CLINICAL PROFILE AND OUTCOME OF ADULT PATIENTS WITH INVASIVE STAPHYLOCOCCUS AUREUS INFECTION IN AMINU KANO TEACHINGHOSPITAL, KANO
BY
DR TAMBUWAL, SIRAJO HALIRU
MBBS (UDUS) 2003 DEPARTMENT OF INTERNAL MEDICINE, USMANU DANFODIYO UNIVERSITY TEACHING HOSPITAL (UDUTH) SOKOTO
A DISSERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL COLLEGE OF NIGERIA IN PART FULFILMENT OF THE REQUIREMENT FOR THE AWARD OF A FELLOWSHIP IN INTERNAL MEDICINE (SUBSPECIALTY-INFECTIOUS DISEASES)
NOVEMBER, 2016
ii CERTIFICATION 1 We hereby declare that the writing and execution of the study contained in this dissertation was carried out by DR TAMBUWAL SIRAJO HALIRU under the supervision of PROF A.G. HABIB, DR. H.M LIMAN AND DR. G. ILIYASU Signature………………………… Date………………………… PROFESSOR A.G HABIB (FWACP, FRCP, FAMS) Professor of Medicine (Infectious Diseases and Tropical medicine) Department of Medicine, Aminu Kano Teaching Hospital, Kano. Signature……………………… Date………………………… DR H.M LIMAN (FMCP) Consultant Nephrologist, Department of Medicine, Usmanu Danfodiyo University Teaching Hospital, Sokoto. Signature……………………… Date……………………… DR. G. ILIYASU (FWACP) Consultant Infectious Diseases, Department of Medicine, Aminu Kano Teaching Hospital, Kano. iii CERTIFICATION 11 I certify that this work was carried out by DR TAMBUWAL SIRAJO HALIRU in the Department of Medicine, Usmanu Danfodiyo University Teaching Hospital, Sokoto, under the supervision of Professor. A.G Habib, DR H.M Liman and DR. G Iliyasu. …………………………………………………………………………………………….. HEAD OF DEPARTMENT OF MEDICINE USMANU DANFODIYO UNIVERSITY TEACHING HOSPITAL, SOKOTO iv DECLARATION I hereby declare that this work was done by me, DR TAMBUWAL SIRAJO HALIRU of Department of Medicine, Usmanu Danfodiyo University Teaching Hospital, Sokoto and that it has not been submitted to any other college for the award of a fellowship or degree, or sent for publication. SIGNATURE…………………………………………….. DATE……………………………………………………... v DEDICATION This work is dedicated to my wife Safinatu Abubakar, without whose support it would not have been possible, and to my parents Alhaji Haliru Tambuwal and late Malama Aishatu Abdullahi who passed on a love of reading and respect for education. vi ACKNOWLEDGEMENTS My appreciation goes to Professor A.G. Habib, Dr. H.M Liman and Dr. G Iliyasu for being my mentors and guides. Professor A.G Habib has been a source of inspiration throughout my training, I am highly indebted to him. My thanks go to all the people that were involved in this study, particularly Mr. Bashar Usman Mohd of the microbiology department AKTH Kano, the technical head microbiology department, AKTH Kano, Malam Nasiru Mohd. My sincere gratitude goes to all my colleagues in the department of internal medicine for their support in various ways during the course of my training and while carrying out this study. vii Contents
CERTIFICATION 1 ...... ii
CERTIFICATION 11 ...... iii
DECLARATION ...... iv
DEDICATION ...... v
ACKNOWLEDGEMENTS ...... vi
LIST OF TABLES ...... x
LIST OF FIGURES ...... xi
ABBREVIATION...... xii
ABSTRACT ...... xv
CHAPTER ONE ...... 1
1.0 INTRODUCTION ...... 1
1.1 DEFINITION OF THE RESEARCH PROBLEM ...... 3
1.2 RELEVANCE OF THE STUDY TO CLINICAL PRACTICE ...... 3
1.3 JUSTIFICATIONS FOR THE STUDY ...... 4
1.4 AIMS AND OBJECTIVE ...... 5
1.4.1 AIMS...... 5
CHAPTER TWO ...... 6
2.0 LITERATURE REVIEW ...... 6
2.1 BACKGROUND ...... 6
2.2 BACTERIOLOGY ...... 6
2.3 TOXINS AND OTHER VIRULENT FACTORS ...... 7
2.4 PATHOGENESIS ...... 8
2.41 INVASIVE STAPHYLOCOCCUS AUREUS INFECTIONS ...... 10
2.5 RISK FACTORS FOR INVASIVE STAPHYLOCOCCUS AUREUS INFECTION ...... 14
2.6 LABORATORY DIAGNOSIS ...... 15
2.7 ANTIBIOTIC RESISTANCE ...... 15
2.8 PREVENTION ...... 16 viii CHAPTER THREE ...... 18
3.0 METHODOLOGY ...... 18
3.1 BACKGROUND OF THE STUDY AREA ...... 18
3.2 STUDY DESIGN ...... 18
3.3 STUDY POPULATION ...... 19
3.3.1 INCLUSION CRITERIA ...... 19
3.3.2 EXCLUSION CRITERIA...... 19
3.4 SAMPLE SIZE ...... 20
3.5 SAMPLING METHOD ...... 20
3.6 INSTRUMENTS OF DATA COLLECTION ...... 20
3.7 STUDY PROTOCOL ...... 21
3.7.1 STUDY PATIENTS AND SOURCE OF DATA ...... 21
3.7.2 DEFINITIONS ...... 22
3.7.3 MICROBIOLOGICAL ANALYSIS ...... 24
3.7.4 DATA COLLECTION ...... 25
3.8 DATA ANALYSIS ...... 26
3.9 ETHICAL CONSIDERATION ...... 26
3.10 LIMITATIONS OF THE STUDY ...... 26
CHAPTER FOUR ...... 27
4.0 RESULTS ...... 27
4.1 PATIENT CHARACTERISTICS ...... 28
4.1.1 AGE AND SEX DISTRIBUTION ...... 28
4.2 PATTERN OF PRESENTATION ...... 30
4.2.1 CLINICAL FEATURES ...... 32
4.3 AGE GROUP BY ISA INFECTION ...... 34
4.4 RISK FACTORS ...... 36
4.5 ANTIBIOTIC SUSCEPTIBILITY PATTERN OF THE ISOLATES ...... 38 ix
4.6 LABORATORY RESULTS ...... 41
4.7 CLINICAL OUTCOME ...... 43
4.7.1 CLINICAL OUTCOME AND COMORBIDITIES ...... 45
4.7.2 MORTALITY AND ANTIBIOTIC RESISTANCE BY ISA INFECTION ...... 47
4.7.3 MORTALITY BY AGE GROUP ...... 50
4.8 PREDICTORS OF MORTALITY...... 52
CHAPTER FIVE ...... 55
5.0 DISCUSSION ...... 55
CHAPTER SIX ...... 61
6.0 CONCLUSION ...... 61
6.1 LIMITATIONS OF THE STUDY ...... 62
6.2 RECOMMENDATIONS ...... 63
6.3 REFERENCES ...... 64
6.4 APPENDIX 1 ...... 77
6.5 APPENDIX TWO ...... 79
X
LIST OF TABLES
Table 1 Diagnosis in 140 patients with invasive staphylococcus aureus infection 30
Table 2 Distribution of Clinical features of patient with ISA 32
