Etiology of Crohn's disease: the role of Mycobacterium avium paratuberculosis.

Crohn's disease is a chronic inflammatory bowel disease characterized by transmural inflammation and granuloma formation. Several theories regarding the etiology of Crohn's disease have been proposed, one of which is infection with Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis), which causes a similar disease in animals, and is present in the human food chain. Considerable evidence supports the presence of M. paratuberculosis in the intestinal tissues of many patients with Crohn's disease including culture, detection of homologous mycobacterial DNA, detection of the mycobacterial insertion sequence IS900 by both PCR and in situ hybridization in tissues, and a serologic immune response to recombinant M. paratuberculosis antigens. Despite this evidence, and our personal belief that M. paratuberculosis is a cause of Crohn's disease, widespread acceptance of this hypothesis will require evidence that specific anti-mycobacterial chemotherapy will cure the disease.

Pattern of primary resistance of Helicobacter pylori to metronidazole or clarithromycin in the United States.

BACKGROUND: Therapy for Helicobacter pylori is generally empiric despite the fact that resistance to metronidazole and clarithromycin compromise therapeutic efficacy. The aim of this study was to aid clinicians in choosing a course of therapy for H pylori infection in the United States. METHODS: The frequency of primary clarithromycin and metronidazole resistance among H pylori isolated from patients enrolled in US-based clinical trials between 1993 and 1999 was reviewed in relation to patient age, sex, region of the United States, and test method (Etest and 2 agar dilution procedures). RESULTS: Clarithromycin and metronidazole resistance rates were based on the results of 3439 pretreatment Etest determinations and 3193 agar dilution determinations. Sex and age were available on 900 and 823 individuals, respectively. Metronidazole resistance was 39% by Etest and 21.6% by agar dilution (P<.001). Clarithromycin resistance was 12% by Etest and 10.6% by agar dilution. Amoxicillin or tetracycline resistance was rare. Metronidazole and clarithromycin resistance was more common in women than men (eg, 34.7% vs 22.6% for metronidazole and 14.1% vs 9.7% for clarithromycin (P =.01 and P =.06, respectively). Antibiotic resistance increased gradually up to age 70 years, then declined significantly (P<.05) regardless of test method. Regional differences in antimicrobial resistance did not occur. CONCLUSIONS: While age and sex had significant effects on resistance rates, regional differences were not present. The high prevalence of resistance to metronidazole and clarithromycin may soon require the performance of antimicrobial susceptibility testing of H pylori isolates prior to initiating treatment.

Antimicrobial susceptibility testing for Helicobacter pylori: sensitivity test results and their clinical relevance.

There are multiple test methodologies to determine the antibiogram of an organism. Standardized susceptibility test methods are based upon rapidly growing, aerobic microorganisms in which overnight incubation results in definitive endpoints. In vitro susceptibility testing for fastidious organisms that require complex media for growth, require incubation in atmospheres other than ambient air, or are slow-growing (anaerobes, mycobacteria, filamentous fungi) are problematic and in general are not standardized. H. pylori falls into this category of troublesome organisms. For the microaerobic organism H. pylori, testing is challenging because the organism grows slowly even under optimal culture conditions. Recently the National Committee for Clinical Laboratory Standards (NCCLS) approved the agar dilution method as the test of choice for testing H. pylori. While not entirely reliable in predicting the outcome of treatment for metronidazole resistant organisms, the resistance determined for clarithromycin by this method generally predicts treatment failure. Quality control breakpoints for H. pylori ATCC 43504 were established and breakpoints for clarithromycin were approved by the NCCLS in 1999. Breakpoints are minimum inhibitory concentrations (MIC) of a drug at which an organism is deemed either susceptible or resistant to the antibiotic using standard dosing regimens containing that drug. Significant progress has been made with respect to development of tests to detect antimicrobial resistance, but there still remains no consensus as to the breakpoints for agents used in the treatment of H. pylori infection other than clarithromycin. This article will address the controversies associated with the reporting of antibiotic resistance data and the interpretation of these data.

Comparative bioavailability and efficacy of fortified topical tobramycin.

