THE PREVALENCE OF SIDE-EFFECTS: CIPROFLOXACIN 500 MG SINGLE DOSE PRO-PHYLAXIS AGAINST NEISSERIA MENINGITIDIS OUTBREAK IN POTCHEFSTROOM DURING JULY 2003

Potchefstroom experienced an outbreak of Neisseria meningitidis (N. meningitidis) during May-July 2003. An opportunity for obtaining valuable data arose when mass prophylactic treatment to approximately 28% of the Potchefstroom community was provided by the Department of Health, North-West Province. The aim of this study was to investigate the prevalence of side-effects experienced by staff and students of the Potchefstroom University for Christian Higher Education (PU for CHE) who received a single prophylactic dose of oral ciprofloxacin 500 mg between 23 and 29 July 2003. Information gained from the Potchefstroom outbreak may be valuable for the future management of similar outbreaks in other communities. Various stakeholders have published related reports, protocols, recommendations and guidelines, which mostly focused on the prevention, management and control of meningococcal disease. Very little has been reported about the side-effects experienced, especially in cases where ciprofloxacin 500 mg single dose had been dispensed. One or more side-effects were reported by 24.2% of the participants, while 5.4% had to consult with a health care worker due to the severity of side-effects resulting from a single dose. Practical significance could not be demonstrated for any of the side-effects reported after single versus


INTRODUCTION
"Few infections can cause the civil, medical, and social stress that occurs when serious meningococcal disease enters a community" (Apicella, 1995:2).
Meningitis is an inflammation of the meninges (the membranes surrounding the brain and spinal cord).
Meningitis can be caused by either bacterial or viral infection. Various bacteria can induce meningitis but the most common causes of the reported cases were N. meningitidis (meningococcus) and Streptococcus pneumoniae (pneumococcus) (Beers & Burkow, 2003:1). Until recently, Haemophilus influenzae type b was the most common cause of meningitis in children older than one month, but vaccination dramatically reduced the incidence (Beers & Burkow, 2003:1). Meningococcus is a serious life-threatening condition that requires immediate medical treatment.  (CDC, 2000:11).

STUDY PURPOSE AND RATIONALE
The purpose of this study was to investigate the prevalence of side-effects experienced by staff and students

PROPHYLACTIC TREATMENT OF MEN-INGITIS
Chemoprophylaxis is highly effective in some clinical settings and in others it is totally without value and may be deleterious. The use of antimicrobial compounds to prevent infections remains controversial in several situations (Chambers, 2001(Chambers, :1164  sharing of food or beverages during the seven days before the onset of disease in the index case. Prophylaxis is not recommended routinely for medical personnel except for those who have had intimate exposure, such as that which occur with mouth-to-mouth resuscitation, intubation or suctioning. The index case should also receive chemoprophylactic antibiotics before discharge unless treated with ceftriaxone. Because the attack rate of secondary disease after a close con-tact is highest in the few days following the onset of disease in the primary case, the delay in providing antimicrobial chemoprophylaxis must be minimised and, ideally, the prophylaxis should be given within 24 hours of case identification. Suggested chemoprophylaxis regimens include rifampin (rifampicin), ceftriaxone and ciprofloxacin and these are shown in Table 1.
Various health departments (Welsh Medicines Information Centre, 2003:5; Massachusetts Department of Public Health, 1999:7) follow similar guidelines as reflected in Table 1 for chemoprophylaxis but for pregnant women they also include Ceftriaxone 250 mg as a single dose, administered intramuscularly.
The WHO provided chemoprophylactic guidelines similar to those reflected in Table 1, but also included spiramycin or minocycline for five days as alternatives (WHO, 1998:28). Their report did not recommend mass chemoprophylaxis to prevent or control epidemics.
Oral rifampicin had been the drug of choice for chemoprophylaxis in recent decades. Rifampicin is 72% to 90% effective in eradicating nasopharyngeal carriage and serious adverse effects with short-term therapy are rare. Urine and stools may be stained orange or red and soft contact lenses may become tinted and therefore warnings would be required. Rifampicin may also interfere with the efficacy of oral contraceptives and is not recommended for use during pregnancy. The impact of rifampicin on the metabolism of other medications such as those for seizure prevention and anticoagulation must also be considered. Ceftriaxone administered as a single intramuscular dose is an alternative to rifampicin and is more than 95% effective in eradicating carriage. In adults who are not pregnant, a single dose of ciprofloxacin is an effective oral alternative to rifampicin in 90% to 95% of cases. Although ciprofloxacin is used in children for chemoprophylaxis of meningitis, it is not currently approved for use in children younger than 18 years and should not be used when safer alternatives are available (CPS, 1997:5;Petri, 2001Petri, :1182. Although sulphonamides were effective in preventing disease for many years, the majority of isolates of N. meningitidis of serogroups B and C in the USA as well as group A isolates from other countries are now resistant (Petri, 2001(Petri, :1172 Gaunt and Lambert (1988:489) when 2100 navy personnel received single oral doses of ciprofloxacin 500 mg and 570 of the personnel were swabbed 2-4 days later. An additional 277 personnel members were followed-up for nine weeks afterwards to determine the elimination rate of the pharyngeal carriage. The overall prevalence of carriage declined from 19% to less than 1.5% as a result of the use of ciprofloxacin.
Ciprofloxacin is one of a number of fluorinated 4quinolones and is of great importance therapeutically due to the agent's broad antimicrobial activity. It is effective after oral administration for the treatment of a wide variety of infectious diseases (Petri, 2001(Petri, :1182.