Table 3 Age Group by ISA infection 34
Table 4 Distribution of Risk factors at Presentation 36
Table 5 Antibiotic Resistance by ISA infection 38
Table 6 Resistance Profile of MSSA and MRSA against other antibiotics 39
Table 7 Laboratory results finding 41
Table 8 Clinical Outcome and Diagnosis 43
Table 9 Clinical Outcome and Comorbidities 45
Table 10 Mortality and Antibiotic Resistance by ISA infection 47
Table 11 Mortality and Antibiotic Resistance 48
Table 12 Univariate Logistic Regression Model 52
Table 13 Multivariate Logistic Regression Model 53 xi
LIST OF FIGURES
Figure 1 Age and Sex distribution of Patients 28
Figure 2 Mortality by Age group 50 xii
ABBREVIATION
2DEcho 2 Dimensional Echocardiography
AIDS Acquired Immunodeficiency syndrome
AKTH Aminu Kano Teaching Hospital
ALT Alanine amino Transferase
ARV Antiretroviral
AST Aspartate amino Transferase
CA-MRSA Community acquired Methicillin Resistant Staphylococcus aureus
CA- MSSA Community acquired Methicillin Sensitive Staphylococcus aureus
CKD Chronic Kidney Disease CLD Chronic Liver Disease
CoNS Coagulase negative Staphylococcus aureus
CP5 Capsular Polysaccharide 5
CP8 Capsular Polysaccharide 8
CT scans Computed Tomography Scan
CXR Chest X-Ray
DNA Deoxyribonucleic Acid
DST Drug Susceptibility Testing
EUCr Serum electrolytes, urea and creatinine xiii
FBC Full Blood Count
HMGB1 High Mobility Group Box Protein 1
HIV Human Immunodeficiency Virus
HHD Hypertensive Heart Disease
ICU Intensive Care Unit
ICAM-1 Intracellular Adhesion Molecule 1
ISA Invasive Staphylococcus aureus infection
IV Intravenous
LFT Liver Function Tests
MRSA Methicillin Resistant Staphylococcus aureus
MSSA Methicillin Sensitive Staphylococcus aureus
PCV Packed Cell Volume
PVL Panton Valentine Leucocidin
RNA Ribonucleic Acid
RNS Reactive Nitrogen Species
ROS Reactive Oxygen Species
S. albus Staphylococcus albus
S. aureus Staphylococcus aureus
SCCmec Staphylococcal cassette chromosome mec xiv
SIRS Systemic Inflammatory Response Syndrome
SSTIs Skin and soft tissue infections
STSS Staphylococcal Toxic Shock syndrome
TSST1 1 Toxic Shock Syndrome Toxin 1
WBC White Blood Cells
WHO World Health Organization xv
ABSTRACT
Introduction: Invasive staphylococcus aureus infection (ISA) is increasingly being recognised as an important cause of morbidity and mortality in developing countries. This problem is confounded by the increasing prevalence of antibiotic resistant Staphylococcus aureus.
Aim: The aim of this study is to determine pattern of clinical presentation and outcome of patients with ISA infection in Aminu Kano Teaching Hospital, Kano.
Materials and methods: This study was carried out on patients with ISA infection who were seen at Aminu Kano Teaching Hospital, Kano. The study was a prospective (longitudinal) study. The patients were recruited consecutively until the target study population was reached.
A clinical evaluation and relevant laboratory investigations were done. The patients were followed up for one month to determine the outcome.
Results: A total of 140 patients were studied. The mean age was 40.7 ± 15.6 years. Male to female ratio 1.4:1. Skin and soft tissue infection, line associated infection, pneumonia and bacteraemia were the most common diagnoses. The mean duration of symptoms was 8.8
± 5.8 days. The spectrum of signs and symptoms varies according to the type of ISA infection.
Fever is present in 42.1% of the patients and 36.4% had sepsis. The prevalence of MRSA was
47.8%. The commonest form of CA-MRSA infection is SSTIs and bacteraemia is the commonest form of HA-MRSA infection. Mortality was higher among patients with bacteraemia. Comparing invasive MRSA and MSSA infections, mortality is higher in patients with MRSA infection for all ISA infection. Independent predictors of mortality were sepsis and infection with MRSA.
Conclusion: This study shows high burden of invasive staphylococcus aureus infection and provides important information on the clinical characteristics of patients with ISA infection.
Staphylococcus aureus is resistant to commonly used antibiotics. Mortality is higher in xvi staphylococcal bacteraemia and MRSA infection and sepsis were independent risk factors for mortality
1
CHAPTER ONE
1.0 INTRODUCTION
Staphylococcus aureus causes wide range of diseases from superficial skin infection to severe sepsis. The number of infections has been increasing in the past 20 years because of increasing risk factors for infection which include increased use of intravascular devices and increased use of immunosuppressive medications (1,2). The burden of Methicillin Resistant Staphylococcus aureus (MRSA) is increasing(2,3) with the need for more costly, potentially more toxic and often less well tolerated antimicrobial agents. In western Sweden, the overall annual incidence of Invasive
Staphylococcal Infection(ISA) among residents of skaraborg was 31.4/100,000 population, or 33.9 cases with relapse included (4); 49% were community acquired,
19% health care associated and 32% nosocomial. In the Calgary Health region, the annual incidence was 28.4 cases/100,000 population; 46% were classified as nosocomial (5). The incidence of MRSA in Nigeria as reported by different workers ranged from 11% to 43% among Staphylococcus aureus isolates (6,7,8).
