Serum sickness-like reaction associated with cefazolin

BMC Clin Pharmacol. 2006; 6: 3. Published online 2006 February 23. doi: 10.1186/1472-6904-6-3.

Michael Brucculeri,#1 Marian Charlton,#2 and David Serur#2
1Division of Nephrology and Hypertension, New York Presbyterian Hospital – Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA
2The Rogosin Institute, New York Presbyterian Hospital – Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA
Corresponding author.
#Contributed equally.

Michael Brucculeri: mjb69@columbia.edu; Marian Charlton: mbc2001@nyp.org; David Serur: serurd@mail.rockefeller.edu

Received October 20, 2005; Accepted February 23, 2006.

Abstract

Background

Although rare, serum sickness-like reactions have been documented to occur following the administration of many antibiotics. Cefazolin, a first generation cephalosporin, is a commonly prescribed antibiotic which is considered to be generally safe and well tolerated. There have been no prior reports linking this drug with sickness-like reactions. We report a probable case of serum sickness-like reaction following a single dose of cefazolin.

Case Presentation

A 23 year old man with no significant past medical history was admitted to undergo a laparoscopic donor nephrectomy as part of a living-related renal transplant. One gram of intravenous cefazolin was administered perioperatively. The surgery was completed without complication and the remainder of his hospital course was uneventful. Ten days following discharge the patient developed fevers, painful and swollen joints, and a cutaneous eruption overlying his trunk and extremities. There was no evidence of systemic vasculitis. These clinical findings were most consistent with a serum sickness-like reaction. A brief course of corticosteroids and antihistaminergic therapy was initiated, and complete resolution of the patient's symptoms followed. The Naranjo probability scale indicated that this adverse drug event was probable.

Conclusion

Serum sickness-like reaction may be associated with cefazolin therapy.

Full Article

Background

Serum sickness-like reactions (SSLR), although rare in clinical practice, have been documented to occur following the administration of many medications. While the pathophysiology which produces SSLR are not clear, they are constituted by an array of clinical findings including fever, cutaneous eruptions and arthralgias/arthritis. Literature reports have implicated several antibiotics including ciprofloxacin [1,2], minocycline[3], cefprozil[4], and cefaclor [5-7]. Herein, we report a probable case of SSLR following a single dose of cefazolin.

Case Presentation

The patient, a 23 year old male with no significant past medical history, underwent left laparoscopic donor nephrectomy as part of a living-related renal transplant. On the day of surgery he was administered one gram of intravenous cefazolin which served as routine perioperative prophylaxis. Anesthesia was achieved with inhaled desflurane, along with fentanyl, propofol, and midazolam. Cisatracurium was employed for neuromuscular blockade. Post operatively, he received morphine sulfate, ketorolac, and ondansetron. His recovery was uneventful, and he was discharged home three days after his surgery with prescriptions for docusate sodium, acetaminophen, and hydrocodone. Upon discharge his serum creatinine was 1.8 mg/dL, WBC 10.0 per 109/L, platelet count 197 per 109/L, hemoglobin 13.4 g/dL. Eosinophils constituted 0.2% of WBC population.

Post operative day ten was marked by the emergence of fevers as high as 38.4 C, generalized weakness, and arthralgias involving bilateral knees, wrists, ankles, and metacarpophalangeal (MCP) joints. Simultaneously, a cutaneous eruption appeared which was initially limited to bilateral upper extremities but soon involved his trunk, back, face and lower extremities. Furthermore, additional MCP joints become swollen and tender in sequential order from medial to lateral. Upon questioning, he denied the presence of any gastrointestinal disturbance such as nausea, emesis, or diarrhea. On physical examination he was found to be afebrile. He appeared uncomfortable but was in no apparent distress. Oropharyngeal, pulmonary, and cardiac examinations were unremarkable. Although there was mild peri-incisional tenderness, his abdomen was soft and his surgical wounds appeared to be healing well with no evidence of local infection. There was no lymphadenopathy. Diffuse urticaria involving all extremities, trunk, back, neck, and face were noted. Nearly all his MCP joints were warm, swollen, and tender to touch. Of note, there appeared to be a sequential pattern of early MCP joint resolution as the medial joints that had been initially affected most, now appeared to be improving somewhat while the lateral ones were now most affected. In addition, the knees, ankles, wrists, and left metatarsophalangeal joint were also affected, although no effusions were appreciated upon physical examination. Repeat laboratory analysis was performed which revealed serum creatinine was 1.6 mg/dL, WBC 9.7 per 109/L, platelet count 353 per 109/L, hemoglobin 13.8 g/dL. Eosinophils constituted 2.6% of WBC population. Serum complement levels, immunoglobulin concentrations, and erythrocyte sedimentations rate were not obtained at this time. Urinalysis revealed trace albuminuria, with no hematuria or glycosuria. Microscopic examination of the urine revealed rare hyaline casts and the distinct absence of red or white cells and cellular casts.

Based on the aforementioned clinical findings, the absence of systemic vasculitis, and a history of a cephalosporin antibiotic exposure approximately two weeks earlier, a diagnosis of a SSLR was made. For five days, he was treated with prednisone 20 mg twice daily, loratadine 10 mg daily as well as famotidine 20 mg twice daily for H2 receptor blockade. Within 48 hours he noted near resolution of the urticaria as well as a significant improvement in the inflamed joints. He was reevaluated two weeks after this treatment and was found to have no further evidence of fevers, rash, or joint involvement. Antinuclear antibodies by enzyme immunoassay were not detected, serum complement levels were within the normal ranges for our laboratory as was serum IgE levels which were measured at 36.8 IU/mL.