Topical treatment of severe ocular infections may require the use of antibiotics fortified in concentration beyond commercially available preparations. The authors studied tear pharmacokinetics, tissue bioavailability, epithelial toxicity, and comparative antibacterial efficacy of topical tobramycin concentrations ranging from 0.3-5.0%. Tear pharmacodynamics demonstrate bioassay-measurable levels with each preparation up to 6 hr after a single 50-microliter drop challenge. Comparing various fortified concentration levels yields progressive parallel-biphasic decay curves in antibiotic tear-film concentrations. Both tear and corneal data demonstrate increases in measured antibiotic levels largely proportional to the increases in drug concentration instilled. Tobramycin was undetectable in corneas treated with 0.3% tobramycin, yet measurable with higher drug levels. A rabbit epithelial wound-healing model demonstrated progressive toxicity ranging from no effect of 0.3% tobramycin on healing rates compared with paired controls, to a significant decrease in re-epithelialization rates with 1.1% (P = 0.03) and 4.0% (P = 0.02) tobramycin. Finally, a Pseudomonas aeruginosa keratitis model in the rat demonstrates the antibiotic efficacy of topical tobramycin treatment over untreated controls (P less than 0.00001), and a progressively enhanced efficacy with increasing tobramycin concentrations is suggested. Concentration enhancement of topical ocular medication is useful in the treatment of severe ocular infection.

Combination drug testing of Mycobacterium chelonae.

PURPOSE: Medical therapy of Mycobacterium chelonae keratitis is difficult because there are so few effective antimicrobial agents and single agent therapy frequently fails clinically. To identify more effective medical treatment regimens, the in vitro antimicrobial efficacy of amikacin, the most frequently used single agent, was investigated in combination with four antibiotics previously reported to have activity against M. chelonae: erythromycin, imipenem, ciprofloxacin, and vancomycin. METHODS: The drug combinations were tested by the checkerboard method against seven corneal isolates of M. chelonae. RESULTS: The combination of amikacin with erythromycin or vancomycin consistently led to synergistic or additive effect, however the minimum inhibitory concentrations for vancomycin were very high. The combination of amikacin with imipenem or ciprofloxacin led to results ranging from antagonism to additive effects. CONCLUSIONS: Of the antibiotics tested, erythromycin showed the most activity against M. chelonae in combination with amikacin. In vitro combination drug testing of M. chelonae by the checkerboard method should be further evaluated for clinical relevance in microbial keratitis.

Citric acid-enhanced Helicobacter pylori urease activity in vivo is unrelated to gastric emptying.

BACKGROUND: In a previous study, the use of a citric acid test meal produced a rapid dose-dependent increase in urease activity that was significantly greater than that resulting from a pudding meal, ascorbic acid or sodium citrate. The mechanism was hypothesized to be related to the ability of citric acid to delay gastric emptying and possibly to enhance intragastric distribution of the urea. OBJECTIVE: To compare the effects of sodium citrate, two doses of citric acid and a pudding meal on gastric motor function. METHOD: Eleven normal healthy volunteers were investigated using non-invasive techniques to measure gastric emptying and gastric motility. We evaluated gastric emptying using the Meretek 13Ceebiscuit solid phase gastric emptying breath test, which employs a 340-calorie biscuit containing 200 mg of the edible 13C-blue-green alga Spirulina platensis, after the administration of test meals of pudding, 2 g and 4 g of citric acid and 2 g of sodium citrate. Electrogastrograms (Digitrapper EGG) were also recorded for 30 min before and 180 min after the test meal. RESULTS: Gastric emptying, as assessed by the half-time (T1/2), was delayed similarly with the pudding (136.8 +/- 9 min) and with 4 g of citric acid (144.5 +/- 7 min) (P > 0.7). Sodium citrate (108.7 +/- 6 min) and 2 g of citric acid (110.1 +/- 6 min) had similar effects on gastric emptying (P=0.986), and were significantly less effective in delaying gastric emptying (P < 0.01) compared to pudding or 4 g of citric acid. The electrogastrograms remained normal and there were no differences among meals and no relation with the gastric emptying results. CONCLUSIONS: The increased intragastric urea hydrolysis associated with citric acid test meals cannot be attributed to delayed gastric emptying. Changes in the intragastric distribution of urea or a direct effect of citric acid on the bacteria (e.g. via the cytoplasmic protein, UreI) are more likely to be responsible.

Early events in proton pump inhibitor-associated exacerbation of corpus gastritis.