The risk of ISA infection is highest in persons undergoing haemodialysis or peritoneal dialysis and in persons infected with human immunodeficiency virus (4,5). Other patients at risk are patients with Rheumatoid Arthritis, Diabetes Mellitus, cancer, and patients colonised with Staphylococcus aureus (4).
Episodes of MRSA bacteraemia had a significantly higher overall mortality rate when compared with episodes caused by methicillin-sensitive Staphylococcus aureus (MSSA) (9). Invasive infections caused by MRSA, particularly those involving persistent bacteraemia, necrotizing pneumonia, osteomyelitis and other deep-seated infections are associated with high mortality (11). Presence of infective endocarditis,
2 septic shock and central intravascular catheter and methicillin resistance of
Staphylococcus aureus were independent risk factors associated with a higher mortality rate (9).
Developing countries continue to bear the brunt of Staphylococcus aureus infections.
The problem is further compounded by the rapid emergence of antibiotic resistance globally and the pandemic of Human Immunodeficiency Virus (HIV) infection. The number of serious infection is increasing for both community and hospital acquired infections. In developing countries empirical treatment of MSSA largely depends on b-lactam antibiotics. For clinical management of MRSA infections Vancomycin and
Fusidic acid are neither readily affordable nor available, and facilities for monitoring plasma concentrations are unavailable making treatment of MRSA challenging. In
Nigeria, nasal isolates of Staphylococcus aureus were found to be resistant to ampicillin
(100%), Cloxacillin (100%), penicillin (100%, tetracycline (82%), chloramphenicol
(73%), erythromycin (68%), gentamicin (64%), streptomycin (58%), and oxacillin
(55%) (11). In Thailand, over 90% of MRSA isolates were resistant to ciprofloxacin, erythromycin, gentamicin, netilmicin, tetracycline and trimethoprim-sulphamethoxazole, and 65% were resistant to clindamycin. Vancomycin and Fusidic acid had the lowest rates of resistance (12).
Considering the morbidity and mortality due to infection with this organism, it is essential that therapy be optimized from the first dose. In order to achieve this, it is necessary to know the local susceptibility pattern of Staphylococcus aureus isolates from clinical specimens of invasive infections. Continuous surveillance on resistance patterns and characterization of Staphylococcus aureus represents simple and lowcost approach to understand and evaluate the effectiveness of empiric antimicrobial treatment. 3
1.1 DEFINITION OF THE RESEARCH PROBLEM
Staphylococcus aureus is a leading cause of septicaemia related death. The organism expresses a variety of virulent factors. The bacterium continues to demonstrate resistance to a broad array of antimicrobials classes, and it is a prominent pathogen in both hospital and community settings in developing countries. The management of
MRSA is a growing clinical challenge, as the rate of this infection continues to rise globally. The impact of increasing frequency of MRSA bacteremia is magnified by poor outcome associated with this serious infection (2,14,15).
Staphylococcus aureus has always been a challenge for antimicrobial chemotherapy as the introduction of new class antimicrobial agents is usually followed by emergence of resistant forms of this pathogen (14).This complicates the management of ISA infections. The recent emergence of CA-MRSA expressing PVL toxin as cause of severe infections in immunocompetent healthy adults has contributed to increase in mortality seen in this condition.
1.2 RELEVANCE OF THE STUDY TO CLINICAL PRACTICE
Invasive Staphylococcus aureus infection (ISA) is the leading cause of morbidity and mortality especially among the elderly and people with underlying immunosuppressive disease(15,16). With the increase in case fatality rates due to Staphylococcus aureus and worldwide emergence of drug resistant Staphylococcus aureus, it becomes imperative to do continuous surveillance of pattern of ISA, and antibiotic susceptibility, to recognize the potential hazards associated with Staphylococcus aureus infections.
It is hoped that findings from this study will provide an insight on the clinical pattern, antibiotic resistance profile and determinants of outcome in ISA, and will help to draw attention of physicians managing Staphylococcus aureus infections on the pattern of
4 presentation, determinants of outcome, need for rational choice of empirical antibiotics and prevention.
1.3 JUSTIFICATIONS FOR THE STUDY The burden of ISA remains high in developing countries including Nigeria. Several studies on ISA have been reported in the western literature but there is paucity of information on this subject in developing countries including Nigeria, where morbidity and mortality related to Staphylococcus aureus invasive diseases may probably be higher due to low socioeconomic status, poor sanitation and poor implementation of infection control policies in our hospitals.
ISA occurs frequently among immunosuppressed patients, but it is unclear whether its manifestations and outcome are different compared to those observed among patients who are immunocompetent. Clinicians must be better informed regarding clinical profile, outcome and antibiotic resistant pattern in ISA to minimize their attendant morbidity and mortality and increase compliance with preventive measures like application of mupirocin ointment and chlorhexidine bath for patients in ICU to eradicate colonisation (68, 69, 70).
5
1.4 AIMS AND OBJECTIVE
1.4.1 AIMS
To describe the clinical pattern and determinants of outcome in ISA infection in Kano
1.4.2 SPECIFIC OBJECTIVES
1. To determine the prevalence, pattern of presentation and outcome of patients with ISA infection in Aminu Kano Teaching Hospital, Kano.
2. To determine antibiotic resistance and its impact on the outcome of ISA infection in Aminu Kano Teaching Hospital.
3. To determine the risk factors for ISA associated mortality
4. To determine the most prevalent co-morbidities associated with ISA infection.
6
CHAPTER TWO
2.0 LITERATURE REVIEW
2.1 BACKGROUND
Staphylococcus aureus is a significant pathogen worldwide, it is reported to be responsible for significant number of nosocomial and community associated infections such as skin and soft tissues infections, pneumonia and bacteraemia. The public health burden caused by Staphylococcus aureus is exercabated by Beta-lactam antimicrobial resistance. The principal site of staphylococcus aureus colonization is the anterior nares.