Discussion

Serum sickness-like reactions have been noted to occur in response to a variety of drugs, a majority of them being antibiotics[5]. Manifestations often include fever, rash, and joint inflammation, but generally lack generalized lymphadenopathy and evidence of systemic vasculitis such as glomerulonephritis [8]. Accordingly, the levels of circulating immune complexes and serum complement are often unaffected[5].

While the underlying pathophysiology remains unclear, SSLR continues to be documented as an adverse event for a small but growing number of drugs. To date there have been no published reports of serum sickness or SSLR following cefazolin administration. Although our patient did receive various other medications, only cefazolin belongs to a drug class which has repeatedly been implicated as a cause for SSLR. In the case just described, the Naranjo probability scale for adverse drug reactions indicates that cefazolin was the probable cause of SSLR[9].

Conclusion

Several drugs have been connected to the development of SSLR including cephalosporin antibiotics such as cefaclor and cefprozil. We now report a probable case of SSLR in connection with cefazolin. Accordingly, we urge clinicians need to be aware of SSLR as a potential complication to this common therapy.

List of abbreviations:

C – Celsius
dL – deciliter
g – gram
IU – international units
L – liter
MCP – metacarpophalangeal
SSLR – serum sickness-like reaction
WBC – white blood count

Competing Interests

The author(s) declare that they have no competing interests.

Authors' contributions

MB: Direct patient care, literature search, case review and summary, drafting of the original article. MC: Direct patient care, article conception and review. DS: Direct patient care, article conception, critical and extensive revision of article for important intellectual content, review and drafting of the original article. All authors read and approved the final manuscript and contributed equally to the manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here: BioMed

Acknowledgements

Written consent was obtained from the patient for publication of study. We wish to thank Dr. Tiina Podymow for her critical and constructive review of the final manuscript. We also wish to dedicate this article to all of the brave individuals and families who make the ultimate gift, the gift of life – by choosing to donate an organ to in order to alleviate the suffering of others.

References

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Guharoy SR. Serum sickness secondary to ciprofloxacin use. Vet Hum Toxicol. 1994;36:540–1. [PubMed]
Elkayam O, Yaron M, Caspi D. Minocycline-induced autoimmune syndromes: an overview. Semin Arthritis Rheum. 1999;28:392–7. doi: 10.1016/S0049-0172(99)80004-3. [PubMed]
Lowery N, Kearns GL, Young RA, Wheeler JG. Serum sickness-like reactions associated with cefprozil therapy. J Pediatr. 1994;125:325–8. doi: 10.1016/S0022-3476(94)70220-9. [PubMed] [Full Text]
Vial T, Pont J, Pham E, Rabilloud M, Descotes J. Cefaclor-associated serum sickness-like disease: eight cases and review of the literature. Ann Pharmacother. 1992;26:910–4. [PubMed]
Grammer LC. Cefaclor serum sickness. JAMA. 1996;275:1152–3. doi: 10.1001/jama.275.15.1152. [PubMed]
Sanklecha MU. Cefaclor induced serum sickness like reaction. Indian J Pediatr. 2002;69:921. [PubMed]
Yerushalmi J, Zvulunov A, Halevy S. Serum sickness-like reactions. Cutis. 2002;69:395–7. [PubMed]
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. [PubMed]

BioMedCentral

The use of prophylactic antibiotics in head and neck oncological surgery

Abstract

Curr Opin Otolaryngol Head Neck Surg. 2006 Apr;14(2):55-61.

Simo R, French G.

Department of Otorhinolaryngology & Head and Neck Surgery, Guy's and St Thomas' Hospital, London, UK.

PURPOSE OF REVIEW:

An overview of best evidence-based current practice in the use of prophylactic antibiotics in elective oncological head and neck surgery is presented.

RECENT FINDINGS:

Patients undergoing head and neck oncological surgery are at great risk of developing complications following surgery. The incidence of wound infection has been reported to be as high as 87%, often with devastating effects. Prophylactic antibiotics have helped to reduce significantly the risk of infection; however, clinicians managing these patients should also have a thorough understanding of the risk factors leading to postoperative infections and should apply the most basic surgical principles at all times, to minimize infection rates.

SUMMARY:

Prophylactic antibiotics usage in clean-contaminated major oncological head and neck surgery is mandatory to reduce the risk of infection. In clean major oncological head and neck surgery their use is also advisable but there is no evidence that in clean surgery for benign disease it offers any advantage. Short antibiotic regimes of four doses per 24 h are as effective as prolonged courses regardless of the complexity of the procedure. A combination of antibiotic agents covering aerobic, anaerobic and Gram-negative bacteria is superior to single agents. High-risk patients should be also given short regimes, as there is no evidence that prolonged courses are of more benefit in these patients. Methicillin-resistant Staphylococcus aureus infection can have devastating consequences for patients undergoing major head and neck surgery. Protocols of prevention and treatment should be in place in all institutions treating patients with head and neck cancer. Close collaboration between surgical, microbiology and infection-control teams is essential.

PMID: 16552259 [PubMed - as supplied by publisher]

Minocycline for short-term neuroprotection.

Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC.1

Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, Georgia; Specialty Care Service Line, Veterans Administration Medical Center, Augusta, Georgia.

April 2006

Minocycline is a widely used tetracycline antibiotic. For decades, it has been used to treat various gram-positive and gram-negative infections. Minocycline was recently shown to have neuroprotective properties in animal models of acute neurologic injury. As a neuroprotective agent, the drug appears more effective than other treatment options. In addition to its high penetration of the blood-brain barrier, minocycline is a safe compound commonly used to treat chronic infections. Its several mechanisms of action in neuroprotection-antiinflammatory and antiapoptotic effects, and protease inhibition-make it a desirable candidate as therapy for acute neurologic injury, such as ischemic stroke. Minocycline is ready for clinical trials of acute neurologic injury.