Side effects of ciprofloxacin
Fluoroquinolones are generally well-tolerated. The most common adverse reactions involve the gastrointestinal tract (nausea, vomiting and/or abdominal discomfort reported by 3% to 17% of the patients). Central nervous system side-effects, predominantly mild headache and dizziness have been reported in 0.9% to 11% of patients. Skin rashes, including photosensitivity reactions (sensitivity of the skin to direct sunlight), may occur. Allergic reactions have been described, such as hives (urticaria) and anaphylaxis (Petri, 2001(Petri, :1182. Three cases of anaphylactic reactions (a rate of about 1:1000, much higher than the 1:100 000 quoted) were reported in approximately 3200 first-year university stu-dents who accepted single dose ciprofloxacin 500 mg as prophylactic treatment (Burke & Burne, 2000:679).
Side-effects reported by naval training personnel after receiving a single dose of oral ciprofloxacin 500 mg were mild in nature with the exception of one recipient who developed an acute urticarial reaction ten minutes after taking the tablet (Gaunt & Lambert, 1988:493).
Quinolones and fluoroquinolones cause arthralgias (pain in joints) and joint swelling in children receiving ciprofloxacin and are, for that reason, not recommended for use in pre-pubertal children or pregnant women.
Many antibiotics, including ciprofloxacin, can alter the normal bacteria in the colon and encourage overgrowth of bacteria responsible for the development of inflammation of the colon (pseudomembranous colitis), causing fever, abdominal pain, diarrhoea, and sometimes even shock (Petri, 2001(Petri, :1182.

Research Design and Setting
An open non-randomised study was conducted, based

Validity and Reliability
The following actions were taken in order to ensure the reliability and validity (face and content) of the questions in the questionnaire: a) special attention was given to ensure that each question only implied one concept; and b) different preliminary versions of the questionnaire were drawn up and evaluated by various experts in the field of pharmacology, pharmacy practise and statistics.
An application for approval of the study was submitted to the Ethics Committee of the PU for CHE and to the Department of Health, North-West Province and both approved the study.