There is high rate of carriage in hospital personnel, Intravenous (I.V) drug users, diabetics and dialysis patient. In a Nigerian study of 346 isolates of Staphylococcus aureus Ghebremedhin et al found the prevalence of MRSA to be 20.23% among the population studied (17). In another Nigerian study by Taiwo et al in Ilorin, South-west
Nigeria, the prevalence of MRSA among Staphylococcus aureus isolates was 29% (86).
In western Sweden, the overall annual incidence of ISA among residents of skaraborg was 31.4/100000 population (4). Forty-nine percent of the cases were community acquired, 19% were health care associated and 32% were nosocomial. Similarly in the
Calgary Health region, the annual incidence of ISA was 28.4 cases/100,000 population, out of which 46% of the cases were nosocomial (5).
2.2 BACTERIOLOGY
Staphylococcus aureus is a Gram positive cocci in the family micrococcacaea. This organism is catalase and coagulase positive, non-motile, aerobic and facultative anaerobe. Staphylococcus aureus is differentiated from other staphylococcal species by its production of coagulase. It also has surface protein A and clumping factor. In
7 addition, it ferments manitol and produces DNAse. Isolates appear golden yellow on blood agar plates hence the name ‘Staphylococcus aureus’ in contrast to Coagulase
Negative Staphylococcus(CoNS) some of which appear white and were previously referred to as ‘Staphylococcus. albus’.
The staphylococcal cell wall is 50% peptidoglycan by weight. Peptidoglycan consists of alternating polysaccharide subunits of N-acetylglucosamine and N-acetylmuramic acid with 1, 4-β linkages. The peptidoglycan chains are cross-linked by tetrapeptide chains bound to N-acetylmuramic acid and by a pentaglycine bridge specific for
Staphylococcus aureus. Peptidoglycan may have endotoxin-like activity, stimulating the release of cytokines by macrophages, activation of complement, and aggregation of platelets. Differences in the peptidoglycan structure of staphylococcal strains may contribute to variations in their capacity to cause disseminated intravascular coagulation. Ribitol teichoic acids, covalently bound to peptidoglycan, are major constituents of the cell wall. Lipoteichoic acid is a glycerol phosphate polymer linked to a glycolipid terminus anchored in the cytoplasmic membrane.
Most Staphylococcus aureus clinical isolates produce capsular polysaccharides which have been divided into 11 serotypes. The Serotypes 5 and 8 account for 75% of human infections. Most MRSA isolates are type 5.
2.3 TOXINS AND OTHER VIRULENT FACTORS
The expression of virulence in Staphylococcus aureus disease depends on a series of regulatory genes e.g age and sar that coordinate and control the expression of many virulent genes. Shittu et al reported isolates of Staphylococcus aureus with toxin genes she and etd and high proportion of Panton Valentine Leucocidin(PVL) positive isolates among MSSA in Nigeria (18). PVL is a leukocytolytic toxin that has been epidemiologically associated with severe cutaneous infections.
8
Isolates of MRSA strains were less toxigenic than MSSA strains in Nigeria which were more frequently positive for PVL. Also the prevalence of superantigenic toxin genes is higher in MSSA than MRSA(17). Almost all strains of Staphylococcus aureus secrete enzymes and toxins. They include four haemolysins (alpha, beta, delta, and gamma), nucleases, lipases, proteases, hyaluronidases and collagenases. Also Staphylococcus aureus produces a staphylokinase which is a potent activator of plasminogen, the precursor of fibronolytic protease plasmin.
Staphylococcus aureus produces several families of exotoxins that have superantigen activity. These include heat stable enterotoxins (A-E, G-T), exfoliative toxins A and B that are the cause of Scalded Skin Syndrome and Toxic Shock Syndrome Toxin
1(TSST1) that causes Staphylococcal Toxic Shock Syndrome (STSS).
2.4 PATHOGENESIS The virulence of Staphylococcus aureus is remarkable. Infections are initiated when a breach of the skin or mucosal barrier allows staphylococcus access to the adjoining tissues or blood stream. The risk of infection is increased in persons undergoing haemodialysis or peritoneal dialysis and persons infected with HIV (4,5), other patients at risk are patients with Rheumatoid Arthritis, Diabetes Mellitus and cancer (4).
Devices such as I.V catheter are rapidly coated with serum constituents that enable
Staphylococcus aureus to adhere through microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) mediated mechanisms.
Infections occur frequently as a consequence of S. aureus inoculation into an open wound. Alternatively, in the upper airway, viral infection damages mucosal linings and predisposes the host to S. aureus pneumonia. Exposure of Staphylococcus aureus to host tissues trigger up regulation of virulence genes (19). For the host, resident
9 phagocytes and epithelial cells in the skin or mucosal tissue respond to either bacterial products or tissue injury by activation of the immune system. S. aureus peptidoglycan and lipoprotein are sensed by host pattern recognition molecules, hyaluronan breakdown products and endogenous toll like receptor ligands (RNA, DNA, HMGB1) released by necrotic tissues during infection further augment pro-inflammatory signalling leading to local immune cell activation, and neutrophil and macrophage recruitment.
Staphylococcus aureus capsular polysaccharides 5 and 8 predominate among clinical isolates of Staphylococcus aureus. The capsule enhances staphylococcal virulence by impeding phagocytosis, resulting in bacterial persistence in the bloodstream of infected hosts. it also promotes bacterial colonization and persistence on mucosal surfaces (20).
Most purified capsular polysaccharides are poorly immunogenic in animals and humans. Neither CP5 nor CP8 elicit serum antibodies when injected into mice (21) and levels of antibodies to CP5 and CP8 in normal human serum are low (21).
However, conjugation of capsular polysaccharide with a protein increases its immunogenicity and T-cell dependent properties (22). S. aureus avoids opsonisation and phagocytosis by expressing clumping factor A, protein A, and a number of complement inhibitors on its surface capsule, all of which inactivate or prevent host opsonins from binding or targeting the bacterium for destruction (23). S. aureus deploys a number of strategies to resist neutrophil killing.
First, it secretes two molecules, Chemotaxis Inhibitory Protein and Extracellular adherence protein, which respectively block neutrophil recognition of chemotactic factors and neutrophil binding to endothelial adhesion molecule ICAM-1 (24,25).