Pharmacotherapy

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Related Article:

The potential of minocycline for neuroprotection in human neurologic disease.

The potential of minocycline for neuroprotection in human neurologic disease.Zemke D, Majid A.Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824, USA.

Minocycline is a member of the tetracycline class of molecules with broad-spectrum antibiotic activity. The unique properties of minocycline result in increased tissue distribution when compared with the other tetracyclines. Of particular interest is the ability of minocycline to diffuse into the central nervous system at clinically effective levels. Aside from its antimicrobial properties, minocycline has been found to have beneficial effects on inflammation, microglial activation, matrix metalloproteinases, nitric oxide production, and apoptotic cell death. Concordantly, minocycline has been found to have neuroprotective effects in animal models of a number of diseases including stroke, multiple sclerosis, and Parkinson disease. The proven safety of minocycline over decades of use as an antibiotic suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.

Publication Types:

Review

PMID: 15613934 [PubMed - indexed for MEDLINE]

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Minocycline

HOW TO USE:

Take minocycline tablets or capsules by mouth. Follow the directions on the prescription label. Swallow tablets or capsules whole with a full glass of water; take tablets or capsules in an upright or sitting position. Taking a sip of water first, before taking the tablets or capsules, may help you swallow them. If possible take bedtime doses at least 10 minutes before lying down. It is best to take minocycline without food, but if it upsets your stomach take it with food. Take your doses at regular intervals. Do not take your medicine more often than directed. Finish the full course prescribed by your prescriber or health care professional even if you think your condition is better. Do not stop taking except on your prescriber's advice.
Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

SIDE EFFECTS:

Side effects that you should report to your prescriber or health care professional as soon as possible: dark yellow or brown urine; difficulty breathing; fever; headache; increased sensitivity to the sun or ultraviolet light; itching in the rectal or genital area; pain on swallowing; redness, blistering, peeling or loosening of the skin, including inside the mouth; stomach pain or cramps; skin rash or itching; unusual bleeding or bruising; unusual tiredness or weakness; yellowing of eyes or skin.

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome): diarrhea; discolored tongue or teeth; drowsiness, dizziness; loss of appetite; nausea, vomiting; sore mouth.

PRECAUTIONS:

Tell your prescriber or health care professional if your symptoms do not improve in 3 to 5 days. Sometimes it will take longer than this before you get better.

Do not take minocycline just before going to bed. It may not dissolve properly when you are lying down and can cause ulceration of your food pipe.

Keep out of the sun, or wear protective clothing outdoors and use a sunscreen. Do not use sun lamps or sun tanning beds or booths.

Birth control pills (contraceptive pills) may not work properly while you are taking this medicine. Use an extra method of birth control for at least one month.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how minocycline affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient.

If you are being treated for a sexually transmitted disease, avoid sexual contact until you have finished your treatment. Your sexual partner may also need treatment.

If you are going to have surgery, tell your prescriber or health care professional that you are taking minocycline.

Antacid can stop minocycline working. If you get an upset stomach and want to take an antacid, make sure there is an interval of at least 2 hours since you last took minocycline, or 4 hours before your next dose.

Never take minocycline if it is past the expiration date; it can make you seriously ill.

DRUG INTERACTIONS:

Antacids; calcium salts; cholestyramine; colestipol; digoxin; female hormones, including contraceptive or birth control pills; ferrous sulfate; magnesium salts; other antibiotics; phenytoin; sodium bicarbonate; warfarin.

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

NOTES:

Prescriber needs to know if you have any of these conditions: kidney disease; liver disease; long exposure to sunlight (working outdoors); an unusual or allergic reaction to minocycline, other tetracyclines; pregnant or trying to get pregnant; breast-feeding.

MISSED DOSE:

f you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses. There should be an interval of at least 4 to 6 hours between doses.

STORAGE:

Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15-30 degrees C (59-86 degrees F). Protect from light and moisture. Throw away any unused medicine after the expiration date.

Allergy to cloxacillin with normal tolerance to amoxicillin and cefuroxime

Case Reports - Antibiotic Allergy

J Domínguez-Ortegaa JC Martínez-Alonsob MC Marcos-Pérezc C Kindelanc A Fradesd aUnit of Allergy. Hospital Universitario de Getafe. Madrid. Spain.bUnit of Allergy. Hospital Virgen de la Concha. Zamora. Spain.cUnit of Allergy. Hospital Universitario de Getafe. Madrid. Spain.dUnit of Allergy. Hospital Virgen de la Concha. Zamora. Spain

Abstract

Background: Cloxacillin is a semisynthetic penicillin widely used in nonmethicillin resistant Staphylococcus aureus infections. Several hypersensitivity reactions to cloxacillin have been reported, although IgE-mediated allergic reactions to the drug are rare and there is little information about possible tolerance to other semisynthetic penicillins or cephalosporins in patients with cloxacillin allergy. We present 2 patients with demonstrated IgE-mediated allergy to cloxacillin and tolerance to amoxicillin and cefuroxime.

Case reports: Case 1. A 47-year-old woman began treatment with cloxacillin due to acute cellulitis. After ingesting 500 mg of the drug, she experience generalized maculopapular eruption and facial angioedema. Case 2. A 55-year-old woman presented an episode of acute urticaria and labial angioedema 60 minutes after ingesting 500 mg of cloxacillin for a skin abscess.