BACKGROUND: Antisecretory therapy may exacerbate Helicobacter pylori corpus gastritis. The rate and mechanism(s) remain unknown. AIM: To investigate the early events in proton pump inhibitor therapy on antral and corpus H. pylori gastritis. METHODS: Nine H. pylori-infected volunteers underwent gastric biopsy with jumbo forceps for culture and histology. Histology was scored in the range 0-5 using a visual analogue scale. The depth of inflammation in gastric pits was scored in the range 1-3 (superficial or less than one-third, one-third to two-thirds and greater than two-thirds of the gastric pit, respectively). Tissue interleukin-1 beta and interleukin-8 levels were measured by enzyme-linked immunoabsorbent assay. Omeprazole, 20 mg b.d., was given for 6.5 days and biopsies were repeated on day 7. RESULTS: Proton pump inhibitor therapy resulted in a fall in H. pylori density in the antrum and corpus. Inflammation and tissue levels of interleukin-8 and interleukin-1 beta decreased in the antrum and increased in the corpus mucosa. There was a significant increase in the depth of inflammation to include the proliferative zone in the corpus. CONCLUSIONS: Within 1 week of starting proton pump inhibitor therapy, there was a marked extension of corpus inflammation into the gastric pit and an increase in corpus mucosal interleukin-1 beta and interleukin-8 levels. H. pylori eradication should be considered for all patients receiving long-term antisecretory therapy.

Comparative efficacy of new investigational agents against Helicobacter pylori.

BACKGROUND: Emergence of antibiotic resistant Helicobacter pylori has necessitated the identification of alternate therapies for the treatment of this infection. AIM: To assess the in vitro efficacy of two investigational agents: DMG-MINO CL 344 (a N,N-dimethylglycylamido derivative of minocycline), and davercin, a cyclic carbonate of erythromycin A as compared to older antibiotics (clarithromcyin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, cefixime) against clinical isolates of H. pylori. METHODS: Testing was performed using the agar dilution method approved by the NCCLS subcommittee on antimicrobial susceptibility testing, Helicobacter pylori working group. Under these guidelines, Mueller-Hinton agar containing 5% aged sheep blood was used. All incubations were done under CampyPak Plus conditions for 72 h at 37 degrees C. The drug concentrations in the agar ranged from 0.016 to 16 microg/mL. Twenty-one clarithromycin-resistant and 16 clarithromycin-susceptible clinical isolates of H. pylori obtained from patients with duodenal ulcer were used. H. pylori ATCC 43504 was used as the control in all determinations. RESULTS: Against clarithromycin susceptible isolates, all antimicrobial agents except the fluoroquinolones were highly effective. Against clarithromycin-resistant H. pylori, the MIC50/MIC90 values showed that the tetracyclines and cefixime were the most efficacious agents. The fluoroquinolones and macrolides were ineffective. Macrolide cross-resistance was detected. CONCLUSION: Macrolide cross-resistance prevents the use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients.

Nitrofurantoin quadruple therapy for Helicobacter pylori infection: effect of metronidazole resistance.

BACKGROUND: Antibiotic resistance has increasingly been recognized as the major cause of treatment failure for Helicobacter pylori infection. New therapies for patients with metronidazole- or clarithromycin-resistant H. pylori are needed. AIM: To investigate the role of nitrofurantoin quadruple therapy for the treatment of H. pylori. METHODS: Patients with confirmed H. pylori infection received nitrofurantoin (100 mg t.d.s.), omeprazole (20 mg b.d.), Pepto-Bismol (two tablets t.d.s.), and tetracycline (500 mg t.d.s.) for 14 days. Four or more weeks after the end of therapy, outcome was assessed by repeat endoscopy with histology and culture or urea breath testing. RESULTS: Thirty patients were entered, including 25 men and five women; the mean age was 54.9 years. The most common diagnoses were duodenal ulcer (23%) and GERD (18%). The intention-to-treat cure rate was 70% (95% CI: 50.6-85%). Nitrofurantoin quadruple therapy was more effective with metronidazole-sensitive strains (88%; 15 out of 17) than with metronidazole-resistant strains (33%; three out of nine; P=0.008). Two of the treatment failures had pre-treatment isolates susceptible to metronidazole, which were resistant after therapy. CONCLUSIONS: Because nitrofurantoin quadruple therapy performed inadequately in the presence of metronidazole resistance, we conclude that nitrofurantoin is unlikely to find clinical utility for the eradication of H. pylori.

Meta-analysis: proton pump inhibitor or H2-receptor antagonist for Helicobacter pylori eradication.