Inhibition of ICAM-1 binding prevents leukocyte adhesion, diapedesis, and extravasation from the bloodstream to the site of infection.
10
Upon arriving at the infection site, neutrophils secrete antimicrobial substances, including antimicrobial peptides, reactive oxygen species (ROS), reactive nitrogen species (RNS), proteases, and lysozyme. S. aureus defence against ROS is mediated by deployment of a large number of antioxidant enzymes (e.g. catalase, pigment, superoxide dismutase) that neutralize ROS and RNS (23). Antimicrobial peptides are destroyed by staphylokinase (26).
Staphylococcus aureus is known to infect humans repeatedly throughout life. The mechanism underlying evasion of adaptive immune response is poorly understood, however studies have shown that staphylococcal enterotoxins and TSST1 could all alter
T cell functions by targeting the T cell receptor activation pathway(27,28). This has been construed as a tactic devised by S. aureus to prevent development of long term memory. Protein A is said to deplete splenic marginal zone B cells which may result in poor generation of specific B cell response(29). These mechanisms, could be important underlying reasons why we remain susceptible to S. aureus infections throughout our lives.
2.41 INVASIVE STAPHYLOCOCCUS AUREUS INFECTIONS
The spectrum of clinical presentation is wide. Fever is a less common presentation even in bacteraemic patients (30). The most common diagnosis, irrespective of primary or secondary focus were soft tissue infections, infection of I.V line, primary bacteraemia and joint/bone infection(5,19).
Staphylococcus aureus is a common cause of skin and soft tissue infections (SSTIs) in
Nigeria(7,8). Patients present with boils, abscesses, cellulitis, wound infection and post-surgical wound infections. Skin and soft tissue infections caused by CA-MRSA are common in the tropics and predisposing factors include poor hygiene, overcrowding, scabies. Treatment options include oral Sulfamethoxazole/Trimethoprin and
11 clindamycin for patients with uncomplicated infection, however for patients with complicated infection requiring admission and intravenous therapy, vancomycin is the drug of choice. Linezolid, tigecycline and daptomycin may also be used. Other therapeutic options for the treatment of uncomplicated CA-MRSA include dalbavancin, telavancin and ceftobiprole (31,32). Studies in Nigeria reported Staphylococcus aureus as the commonest isolate in wound infections (33–35). Surgical drainage is crucial for the cure of soft tissue abscesses. SSTIs due to CA-MRSA predominantly affect children, healthy young adults, middle-aged adults (36).
The recent increase in staphylococcal infections caused by MRSA has ultimately resulted in increase in the incidence of pneumonia caused by both CA-MRSA and HA-MRSA. This combined with frequent, prolonged ventilatory support of an aging, often chronically ill population, has resulted in a large increase in cases of MRSA pneumonia in the health care setting.
CA-MRSA pneumonia historically affects younger patients, follows infection with influenza virus, and is often severe, requiring hospitalization and causing the death of a significant proportion of those affected (37). In a study Rubinstein et al found
Staphylococcus aureus as a major pathogen in all pneumonias with higher rates in non-community acquired pneumonias (38). Fiberesima et al. in Port-Harcourt (39) reported the prevalence of Staphylococcus aureus pneumonia as 7.7% while Udeani et al(40) reported Staphylococcus aureus as the leading cause of pneumonia in patients with
Tuberculosis and HIV infection. Cases of Staphylococcus aureus pneumonia carrying the PVL toxin cause necrotising pneumonia and has worse prognosis (41). Patients with
Hospital Acquired Pneumonia are often infected with HA-MRSA. These patients are frequently elderly and have significant underlying diseases while CA-MRSA pneumonia is a disease of the young usually preceding influenza or influenza-like
12 illness in up to 75% of cases (38). The clinical presentation of Staphylococcus aureus pneumonia include fever, cough, difficulty in breathing, haemoptysis. CA-MRSA pneumonia is more often associated with hypotension, severe respiratory symptoms and chest x-ray showing multilobar cavitating alveolar infiltrates (38). Vancomycin is the mainstay for treatment of MRSA pneumonia. Other antibiotics for the treatment of
MRSA pneumonia include linezolid, teicoplanin and quinupristin/dalfopristin (42).
Staphylococcus aureus bacteraemia is an important cause of morbidity and mortality.
Mortality is higher in tropical settings than in temperate industrialised countries due to delays in the diagnosis of MRSA infection and delays in receiving effective antibiotic therapy for MRSA(12). Mortality is also higher in MRSA bacteraemia compared with
MSSA bacteraemia(16,43). Increased mortality was significantly associated with older age, European ethnicity, MRSA infection, infections not originating from a medical device, sepsis syndrome, pneumonia/empyema (9,12,43). Infection sources included 14
(18.4%) vascular catheter associated, 16 (21.1%) wound related, seven (9.2%) endocarditis, five (6.6%) intravascular, and 19 (25%) with unknown source (44).
Septic arthritis is a disabling disease that requires early diagnosis and prompt management for optimal outcome. Knee is the most commonly affected joint(45). In a study Eyichukwu et al found Staphylococcus aureus as the commonest organism implicated and 27.2% of the patients studied developed complications (46) most of which were flexion deformities. The most frequent predisposing factor was a pre-existing rheumatologic condition(47), other predisposing conditions are old age, diabetes mellitus, skin infection, hip/knee prosthesis and joint surgery(48). The treatment of choice is Flucloxacillin for MSSA and vancomycin for MRSA.
Ciprofloxacin and rifampicin combination may be used in patients with infected prosthetic joint infection device.
13 Meningitis caused by Staphylococcus aureus is not common in Nigeria(49). However,
S. aureus meningitis can occur following neurosurgical procedures and haematogenous spread from primary foci. Staphylococcus aureus haematogenous meningitis has devastating clinical consequences and elevated mortality rates, especially if it is acquired in the community(50). Postoperative and spontaneous S. aureus meningitis are two different clinical syndromes. Postoperative meningitis usually appears as hospital-acquired infection in young people, and most cases are associated with cerebrospinal fluid shunt devices. On the other hand, hematogenous meningitis is a community-acquired infection associated with a variety of clinical sources (i.e., primary bacteremia, infective endocarditis, osteomyelitis) that mainly affects older patients with severe underlying conditions(51,52). In a clinical study of 44 cases of Staphylococcus aureus meningitis(51), it is found to be the fifth most common cause of bacterial meningitis.