Methods and results: Skin prick tests were positive to cloxacillin in case 1 and negative in case 2. However, an intradermal test was positive to cloxacillin (2 mg/ml) in case 2. Simple-blind oral challenge tests with amoxicillin (1 g) and cefuroxime (500 mg) were well-tolerated by both patients.

Conclusions: We present 2 patients allergic to cloxacillin with normal tolerance to other betalactam antibiotics, confirming that cross-reactivity among these antibiotics seems to be uncommon. Complete allergy study, including an oral challenge test, should be considered in these patients.

INTRODUCTION

Cloxacillin is a semisynthetic penicillinase-resistant penicillin widely used in non-methicillin resistant Staphylococcus aureus infections. Most frequent side effects of cloxacillin are gastro-intestinal manifestations like vomiting or diarrea, although there have been reported different hypersensitivity reactions 1,2 . However, IgE-mediated allergic reactions to the drug are rare and there is little previously reported information about the management of allergic patients to cloxacillin in order to demonstrate tolerance to other semi-synthetic penicillins or cephalosporins 3 . We present two different patients with demonstrated IgE-mediated allergy to cloxacillin with normal tolerance to amoxicillin and cefuroxime.

CASE REPORT

Case 1. A 47-year-old woman diagnosed of chronic lymphedema after a radical mastectomy, began treatment with cloxacillin due to an acute cellulitis. Shortly after the intake of Orbenin® 500 mg (Glaxo-SmithKline-Beecham,Toledo.Spain) she experience generalized pruritic maculo-papular eruption, hives and angioedema of the face.

Case 2. A 55-year-old woman, with a personal background of smoking, who had taken cloxacillin 500 mg for an abscess involving the bulbous end of a finger. 60 minutes after the intake of the first pill, she presented an episode of acute urticaria and labial angioedema. Both patients were completely recovered after the administration of parenteral treatment (40 mg of 6-methyl-prednisolone and intravenous dyphenhydramine). They both had previously taken cloxacillin without any reaction and they had not eaten any food or had not being doing exercise in the previous 4 hours.

ALLERGIC STUDY

In the Allergy Unit at our Hospital, Skin prick tests (SPT) with benzylpenicillin (10.000 U/ml), mayor and minor determinants mixture of benzylpenicillin (BPO and MDM. Diater. Madrid. Spain), cloxacillin (20 mg/ml), amoxicillin (20 mg/ml) and cefuroxime (200 mg/ml) were performed 30 days later according to standardized procedures 4 . If they were negative, intradermal tests were carried out. Prick test was positive only to cloxacillin in case 1 with a mean diameter of the obtained wheal of 5mm. Prick test were all negative in case 2, but the intradermal test was positive to cloxacillin (2 mg/ml) presenting a 14 mm wheal of mean diameter, double that of the histamine wheal (1 mg/ml) at the 20 min. reading. All the other tests were negative and no positive results were obtained at the 24 h reading. Simple-blind oral challenge tests with increasing doses until an accumulative dosis of amoxicillin (1 g) and cefuroxime (500mg) were performed, being well-tolerated in both patients.

DISCUSSION

Adverse reactions to betalactam antibiotics constitute a major hazard in medical practice.

Although the use of cloxacillin is widely extended, data of immediate allergic reactions after using this drug are very scarce. It could be explained due to it is not frequently involved in allergic reactions 5 but there could exist an inssufficient communication that leads to remain cloxacillin allergic reactions to be underdiagnosed. This fact could explain the lack of reported experience in clinical management of those patients. There is a general tendency to avoid using other betalactam antibiotics due to that there are similarities in chemichal structure between them to justify a cross-reactivity mechanism between cloxacillin and amoxicillin or cephalosporins.

However, if we remember that many of the allergic patients to penicillin or amoxicillin tolerate any cephalosporin, the allergologist might be asked to find out which of the other betalactam antibiotic could be used as secure alternatives in cloxacillin allergic patients. We should not forget that previous observations indicate that, in some instances, subjects allergic to cloxacillin may experience an allergic reaction after taking the drug orally but have good tolerance after being administered the same drug by parenteral route 6 .

In conclusion, we present two different patients allergic to cloxacillin with normal tolerance to other betalactam antibiotics, confirming that cross-reactivity seems to be uncommon among those tested antibiotics. A complete allergologic study, including an oral challenge test, should be considered in these patients.

Correspondence:Dr. Javier Dominguez OrtegaUnit of Allergy. Hospital Universitario de GetafeCtra. de Toledo. Km. 12,500.28905 Getafe. Madrid. Spain.E-mail: jdort@mixmail.com

Referencias Bibliográficas:

Importante

-->1. Novalbos A, Bombin C, Figueredo E, Lluch M, Sastre J. Localized pustulosis induced by betalactams. J Investig Allergol Clin Immunol 2000;10:178-9.
2. Dodek P, Phillips P. Questionable history of immediate type hypersensitivity to penicillin in Staphylococcal endocarditis- treatment based on skin test results versus empirical alternative treatment. A decision analysis. Clin Infect Dis 1999;29: 1251-6.
3. Gamboa P, Jauregui I, Urrutia I, Gonzalez G, Antepara I. Contact sensitization to cloxacillin with oral tolerance to other betalactam antibiotics. Contact Dermatitis 1996;34:75-6.
4. Silviu-Dan F, McPhillips S, Warrington RJ. The frequency of skin test reactions to side-chain penicillin determinants. J Allergy Clin Immunol 1993;91:694-701.
5. Ponvert C, Le Clainche L, de Blic J, le Bourgeois M, Cheinmann P, Paupe J. Allergy to beta-lactam antibiotic in children. Pediatrics 1999; 104:e 45.
6. Torres MJ, Blanca M, Fernández J, Esteban A, Moreno F, Vega JM, García J. Selective allergic reaction to oral cloxacillin. Clin Exp Allergy 1996;26:108-11.