AIM: To compare H2-receptor antagonists and proton pump inhibitors as adjuvants to triple therapy for Helicobacter pylori eradication. METHODS: H. pylori-infected patients with peptic ulcer were randomized to receive either 300 mg nizatidine or 30 mg lansoprazole plus 1 g amoxicillin and 500 mg clarithromycin taken b.d. for 7 days. H. pylori eradication was assessed 4 weeks after therapy. Using meta-analytical techniques, we combined the results of this study with other randomized controlled comparisons of H2-receptor antagonists and proton pump inhibitors as adjuvants to triple therapy. RESULTS: One hundred and one patients were randomized. H. pylori eradication was 94% (47/50) [95% confidence interval (CI), 83-99%] (intention-to-treat) in the H2-receptor antagonist group vs. 86% (44/51) (95% CI, 74-94%) in the proton pump inhibitor group (P = 0.3). There has been a total of 12 similar studies (1415 patients). The overall efficacy was similar in intention-to-treat analysis: 78% (549/701) with H2-receptor antagonists vs. 81% (575/714) with proton pump inhibitors (odds ratio, 0.86; 95% CI, 0.66-1.12). A non-significant trend favouring H2-receptor antagonist (79% vs. 69%; odds ratio, 1.14; 95% CI, 0.76-1.71; P = 0.5) was seen in the comparison of clarithromycin-containing regimens. In contrast, in non-clarithromycin-containing trials, there was a slight, but significant, advantage with proton pump inhibitors (85% vs. 78%; odds ratio, 0.64; 95% CI, 0.45-0.92; P = 0.02). CONCLUSION: Overall, proton pump inhibitor and H2-receptor antagonist antisecretory agents appear to be similarly effective as adjuvants for H. pylori triple therapy. It is unlikely that the direct anti-H. pylori effect of proton pump inhibitors is responsible for their ability to enhance anti-H. pylori therapy.

Furazolidone combination therapies for Helicobacter pylori infection in the United States.

BACKGROUND: Antibiotic resistance has begun to impair the ability to cure Helicobacter pylori infection. AIM: To evaluate furazolidone as a component of combination therapies for treatment of H. pylori infection in the United States. METHODS: Patients with active H. pylori infection received furazolidone combination therapy for 14 days (furazolidone 100 mg and tetracycline 500 mg t.d.s.; omeprazole 20 mg o.d. in the morning and, depending on the pre-treatment antimicrobial susceptibility pattern, 500 mg of metronidazole or clarithromycin t.d.s.). RESULTS: A total of 27 patients received the metronidazole containing combination (cure rate 100%) and seven received the clarithromycin combination (cure rate 86%). Overall the cure rates for intention-to-treat was 97% (95% CI: 85% to 100%). The single failure took the clarithromycin containing combination for only 2 days (per protocol cure rate = 100%). Side-effects were common and led to discontinuation of therapy in 26% of patients. An attempt to eliminate metronidazole and clarithromycin and use furazolidone, tetracycline, and lansoprazole b.d. produced an unsatisfactory cure rate of 72%. CONCLUSION: Furazolidone combination therapy appears to be effective. Additional studies with different antimicrobial combinations and duration of therapy are warranted.

Metronidazole containing quadruple therapy for infection with metronidazole resistant Helicobacter pylori: a prospective study.

BACKGROUND: Metronidazole remains a key component of H. pylori infection therapy. It has been suggested that despite resistance, metronidazole may be effective when given at high dose with bismuth, tetracycline, and a proton pump inhibitor (quadruple therapy). AIM: To prospectively evaluate metronidazole quadruple therapy for treatment of metronidazole resistant H. pylori infection in the United States. METHODS: Patients infected with metronidazole resistant H. pylori were prospectively prescribed 14 days of quadruple therapy consisting of metronidazole 500 mg t.d.s., tetracycline 500 mg q.d.s., two bismuth subsalicylate tablets q.d.s., and omeprazole 20 mg o.d. RESULTS: A total of 26 patients were entered into the study; 22 for their first treatment and four as re-treatment for failed therapy. Of the 26 patients, 24 were cured (cure rate 92%; 95% CI: 78-99%). Both treatment failures reported full compliance to 14 days of therapy. Side-effects were common and resulted in premature discontinuation of therapy in 31%. Premature discontinuation did not reduce the cure rate. CONCLUSION: Quadruple metronidazole combination therapy is effective despite the presence of metronidazole resistance and should be considered as either first line therapy or for failures of twice-a-day combination therapies.