There were 63% post-operative and 27% spontaneous cases. Overall mortality was
27%, and the mortality rate was higher for cases of spontaneous than postoperative meningitis. Mortality correlated significantly in patients with advanced age, spontaneous meningitis, altered mental status, and in patients with severe underlying diseases, bacteremia, and septic shock (95). In another study,
Staphylococcus aureus was the fifth most common cause of meningitis, only 44 cases were seen over a 20 year period(51). The clinical manifestation of Staphylococcus aureus meningitis includes fever, altered mental status, meningeal signs, petechial rashes and septic shock(50–53). Diagnosis is by culture of cerebrospinal fluid. Gram staining was positive in 40% of cases only(52). Although the mainstay for the treatment of MRSA meningitis is vancomycin, Teicoplanin and Daptomycin were used successfully(54,55).
14
Intravascular catheters are indispensable tools in acute care, but with the benefits come the risk of local or systemic Health care associated infections. Intravenous catheter is the most common cause of Staphylococcus aureus bacteraemia(56,57) and majority of intravenous catheter infection by Staphylococcus aureus is caused by MRSA(58). Mortality rate due to bloodstream infection related to the use of intravascular catheter in the united states is 12-15%(59). Central line infection is not usually accompanied by local signs of infection and usually presents with unexplained fever in the ICU(60).
Therefore, it is a diagnosis of exclusion. Empiric antibiotic therapy directed against gram-positive cocci and aerobic gram-negative bacilli is usually started after blood cultures have been obtained and the removed catheter tip sent for culture.
In spite of better diagnosis and treatment of ISA infection, the mortality is high
(61,62)and the presence of pre-existing cardiac, renal or lung disease was significantly associated with all-cause mortality and pre-existing cardiac and renal disease with attributable mortality. The overall mortality is higher in bacteraemic patients compared to non-bacteraemic patients(63).
2.5 RISK FACTORS FOR INVASIVE STAPHYLOCOCCUS AUREUS
INFECTION
The risk factors for invasive Staphylococcus aureus infection include diabetes, alcohol abuse, admission to hospital or Intensive Care Unit(ICU), nasal colonisation by
Staphylococcus aureus, immunosuppression, I.V drug abuse, haemodialysis, old age, newborn, male or the presence of foreign body(64). Those at highest risk are haemodialysis patients, peritoneal dialysis, HIV infection and solid organ transplant recipients(9, 51). In a study of Staphylococcus aureus bacteraemia in hospitalized patients with HIV, long term indwelling catheters were the most common predisposing factor for Staphylococcus aureus bacteraemia (65).
15
2.6 LABORATORY DIAGNOSIS
Staphylococcal infections are diagnosed by gram staining and microscopic examination of relevant clinical specimen. Culture of infected material usually yields positive results.
Blood cultures are usually positive in conditions such as acute staphylococcal arthritis, osteomyelitis, and endocarditis but less often in localized infection such as deep abscesses. Nucleic acid amplification tests provide rapid diagnosis and are increasingly used in clinical microbiology laboratories.
Commercial kits for the rapid detection of clumping factor and protein A based on latex agglutination are widely available.
2.7 ANTIBIOTIC RESISTANCE
Penicillins and cephalosporins are active against Staphylococcus aureus cell wall peptidoglycan and vary in their susceptibility to inactivation by B-lactamases. Although penicillin G is the drug of choice for susceptible strains, the penicillanase resistant
Penicillins (methicillin, nafcillin, and oxacillin) and first generation cephalosporins are more commonly used because of resistance.
Staphylococcus aureus strains were highly susceptible to Penicillins when the drug was introduced following World War II, but now 80-90% of isolates are penicillin resistant.
Resistance to penicillin is mediated by a plasmid encoded B-lactamase which hydrolyses the B-lactam ring of the drug. Resistance to methicillin is mediated by the acquisition of mecA gene which is part of a large mobile genetic element—a pathogenicity or genomic island—called SCCmec that encodes a protein binding protein for which methicillin and related antibiotics lack affinity. To date, five
SCCmecs have been identified. Type 4 and type 5 SCCmecs have been associated with community-acquired MRSA strains. The prevalence of MRSA in Nigeria ranges from
16
11-43%(6,7,8,17). Initially, MRSA were limited to hospitals but recently MRSA outbreaks have been reported in the community. Interestingly, the community-associated MRSA strains appear to be clonally related, but unrelated to hospital
MRSA(66,67).
The carbapenem imipenem has excellent activity against methicillin-sensitive S. aureus
(MSSA), but not MRSA. Many MRSA isolates are also resistant to other antimicrobial families, including aminoglycosides, quinolones, and macrolides.Ghebremedhin B, et al in Nigeria, reported the susceptibility of the CA-MRSA strains to antibiotics to be
3% for septrin and 100% for ciprofloxacin, erythromycin, fusidic acid, gentamicin, rifampin, tetracyclin, teicoplanin, linezolid, and vancomycin(17). In another study, all MSSA isolates were susceptible to clindamycin and moxifloxacin and less than 4% were resistant to erythromycin, 21.1% to ciprofloxacin, 47% to tetracycline, 68% to
Sulfamethoxazole/Trimethoprin, and 86% to penicillin(18). High rates of resistance of
Staphylococcus aureus to Sulfamethoxazole/Trimethoprin and tetracycline 77% and
55% respectively has also been reported by Shittu et al(18).Vancomycin remains the drug of choice for the treatment of MRSA infections.
2.8 PREVENTION
The use of topical agents (e.g., mupirocin) to eliminate staphylococcal colonization in high-risk groups, such as patients undergoing hemodialysis or surgery or patients in
ICU, has been shown to reduce the incidence of subsequent infections(68,69).
Improved Hand hygiene and chlorhexidine bath reduce acquisition of MRSA in
ICU(70)
It is generally believed that antibody response toward Staphylococcus aureus is not protective. An individual could suffer from repeated infections in spite of demonstrable
17 antibody levels. There is no vaccine available and immunoprophylaxis has not been successful.