Allergologia et immunipathologia

Antibiotic Effective Against Leading Cause of Blindness Throughout the World

A Single Dose of One Antibiotic for Treating Trichiasis is More Effective than a Six-week Regimen of Another Antibiotic

A clinical trial funded by the National Eye Institute (NEI), part of the National Institutes of Health (NIH), has concluded that a single dose of azithromycin taken by mouth after surgery reduces by one-third the recurrence of a vision-threatening eyelid condition called trichiasis. This is in contrast to the usual six-week regimen of tetracycline ointment applied directly to the eye. This study is published in the March 2006 issue of Archives of Ophthalmology.

“This study illustrates the importance of NIH clinical trials to find treatments for diseases that affect people throughout the world,” said Elias A. Zerhouni, M.D., director of the NIH. “When we consider that an estimated 11 million people worldwide develop trichiasis every year, we see the impact that the findings of this study may have in preventing future vision loss.”

Trichiasis is a condition in which the eyelid turns inward and eyelashes rub against the eye, resulting in corneal scarring and loss of vision. It results from trachoma, an eye infection that is the leading preventable cause of blindness in the world. It is spread through contact with flies and other insects, clothing or household items that harbor the bacterium, or infected people.
Trachoma occurs in poor, overcrowded communities that have little access to clean water, waste treatment facilities, or health care. These communities are located mainly in Africa, the Middle East, Asia, Australia and some areas of Latin America.

The World Health Organization (WHO) previously endorsed a multi-faceted strategy to control trachoma, including surgery for trichiasis and application of tetracycline after surgery.
In this study, called Surgery for Trichiasis, Antibiotics to Prevent Recurrence (STAR), eye infection with the bacterium that causes trachoma was present in 19 percent of the adults with trichiasis in Wolayta Zone, Ethiopia, the location of the clinical trial. More than 77 percent of the patients were women, who have four times the rate of trichiasis than men. Women often contract trachoma repeatedly by taking care of infected children.

“This clinical trial was relatively inexpensive to conduct, and produced results that may well save the vision of millions of people,” said Paul A. Sieving, M.D., Ph.D., director of vision research at NIH. “We look forward to supporting future trials to treat blinding eye diseases worldwide.”

“The simple surgical repair of the eyelid to prevent blindness has been plagued by high rates of recurrence of trichiasis — up to 50 percent in some areas,” said study chairman Sheila K. West, Ph.D., Wilmer Eye Institute, Johns Hopkins University. “In this study, by administering a single dose of azithromycin after eyelid surgery, we were able to reduce recurrence of trichiasis by 33 percent. This finding has major implications for improving the outcome following surgery.”
Continuing, Dr. West explained, “Some of the high rate of recurrence, no doubt, is due to poor surgical technique. Surgeons should be well trained and certified to ensure optimal outcomes. Future trials will need to standardize the procedure when testing surgical therapies.”

For this trial, the researchers from Wilmer Eye Institute partnered with ORBIS International, a nonprofit organization that works to eliminate blindness in developing countries. ORBIS trained Integrated Eye Care Workers (IECWs) to perform the eyelid surgeries, and Wilmer Eye Institute certified them, following WHO guidelines to ensure quality. The surgeries performed by the IECWs were as successful as those performed by ophthalmologists, and recurrence rates overall were low.

The results of this clinical trial, Dr. West believes, are transferable to other settings because most countries with widespread trichiasis now have access to a free azithromycin distribution program.

Thomas Quinn, M.D., an investigator with the National Institute of Allergy and Infectious Diseases, another component of NIH, and Johns Hopkins University, was a collaborator and co-author on the study.

Pfizer, Inc., through the International Trachoma Initiative that it co-sponsors with the Edna McConnell Clark Foundation, provided the azithromycin used in this trial.

For more information about eye health, the causes and treatment of vision problems and much more, visit the National Eye Institute Web site at www.nei.nih.gov.

The National Eye Institute is part of the National Institutes of Health (NIH) and is the Federal government’s lead agency for vision research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness. The NIH is an agency of the U.S. Department of Health and Human Services.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

Article

Antibiotics for Irritable Bowel Syndrome?

Novel Treatment For Irritable Bowel Syndrome Patients

February 15, 2006 12:30 p.m. EST

Ayinde O. Chase - All Headline News Staff Writer

Lebanon (AHN) - Researchers discovered that rifaximin, an antibiotic used to treat diarrhea, is also effective in treating abdominal bloating and flatulence, including in irritable bowel syndrome patients.

Researchers at American University of Beirut in Lebanon treated 124 patients with rifaximin therapy and found that it was effective at relieving the symptoms of bloating and excess gaseousness by way of reducing the amount of hydrogen gas produced in the large intestine.

Researchers published their data and findings in the February issue of The American Journal of Gastroenterology and also note because rifaximin is non-absorbable, there are no side effects, making it viable for chronic use.

All Headline News

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Related Story

Is IBS a Bacterial Infection?

By: William E. Whitehead, Ph.D., Professor of Medicine and Co-Director, University of North Carolina Center for Functional GI and Motility Disorders

A recent article by Dr. Mark Pimentel and colleagues at Cedars-Sinai Medical Center caused a great deal of excitement because it suggested that irritable bowel syndrome is a bacterial infection that can be treated with antibiotics [1]. These claims were widely reported in newspapers [2]. If they are true, then the understanding and management of IBS will be revolutionized. However, a careful reading of the study suggests caution.