Ranitidine bismuth citrate, tetracycline, clarithromycin twice-a-day triple therapy for clarithromycin susceptible Helicobacter pylori infection.

BACKGROUND: Although many combination therapies have been proposed, there is still interest in identifying simple, inexpensive, effective protocols that have high rates of success. AIM: To investigate the role of the new soluble form of bismuth, ranitidine bismuth citrate, in twice-a-day therapy for Helicobacter pylori infection. METHODS: Patients with histologically and culture proven H. pylori infection received ranitidine bismuth citrate 400 mg, tetracycline HCl 500 mg, and clarithromycin 500 mg, each b.d. for 14 days, followed by 300 mg ranitidine once a day for 4 additional weeks. Outcome was assessed 4 or more weeks after the end of antimicrobial therapy by repeat endoscopy with histology and culture (49 patients) or urea breath testing (14 patients). RESULTS: Sixty-three patients completed the therapy, 59 men and four women (average age 56.7 years; range 31-75 years). All patients had clarithromycin-susceptible strains prior to therapy. H. pylori infection was cured in 94% (95% CI: 85-98%). There was a therapy failure in one patient who took the medicine for only 1 day and stopped because of side-effects. Three of the isolates from treatment failures were available post-failure; two were clarithromycin-resistant and one was susceptible. Side-effects were severe in two patients (3%) and moderate in three (primarily diarrhoea). CONCLUSIONS: Twice-a-day ranitidine bismuth citrate, tetracycline, clarithromycin triple therapy was well tolerated and effective for the treatment of H. pylori infection in patients with clarithromycin-susceptible H. pylori.

Novel therapies for Helicobacter pylori infection.

BACKGROUND: Increasing antibiotic resistance has begun to impair our ability to cure Helicobacter pylori infection. AIM: To evaluate orally administered novel therapies for the treatment of H. pylori infection. METHODS: Healthy H. pylori infected volunteers received: (a) hyperimmune bovine colostral immune globulins, (b) an oligosaccharide containing an H. pylori adhesion target, Neu5Aca2-3Galb1-4Glc-(3'-sialyllactose), or (c) recombinant human lactoferrin. Outcome was assessed by urea breath test or histological assessment of the number of H. pylori present. RESULTS: None of the novel therapies appeared effective and no adverse events occurred. CONCLUSION: Although in vitro data appeared promising, in vivo results were disappointing. Higher doses, longer duration of therapy, adjunctive acid suppression, or a combination could possibly yield better results.

Rapid diagnosis of Acanthamoeba keratitis using calcofluor white.

Calcofluor white (CFW) is a chemofluorescent dye with an affinity for the polysaccharide polymers of amebic cysts. Using CFW staining with fluorescent microscopy, we demonstrated amebic cysts in corneal scrapings and keratectomy specimens from four patients with culture-proved Acanthamoeba keratitis and from one in whom CFW was the only positive laboratory test. Calcofluor white staining is simple, rapid, and highly reliable in the diagnosis of Acanthamoeba keratitis.

The effects of freezing and antibiotics on the viability of Acanthamoeba cysts.

The effects of cryotherapy and antibiotics (paromomycin, neomycin, or propamidine isethionate) on the viability of Acanthamoeba polyphaga and Acanthamoeba castellani cysts were studied in vitro. Either cryotherapy or exposure to antibiotic led to a decrease in the number of viable A castellani detected; A polyphaga showed variable response to the antibiotics tested. The combination of cryotherapy and antibiotic therapy was more cysticidal than either modality alone and eliminated detectable viable organisms in five of six experiments. Of the antibiotic solutions tested, paromomycin (15 mg/mL) was the most effective.

Endogenous Candida albicans endophthalmitis in the rabbit. Chemotherapy for systemic effect.