At present, prevention of the spread of infection relies on the application of appropriate principles of infection control. These approaches have been effective in reducing the nosocomial spread of staphylococcal infection(71)
18
CHAPTER THREE
3.0 METHODOLOGY
3.1 BACKGROUND OF THE STUDY AREA
The study was conducted at Aminu Kano Teaching Hospital, Kano, Nigeria. The hospital was established in 1988, is situated in the North Western geopolitical zone of
Nigeria. The hospital serves as a referral centre for Kano state and the neighboring states of Jigawa, Katsina, Zamfara, Bauchi, Gombe, and Yobe. It receives patients even from the neighboring countries like Niger republic. The Hospital has a bed capacit y of five hundred (500). It has 14 clinical departments including Medicine, Surgery,
Pediatrics, Obstetrics and Gynecology with full support of well-equipped laboratories.
The study was carried out in the Medical wards, surgical wards, Dialysis centre, ICU and Medical and Surgical outpatient departments. These departments manage adult patients with various infections ranging from skin and soft tissue infection, meningitis, pneumonia, bacteraemia etc. Patients managed in dialysis centre and ICU often have central venous line inserted and are more at risk of ISA. The prevalence of MRSA infection is higher among patients in ICU and patients with indwelling venous catheters
3.2 STUDY DESIGN
The study is a prospective study among patients with Invasive Staphylococcus aureus infection in Aminu Kano Teaching Hospital.
19
3.3 STUDY POPULATION
Adult patients presenting to Aminu Kano Teaching Hospital with skin and soft tissue infections, pneumonia, septic arthritis, bacteraemia and meningitis, proven to be related to Staphylococcus aureus infection.
3.3.1 INCLUSION CRITERIA
All adult patients admitted into medical wards, surgical wards, dialysis centre, ICU or seen at medical or surgical outpatient departments of Aminu Kano Teaching Hospital with features compatible with case definitions for Invasive Staphylococcus aureus infection. They have to be currently active patients with microbiologically confirmed
ISA infection as defined on page 22.
3.3.2 EXCLUSION CRITERIA
Patients less than 18 years of age were excluded
Patients who do not give informed consent for the study.
Patients with mixed bacterial infection
20
3.4 SAMPLE SIZE
The sample size was determined using the formula for single proportion - -πo)]}
2
(π-πo)
2
N= required minimum sample size
π = proportion of Staphylococcus aureus bacteraemia 10.3%(72)
πo = null hypothesis proportion is assumed to be 20.8%(73) u = power and at 90% it equals = 1.28 v = standard normal deviation at 5% confidence limit 1.96
- -0.21)]}
2
(0.10-0.21)
2
= 139
Sample size will be approximated to 140
3.5 SAMPLING METHOD
All patients that fulfil the inclusion criteria were recruited consecutively until the required sample size was obtained.
3.6 INSTRUMENTS OF DATA COLLECTION
Data was collected using the pre-tested interviewer administered questionnaire. The questionnaire has three sections;
1. Section on personal data of the respondents.
2. Section on clinical details and outcome
3. Section on laboratory data
21
3.7 STUDY PROTOCOL
3.7.1 STUDY PATIENTS AND SOURCE OF DATA
The study was conducted in medical wards, surgical wards, dialysis, ICU and medical and surgical out patient’s clinic of Aminu Kano Teaching Hospital. Each consecutive patient that met the inclusion criteria was recruited. Wound swabs were obtained from all patients with ulcers and post-surgical wound infection for culture. Pus aspirate was taken for culture in patients presenting with abscesses and intravenous catheter tips were taken for culture in patients with features of phlebitis. Sample for blood culture was taken for all patients with features of sepsis as defined by fulfillment of two out of the following tarchycardia, systolic BP < 90 mmHg or diastolic BP < 60mmHg,
Respiratory rate >25, Temperature <36
0
C or >38
0
C and White blood cell count of < 4 x 10
9 or > 12 x 10
9
. Sample for blood cultures were also taken for all patients with features of Septic arthritis and Pneumonia. Echocardiography was done for all patients with bacteraemia to rule out Infective endocarditis. Lumber puncture was done on patients with features of meningitis and CSF sample transported to the laboratory in a sterile container. Those with evidence of raised intracranial pressure, bleeding dyscrasia, and skin infection in the areas of the back used in lumber puncture will be excluded. A sputum specimen was collected in a clean sterile container from patients with clinical evidence of Pneumonia. All samples were transported to the laboratory immediately. An informed consent was obtained before taking blood samples, joint aspirates, pus aspirates and before lumbar puncture. Medical history was obtained and detailed examinations were conducted on each patient. Isolates of Staphylococcus aureus obtained from various clinical samples were processed by the investigator with help of a qualified medical laboratory scientist at the Medical Microbiology Department of Aminu Kano Teaching Hospital (AKTH). 22
All patients with Positive Culture for Staphylococcus aureus from a clinical specimen example blood, catheter tip, pus aspirate, cerebrospinal fluid, sputum, wound swab were recruited consecutively. A standardized questionnaire including personal data, clinical information, and laboratory details was completed prospectively for each patient by the investigator (Appendix 1). Final outcome was determined 30 days after the diagnosis. Data on mortality and morbidity was obtained by following the patients during hospitalization and follow-up at home through contact phone number after discharge where available.
3.7.2 DEFINITIONS
ISA was defined as isolation of S. aureus from an otherwise sterile site.
Bacteraemia was defined as the presence of at least one positive blood culture for
Staphylococcus aureus.
Invasive Staphylococcus aureus Pneumonia was defined based on the clinical findings plus a chest radiograph consistent with Pneumonia in addition to Gram positive cocci in clusters on microscopy and/or positive culture of Staphylococcus aureus from an ideal sputum specimen or Pleural aspirate. Ideal sputum sample for culture must have
>25 neutrophils and <10 squamous epithelial cells per low-power field.
Meningitis was defined based on clinical features and isolation of Staphylococcus aureus from CSF ± CSF pleocytosis (>5 white blood cells), CSF glucose < 2/3 of blood glucose and CSF protein >1.5g/l.
Skin and soft tissue infection was defined by clinical features of abscesses, wounds, ulcers, cellulitis and necrotizing fasciitis, Pyomyositis and isolation of S. aureus from wound swab or pus aspirate.