The authors made two important observations: first, that 78% of IBS patients had small bowel bacterial overgrowth and second, that eradication of bacterial overgrowth decreased the symptoms of diarrhea and abdominal pain and "cured" IBS in 48%. Let's take these observations one at a time.

The patients who entered this study were not a representative group of IBS patients; they were patients who were referred for breath testing because their doctors suspected they had small bowel bacterial overgrowth. Selecting patients for testing in this way may have led to an overestimation of the proportion of IBS patients who have small bowel bacterial overgrowth. The only way to know what proportion of IBS patients have small bowel bacterial overgrowth is to test a large, representative group of patients.

The criteria for diagnosing small bowel bacterial overgrowth may also have been rather liberal. The investigators appropriately considered a test as positive only if they saw two peaks in breath hydrogen concentration, one representing intestinal bacteria and the second representing bacteria in the colon. However, they are unclear how high the first peak had to be for the test to be considered positive. Their rate of positive tests was much higher than expected; for example, out of 144 tests for suspected small bowel bacterial overgrowth carried out in our laboratory during a one year period, only 28% were positive.

It is also difficult to evaluate the authors' claim that eradication of abdominal pain and diarrhea with antibiotics "cures" IBS because only 30% of the IBS patients treated with antibiotics returned for evaluation. This was a retrospective study, so it was left to the discretion of the primary physician (not the investigators) which antibiotics were used to treat and whether the patient was asked to return for testing. It is important to know whether the other 70% were not sent back because they no longer had symptoms or whether they were not sent back because diagnosis and treatment of small bowel bacterial overgrowth made no difference, so their doctors had moved on to other tests.

Quite apart from these concerns about the study design, there is a question whether these patients should be diagnosed as IBS. The Rome criteria [3] state that a patient should be diagnosed IBS if they have a sufficient number of a list of positive symptoms (which these patients had) and if there is no alternative, disease explanation for these symptoms. Many gastroenterologists are aware that small bowel bacterial overgrowth can produce symptoms similar to IBS, just as inflammatory bowel disease and lactose malabsorption can; they do not label a patient as IBS if there is evidence for one of these alternative diagnoses.

Although it is premature to conclude that the authors have found the cause and the cure for IBS, they have drawn attention to the fact that small bowel bacterial overgrowth is a relatively common condition that can cause symptoms suggestive of IBS. This may have the beneficial effect of causing physicians to consider this diagnosis more frequently, to test for it, and to treat appropriately when it is found.

However, antibiotics should only be prescribed when there is definite evidence of small bowel bacterial overgrowth because antibiotics occasionally cause harmful side-effects, and their indiscriminant use may lead to the development of antibiotic-resistant strains of bacteria.

References:

[1] Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503-3506.
[2] Beasley D. Study links intestinal bacteria to irritable bowel syndrome. Reuters, Los Angeles, December 13, 2000.
[3] Thompson WG, Longstreth G, Drossman DA, Heaton K, Irvine EJ, Muller-Lissner S. Functional bowel disorders and functional abdominal pain. In: Drossman DA, et al. Rome II: The functional gastrointestinal disorders, 2nd edition. Degnon Associates, McLean, Va, 2000. Pp 351-432.

For more on this topic, read the comments of Dr. Douglas Drossman

About IBS

Mass Antibiotic Treatment Doesn't Thwart Eye Disease

HealthDayBy Robert PreidtTuesday, March 7, 2006

TUESDAY, March 7 (HealthDay News) --

A single mass antibiotic distribution is not an effective way to treat and eliminate trachoma -- an eye infection that can cause blindness -- in Ethiopian communities with high rates of the disease.

That's the conclusion of a study in the March 8 issue of the Journal of the American Medical Association.

Community-wide antibiotic distributions are part of the World Health Organization's strategy to eliminate trachoma as a public health concern by 2020. It has been suggested that a single mass antibiotic treatment in a community might eliminate trachoma. However, current WHO guidelines recommend three mass distributions per year.

To assess this approach, researchers monitored eight Ethiopian villages for up to 24 months after all residents over 1 year old were offered a single oral dose of the antibiotic azithromycin. Fifteen other villages were enrolled 12 months into the program.

The researchers, led by Jaya D. Chidambaram of the University of California, San Francisco, focused on children aged 1 to 5, because they have the highest rates of trachoma and may form the core group for transmission of the infection.

Prior to treatment, the average prevalence of infection in the children was 43.5 percent. By two months after the mass treatment, the rate was 5.1 percent. Two years after the treatment, the infection rate was 11.3 percent.

"Our results suggest that if infection is not eliminated by a single mass antibiotic treatment, then it predictably returns into the community, at least in this hyperendemic (area of high prevalence) area in 1- to 5-year-old children," the study authors wrote." However, infection comes back slowly and does not approach baseline prevalence even by two years."
They concluded that "repeated treatments or other measures will be necessary for elimination of infection, as recommended by WHO. A single treatment will not suffice."

HealthDay

Antibiotic Found to Cause Blood-Sugar Ailments in Seniors

March 2, 2006

Elderly patients taking the widely used antibiotic gatifloxacin were almost 17 times as likely to be hospitalized for very high blood sugar levels and four times as likely to be hospitalized for unusually low levels, a finding that is leading some physicians to call for the drug's withdrawal from the market.

Overall, one of every 100 patients who took the drug was hospitalized, according to a study released online Wednesday by the New England Journal of Medicine. The study was released before its March 30 publication because of its health implications.