Statistical Analysis
The SAS System for Windows (SAS Institute, 2001) was used to create the database and to analyse the data by calculating certain descriptive and inferential statistics. The descriptive statistics included frequency tables, histograms and percentage expressions. Chisquare tests (χ 2 ) were used as inferential statistics to determine whether a difference existed between the side-effects reported by the participants who received only a single dose versus the participants who received multiple dose ciprofloxacin 500 mg; single dose versus gender effect, multiple dose versus gender effect and single dose-gender versus consultation required.
Because the responses were voluntary, the participants were not randomly selected. As a result, the following equation and guidelines were used to interpret the practical significance (the effect size) of the results (Steyn, 2002:11): n w 2 χ = where (χ 2 ) is the usual Chi-square statistic for a twoway frequency table and n = number of participants.
The guidelines used to interpret the results followed the criteria provided by Cohen (1988:227): w = 0.1 small effect (non significant) w = 0.3 (medium effect) w = 0.5 large effect (significant and of practical importance)  (741)  The data reflected in Table 3 indicate the frequencies and percentages of all the side-effects reported by the participants (expressed as a percentage of 741 participants) who indicated that they took a single dose of ciprofloxacin 500 mg. All the responses of the participants (staff; on-campus students; and off-campus students) were combined and the gender contributions are reflected.

RESULTS AND DISCUSSIONS
The data in Figure 1 indicate the percentage of sideeffects greater than 1%, as reported by the participants who indicated that they took a single dose of ciprofloxacin 500 mg (expressed as a percentage of 741 participants). These side-effects included headache (9.3%), nausea (8.5%), sleepiness (8.0%), dizziness (5.9%), stomach cramps (4.6%), listlessness (3.4%), trembling (2.2%), insomnia (1.8%), diarrhoea (1.4%), itchiness (1.2%) and heart palpitations (1.1%). Table 4 comprises comparative data with respect to the number of participants who experienced side-effects due to single dose versus multiple doses and the number of participants who consulted a healthcare worker due to the side-effect(s) they experienced. It is indicated that 392 (25.5%) of the 1537 participants (295 females or 19.2% and 97 males or 6.3%) reported one or more side effects. Of these 392 participants, 179 participants (11.6%) indicated that they took a single dose and 189 (12.3%) participants indicated that they took more than one dose of ciprofloxacin (24 (1.6%) participants did not indicate their dosage). for all the various side-effects due to a single dose, and those due to multiple doses, were used in the effect size equation to establish whether the effects experienced were significant. None of the w-values reached significance. The effect of gender was tested on the different side-effects reported with a single dose as well as with the side-effects reported after ingestion of multiple doses. Once again, no significance due to gender differences could be shown for any of the side-effects.
The effect size tested to measure the relationship be-  B= 13 participants indicated that they were students (off-campus and on-campus) but did not indicate their gender.
C= 26 participants did not indicate where they received their treatment.
D= 94 participants did not reply to this section by indicating whether or not they took a single or multiple dose. tween the side-effects due to a single dose, gender or causing consultation requirement with a health care worker, also indicated no practical significance. These results are not included, as no significance could be shown.
The information obtained through this questionnaire on possible drug interactions and the effect thereof on greater side-effect prevalence was not included in the scope of this article but the data is available for further statistical analysis.

Limitation of the study
In order to obtain a reliable response in the shortest possible time following the outbreak and accompanying prophylactic treatment, the design and execution of the study were somewhat complicated by the high level of social fear surrounding the outbreak. As a result, the decision to conduct this investigation was only made after the mass prophylaxis exercise had been completed. Therefore, the opportunity to issue the questionnaire simultaneously with the medication was lost, which could have impacted negatively on the response rate. However, in support of the method used the possibility of perceived side-effects being reported was eliminated.

CONCLUSIONS
One of the main aims of this study was to investigate the prevalence of side-effects after the administration of a single dose of ciprofloxacin 500 mg. It is apparent from the data analysis of the 1537 voluntary partici-   Cohen (1988) no practically significant relationship was shown for any of the side-effects reported on single dose, multiple doses, nor when the effects of gender or requirement for medical consultation were tested.

ACKNOWLEDGEMENTS
All participants who were involved in this study are hereby thanked for their cooperation and input.
Professor completing this questionnaire is therefore much appreciated. All information will be treated confidentially.
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