exhibited GrlA alterations, namely Ser-80-->Phe or Tyr or Glu-84-->Lys or Ala-116-->Glu or Pro or a combination of Ser-80-->Phe and Glu-84-->Val. These alterations in GrlA were combined with alterations in GyrA, namely Ser-84-->Leu or Lys or Glu-88-->Lys or Val. (3) Reserpine reduced ciprofloxacin MIC values in ca. 30% of the clinical isolates tested. CONCLUSIONS: (1) This current European overview of mutations involved in FQ resistance demonstrates that only a limited number of classical mutations in grlA and gyrA contributed to resistance in clinical isolates. (2) An efflux pump is involved in ca. 30% of ciprofloxacin-resistant S. aureus isolates. (3) Sitafloxacin and clinafloxacin are two very promising new FQs with good anti-staphylococcal activity. New FQs, perhaps in combination with efflux pump inhibitors, might play a role in the treatment of S. aureus infections.

Anti-Infective Agents↗
PubMed1999

Association of alterations in ParC and GyrA proteins with resistance of clinical isolates of Enterococcus faecium to nine different fluoroquinolones.

The parC and gyrA genes of 73 ciprofloxacin-resistant and 6 ciprofloxacin-susceptible Enterococcus faecium clinical isolates were partly sequenced. Alterations in ParC and GyrA, possibly in combination with other resistance mechanisms, severely restricted the in vitro activities of the nine quinolones tested. For all isolates, clinafloxacin and sitafloxacin showed the best activities.

Anti-Infective Agents↗
PubMed1999

Comparative in vitro activities of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, and Enterobacter aerogenes clinical isolates with alterations in GyrA and ParC proteins.

The in vitro activities of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin were tested against 72 ciprofloxacin-resistant and 28 ciprofloxacin-susceptible isolates of Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, and Enterobacter aerogenes. Irrespective of the alterations in GyrA and ParC proteins, clinafloxacin exhibited greater activity than all other fluoroquinolones tested against K. pneumoniae and E. aerogenes.

Anti-Infective Agents↗
PubMed1998

Azithromycin versus cefaclor in the treatment of pediatric patients with acute group A beta-hemolytic streptococcal tonsillopharyngitis.

An open, comparative multicenter study was performed to evaluate the efficacy and safety of azithromycin (10 mg/kg) given once daily for three days in comparison with cefaclor (30 mg/kg) divided into three daily doses and given for a period of ten days. One hundred and twenty-two children aged 1-12 years with clinical symptoms of group A beta-hemolytic streptococcal tonsillopharyngitis and a positive throat culture were randomly allocated to the treatment groups. Overall, the clinical success (cure or improvement) of both regimens was identical in the evaluable patients (86.3%, 44 of 51 patients in either treatment group). In contrast, bacterial eradication after completion of treatment was lower with azithromycin than with cefaclor. Possible reasons for this discrepancy between clinical success and eradication rates could be antibiotic resistance, pre-disease carriage or insufficient dosage. Both agents were well tolerated; only mild or moderate side effects most frequently involving the gastrointestinal tract, were recorded in either therapy group.

Anti-Bacterial Agents↗