Several previous studies have shown an increased risk of glucose abnormalities and several deaths in diabetic patients who received the antibiotic, trade-named Tequin. The drug's label was changed last month to say it should not be given to diabetics. The latest study, which is larger and more definitive, showed that all patients were at risk, even those who were not diabetic. The study's authors said that because other antibiotics were as effective, there was no reason to continue prescribing gatifloxacin.

"Speaking as a clinician, I would never prescribe this drug," said Dr. David N. Juurlink of the Institute for Clinical and Evaluative Sciences in Toronto, who led the study.

Dr. Sidney Wolfe of the Public Citizen Health Research Group in Washington, D.C., said: "This represents a unique danger in the absence of a unique benefit…. This is more than enough reason to think about petitioning the Food and Drug Administration to ban the drug, and we probably will.

"Eric Miller, a spokesman for Bristol-Myers Squibb Co., which makes Tequin, said that the findings "were consistent with the post-marketing experience we have had to date." He said the labeling changes in February took the findings into account.

Miller said the company's annual sales of the drug were about $100 million in the United States and $150 million worldwide — a relatively minor portion of Bristol-Myers' $19.4 billion in total revenue.

Gatifloxacin is a member of the family of broad-spectrum antibiotics known as fluoroquinolones.

It is typically used to treat gonorrhea and lung, sinus and urinary tract infections. Physicians often use it when the nature of an infection is unknown, Juurlink said, because it kills a wide variety of bacteria.But the quinoline family has proved problematic. Four other fluoroquinolones have been withdrawn from the market or had their use severely restricted: temafloxacin, for causing red blood cell damage, kidney failure and hypoglycemia; grepafloxacin and sparfloxacin because of heart problems; and trovafloxacin because of liver damage.

"That is an alarming proportion of drugs in that class that have been taken off the market," said Wolfe of Public Citizen.Gatifloxacin was introduced in 1999. By 2001, 3.3 million prescriptions per year were being written.

Researchers began noticing health problems that year, particularly alterations in glucose metabolism. Changes in blood sugar levels can induce coma and other serious problems, including death. Symptoms usually began five to 10 days after patients took the drug. In most cases, the symptoms could be reversed when drug use was halted.

By 2003, 17 deaths had been linked to the drug and prescriptions were down to about 1.7 million per year.One major contributor to that number is the Department of Veterans Affairs, which added the drug to its formulary and designated it an antibiotic of first choice, in part because Bristol-Myers offered the government a price of $1.35 per pill, compared with the $8 to $10 per pill charged for it and other fluoroquinolones at pharmacies, said Dr. Richard Frothingham of Duke University.

The government also chose it because the risk of glucose abnormalities caused by gatifloxacin did not seem to be any higher than that caused by other antibiotics in the class, Juurlink said.In light of the new findings, he said, "the VA needs to very promptly revisit their policy.

"The Canadian researchers studied health records for 1.4 million Ontario residents over age 65. Among them were about 17,000 gatifloxacin patients.

Juurlink and his colleagues then looked at all patients who had been hospitalized after taking an antibiotic. They found 788 were hospitalized for excessively low blood sugar within 30 days of taking an antibiotic and 470 patients hospitalized for excessively high blood sugar.Within that group, there were 61 gatifloxacin recipients with hypoglycemia and 86 with hyperglycemia.

Compared with other patients in the group, the gatifloxacin recipients had four times the risk of hypoglycemia and 17 times the risk of hyperglycemia.

"This is the most compelling evidence to date showing a connection between gatifloxacin and glucose problems," Frothingham said.

No other fluoroquinolone showed an unusual risk.

Juurlink said the study probably underestimated the risks of the drug. "If they died at home or in a pre-hospital setting, they would not have made it into the study," he said.

LA Times

Antibiotic work afflicted by the bottom line blues

March 1, 2006

BY LAURA BEIL
The Dallas Morning News

DALLAS - Sylvia LaRue had been a nurse long enough to know that the golf-ball size lump shooting pain into her scalp was a staph infection. The test results still stunned her.

"I've been a nurse since 1977, and I've never seen a lab report like that," LaRue said of her 2004 encounter with Staphylococcus aureus. The bacteria were resistant or just marginally vulnerable to 10 of the 11 medicines on the list. The single option left to her was trimethoprim/sulfa - not a creation of high-tech science, but a combination developed decades ago.

In the modern antibiotic era, the old drugs are often the only drugs. Many of the world's pharmaceutical giants are losing interest in the pursuit of new antibiotics and slashing their antimicrobial research divisions. At the same time, the germs continue to strengthen their ability to defy the drugs already on the market.

Already, some patients are left with only one or two useful medications. As resistance climbs and research interest falls, infectious disease experts worry about a day when some infections may reach the point of being virtually unstoppable.

"I don't think it's a crisis right now," said Dr. George McCracken, head of infectious disease at Children's Medical Center Dallas. But it might be, he says, "in the next three to five years."
He and other experts are most concerned about the microbes that breed in hospitals, such as staph, pseudomonas and vancomycin-resistant enterococci. These germs seize on weakened patients connected to tubes that offer bacteria inviting portals to the body's innermost reaches. About 2 million people each year will contract an infection they didn't have upon admission.
"In most American hospitals, we are going to have at any point in time somewhere between one and two patients where we have to scramble to find adequate treatment," said Dr. John Bartlett, head of infectious diseases at Johns Hopkins University School of Medicine.

Once, new antibiotics flowed readily. Between 1935 and 1968, 11 new classes of antibiotics - a "class" targets bacteria in a unique way - came on the market. After that, none appeared for more than 30 years. One was approved in 2000, with two more in 2003 and 2005. But those newest antibiotic classes were the outcome of research that began more than a decade ago. Today, doctors lament the paucity of new drugs in the wings and say much of what are in the pipeline are simply updated versions of old medications.