Progressive endogenous Candida albicans endophthalmitis was established in rabbits by intravenous (IV) injection of blastospores (2.0 to 5.0 x 10/kg). Severity of infection was directly related to the strain and inoculum size. Intravenous amphotericin B (1.0 mg/kg/day), IV amphotericin B methyl ester ascorbate (5.0 mg/kg/day), and oral ketoconazole (80 mg/kg/day) effectively prevented or reduced the severity of infection when therapy was initiated 24 hours following inoculation of blastospores and continued for five to seven days. Intravenous miconazole (30 mg/kg/day) was ineffective in this model. Intravenous amphotericin B(1.0 to 2.0 mg/kg on alternate days), IV amphotericin B methyl ester ascorbate (5.0 mg/kg/day), and oral ketoconazole (80 mg/kg/day reduced the severity of C albicans endophthalmitis when therapy was initiated seven days following injection of blastospores and continued for 28 days. Oral flucytosine (75 and 150 mg/kg/day in four doses) produced uniformly fatal hepatic necrosis in uninfected rabbits.

Infectious crystalline keratopathy. The role of bacterial exopolysaccharide.

OBJECTIVES: Infectious crystalline keratopathy is a unique pauci-inflammatory infection of the cornea most commonly due to viridans type streptococci. We investigated the hypothesis that production of exopolysaccharide by streptococci, a property that can be induced by growth conditions, may contribute to the pathogenesis of infectious crystalline keratopathy by suppressing the ocular immune response. METHODS: Streptococcus sanguis type II was grown under two conditions, conventionally in brain-heart infusion broth and in 5% sucrose-supplemented brain-heart infusion broth, to promote exopolysaccharide formation. Rabbit corneas were inoculated by passage of 9-0 silk sutures soaked in bacterial suspensions. RESULTS: Arborizing, sharply demarcated pauci-inflammatory lesions were noted in 71% of rabbit corneas inoculated with S sanguis type II grown in sucrose-supplemented media and in 25% of control corneas (P = .05). Suppurative lesions developed in the remaining corneas. Histologic evaluation of infectious crystalline keratopathy lesions revealed characteristic features. CONCLUSION: Increased exopolysaccharide formation by S sanguis type II is associated with production of infectious corneal lesions that resemble those of infectious crystalline keratopathy.

Quantitative and bioluminescent assay to measure efficacy of conventional and DNA vaccinations against Helicobacter pylori.

Vaccination against Helicobacter pylori using DNA sequences encoding Urease A and B subunits was compared to immunization with urease antigen and MTP-PE in a liposome formulation. To determine the effectiveness of a vaccine against H. pylori in a mouse model it is essential to quantify the number of H. pylori remaining in the stomachs following challenge with an inoculum of live bacteria. Culture assays and enzymatic assays produce inconsistent results often unsuitable to conclude if vaccine candidates are protective. To overcome this problem, we developed two assays: 1) a competitive quantitative PCR using a colorimetric readout and 2) a non-competitive direct quantitative PCR using a highly sensitive bioluminescent readout. The competitive PCR requires coamplification of a segment of the urease C sequence and an internal control standard in a competitive manner using a single set of primers. PCR products were quantified colorimetrically by an enzyme-linked immunosorbent assay and compared with known quantities of the internal control standard added to the PCR reaction. The highly sensitive, bioluminescent assay measures the amplified DNA directly using a flash-type luminescent tag and a specific probe. The Sydney strain of H. pylori was used for the mouse infection model. Quantification of H. pylori by either the bioluminescent assay or the competitive PCR was reliable, specific and sensitive compared to quantitative growth assays which often gave false results. The bioluminescent assay was much more sensitive and less labor/time intensive than the competitive PCR. The bioluminescent assay was able to quantitate as few as 100 bacteria, while the competitive assay could not detect less than 10(3) bacteria per mouse stomach. Quantification of H. pylori by bioluminescent assay was superior to the competitive assay and may be used for research applications, such as the development of vaccines, pathogenesis of gastric disease and monitoring of antibiotic treatment.

Tobramycin in ophthalmology.

Selman Waksman's laboratory at Rutgers University discovered the first aminoglycoside antibiotic, streptomycin, in 1943. Other aminoglycoside antibiotics, such as gentamicin and tobramycin, soon followed. Tobramycin is compatible with most intravenous fluids and tear substitutes, but it is incompatible with heparin and some beta-lactam antibiotics such as penicillin and cephalosporins. Due to tobramycin's broad spectrum of activity, it has proven useful in controlling both superficial and deep infections of the eye and ocular adnexa (i.e., blepharitis, conjunctivitis, keratitis, and endophthalmitis). However, since tobramycin has been associated with neuromuscular blockade, as well as possessing ototoxic and nephrotoxic effects, care must be taken to minimize toxicity by monitoring patients undergoing systemic tobramycin therapy.