Since 2000, some of the household names in the drug business - including Wyeth, Aventis, Eli Lilly, Bristol-Myers Squibb, Abbott Laboratories - have cut or eliminated antibiotics research. The reasons are complicated, but the bottom line is still about money. Drug companies are amassing into ever-larger conglomerates, and Wall Street is demanding the highest possible profit margins. From a strictly business standpoint, the most attractive prescription is the one taken by a lot of patients for a long time.

A successful new antibiotic - generally designed to be taken for short periods - might reap a few hundred million dollars a year during its brand-protected life. Compare that with the cholesterol-lowering Lipitor, which a patient might take for a lifetime. It brought in more than $12 billion to Pfizer in 2005. Among the top 20 prescription sellers last year, none was an antibiotic.

"These are critically important drugs. They save lives, and they save them fast," said Steven Projan, vice president of biological technologies for the drug giant Wyeth, which abandoned antibiotics discovery in 2002. But the reality is, "the therapy is going to be for three days to two weeks. It's not like you're giving somebody Lipitor for the rest of their lives."

Other issues, however, both scientific and regulatory, also discourage antibiotics research, Projan said. Antibiotic development can be harder than other drug endeavors, he believes, "and it's harder for reasons we are just starting to understand."

Bacteria have occupied the planet longer than humans, evolving sophisticated mechanisms to outsmart chemical assaults. Most of the current antibiotics, often found by accident, are based on substances extracted from other living things that have spent eons refining the tactics of chemical warfare. Today, the vein of natural compounds largely has been mined, and more modern approaches - techniques that rely on disabling a microbe's inner genetic machinery - have been disappointing.

When drug maker Eli Lilly & Co. mulled its future direction in 2002, the feeling was that "this is one area of drug discovery where I think the low-hanging fruit had been picked," said vice president Gail Cassell.

Each company has its own reasons for leaving antibiotic research, said Cassell, who is a microbiologist. "We consciously made the choice to focus our efforts in the area of oncology, diabetes and neuroscience. We viewed those as equally unmet needs."

Companies who continue to pursue antibiotics say they aren't expecting breathtaking payoffs. "This is not something that is a major blockbuster type of product," said Dr. Lynn Marks of GlaxoSmithKline, which submitted a new topical antibiotic for FDA approval in February. "I think our stockholders understand there's more to being a great corporation that just turning pure profit."

But where many big pharma companies see anemic profits for enormous effort, small entrepreneurs see opportunity. "Where it's happening," McCracken said of antibiotics research, "is with the small companies."

Biotech companies don't depend on a Lipitor-scale return.

"If we made $100 million, that would be real money to us," said Simon Lynch, director of research for Dallas-based Cumbre Inc. And smaller companies tout themselves as being leaner and more passionate than their famous counterparts, knowing that their entire survival depends on having a product to show for their time.

Companies like Cumbre have maybe two dozen or so research scientists, while the larger firms might employ hundreds. Yet finding a drug isn't necessarily a matter of having the most Petri dishes.

For example, Cumbre is tightly focused on defeating biofilm infections - the slimy, often impenetrable communities of bacteria that can coat the insides of catheters and the surface of bones.

But can small pharma succeed where big pharma can't? Wyeth's Projan remains skeptical. "We have a huge amount of experience doing this, and they tend to make all the mistakes we do," he said. He says he believes in the need; the last approved new drug class was a Wyeth invention. A turnaround in antibiotic discovery, he said, will depend on better innovation, not just better economics.

"What we need are new chemistries. We've been stuck in the solar system, and we need to get out into the galaxy."

Lynch's company, for example, is looking at how a bacterium shields itself from a chemical that would otherwise kill it. Many potential drugs don't work because bacteria have molecular pumps that enable them to bail out foreign chemicals as quickly as they come in. Disabling those pumps would allow antibiotics to become trapped in cells.

Other companies are exploring how to jam the communications that allow bacteria to sense one another's presence and, in essence, transform from a disorganized militia into a precision-trained force. Working together, bacteria can become meaner and more resistant to drugs than they could ever be in lesser groups.

"The optimistic view is that some of these biotechs are going to hit paydirt," said David Shlaes of Connecticut-based Anti-Infectives Consulting. "They will challenge big pharma in the marketplace, and big pharma is going to wake up."

Doctors have also taken proposed solutions to Congress, including measures that would provide financial incentives for antibiotic research and streamline clinical trials. However, some experts point out that more favorable regulation, by itself, won't bring new chemicals into the research pipeline.

Doctors campaigning for more antibiotics research are not against making money, said Dr. Richard Wenzel of Virginia Commonwealth University. The pharmaceutical industry is "driven by the free enterprise system in a straightforward, American way.

"We need drug companies to be able to make a profit," he continued. "The real question is how much when the public's health is at risk."

It's a public health issue that Beverly Perry hadn't considered until November, when her mother, Jean Baccus, suffered a stroke. Five days after Baccus entered the hospital, bacteria invaded her IV line and set up an outpost in her spine.

More than three months later, Baccus' stroke rehabilitation can't begin because the drug-resistant staph infection hangs on.

"You think, `OK, let's give her antibiotics and get it over with,'" Perry said. The stubbornness of the infection astonished her. "We tell her, `It's just going to be a couple more weeks.'"
And a couple of weeks turn into a couple more weeks. Baccus now must be taken to the hospital each day for antibiotic infusions that are sluggish in working. "She's in so much pain," Perry said. "I think everybody needs to know how serious this is."

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