23
Line associated infection was defined as infection of either a central or peripheral line based on symptoms and signs and isolation of staphylococcus aureus from the catheter tip specimen.
The definition of Staphylococcus aureus infective endocarditis was based on Modified Duke’s Criteria which defined infective endocarditis as follows:
Definite infective endocarditis: endocarditis is definitely present if any one of the following pathological findings or combination of clinical findings is present.
1. Direct evidence of endocarditis based upon histological findings
2. Positive gram stain results or cultures of specimens obtained from surgery or autopsy
3. Two major clinical criteria
4. One major and any three minor clinical criteria
5. Five minor clinical criteria
Possible endocarditis is defined as the presence of one major and one or two minor clinical criteria or the presence of three minor clinical criteria.
Sepsis was defined as patients with two or more of the following features of SIRS
(Systemic Inflammatory Response Syndrome) due to documented Staphylococcus aureus infection; tarchycardia, systolic BP < 90 mmHg or diastolic BP < 60mmHg,
Respiratory rate >25, Temperature <36
0
C or >38
0
C and White blood cell count of < 4 x 10
9 or > 12 x 10
9.
Hypotension was defined as systolic blood pressure <90mmHg and diastolic blood pressure <60mmHg.
Primary bacteraemia was defined as bacteraemia with no known focus of infection while secondary bacteraemia was defined as bacteraemia with known primary focus of infection.
24 Community-acquired MRSA infection was defined as all infections occurring among outpatients or among inpatients with an MRSA isolate obtained earlier than 48 h after hospitalization.
Hospital acquired MRSA infection will be defined as onset of infection after 48 hours of admission. A diagnosis was assigned on the basis of clinical, radiological and microbiological information.
Outcome was defined as (i) cure- as resolution of clinical signs and symptoms and after completion of antibiotic treatment; (ii) death attributable to S. aureus- when ISA infection is the major contributing cause of death; (iii) recurrence was defined as recurrence of infection based on clinical signs and symptoms and isolation of staphylococcus aureus from a clinical sample after resolution of signs and symptoms for a particular type of ISA infection.
3.7.3 MICROBIOLOGICAL ANALYSIS
All Specimens were collected in a sterile container and transported immediately to the
Laboratory. Specimens were inoculated on Blood agar and manitol salt agar plates and incubated at 37
0
C for 24hrs. Characteristic Staphylococcus aureus colonies were identified by gram stain, catalase and coagulase testing according to standard bacteriological procedures.
A suspension of each confirmed Staphylococcus aureus isolates was prepared in peptone water to match 0.5 Mcfarland turbidity standards. Staphylococcus aureus
ATCC 25923 was used as control strain.
All confirmed Staphylococcus aureus isolates were screened for methicillin resistance by inoculation of Mueller Hinton agar supplemented with 4% NaCl. The 30ug cefoxitin discs (oxoid, USA) was aseptically placed on the surface of the inoculated plates and incubated aerobically at 35
0
C for 24hrs. The isolates were similarly inoculated onto the 25 surfaces of plain Mueller-Hinton agar plates and Cloxacillin (1ug), Erythromycin
(15ug), Cotrimoxazole (25ug), Tetracycline (30ug), Ciprofloxacin (10ug), amoxyclav
(10ug), cephalexin (10ug), gentamicin (10ug), Ceftriazone (30ug) and clindamycin
(2ug) discs were placed and incubated at 37
0
C for 24hrs.
Antibiotic susceptibility tests were carried out by disc diffusion method according to
Clinical and Laboratory Standard Institute (CLSI) guidelines for Drug susceptibility testing (DST) against S. aureus. At least one antibiotic was used for DST from the following groups of antibiotics recommended in the CLSI guidelines: Penicillins,
Aminoglycosides, Macrolides, Tetracyclines, Fluoroquinolones, Lincosamides,
Cephalosporins and Folate pathway inhibitors. Vancomycin was not tested because disc test does not differentiate vancomycin-susceptible isolates of S. aureus from vancomycin intermediate isolates. Commonly used antibiotics were selected from each group. The Zones of inhibition were measured and compared with clinical laboratory standards (CLSI) guidelines(74). Isolates that are resistant to Cefoxitin(≤21 mm) will be termed Methicillin resistant Staphylococcus aureus (MRSA) while those with zone of inhibition as (≥22 mm) were termed Methicillin Susceptible Staphylococcus aureus
(MSSA)(74).
3.7.4 DATA COLLECTION
The following clinical data on patients with bacteriologically proven Invasive
Staphylococcus aureus Infection (ISA) were collected and analyzed: demographic data, clinical presentation, organ dysfunction, co morbidities, risk factors, antibiotic susceptibility result, other laboratory results (FBC, Chest X Ray, Electrolytes, LFT) and outcome.
26
3.8 DATA ANALYSIS
Analysis was carried out using descriptive statistics with differences and relationships determined using Chi squared and Fisher’s exact tests as appropriate, with p ≤ 0.05 regarded as significant.
Determinants and predictors of mortality were explored using univariate and multivariable analysis with unadjusted (crude) odds ratio (OR) and logistic regression adjusted OR estimates respectively. Statistical Package for Social Sciences version 21.0 was used for data analysis.
3.9 ETHICAL CONSIDERATION
1. Ethical clearance was obtained from the ethical committee of Aminu Kano
Teaching Hospital before the commencement of the study.
2. The provision of the HELSINKI declaration shall be respected.
3. Informed consent was sought and obtained from each subject.
4. All data collected from participants were kept confidential.
5. Participants were adequately informed in a language they adequately understand.
6. The study was not in any way be used to the detriment of the patient.
Participation in the study is voluntary and the participant has liberty to refuse to participate in the study without any negative consequences.
3.10 LIMITATIONS OF THE STUDY
1 Lack of molecular diagnosis for MRSA.
2 Ideal sputum sample cultures were used to define Staphylococcus aureus
Pneumonia instead of lung biopsy
3 Wound swab cultures were used to define infected ulcers instead of wound biopsy
27
CHAPTER FOUR
4.0 RESULTS
During the study period from 2 nd
November 2014 to 15 th
April 2015, 140 adult patients with ISA infection were recruited out of 34867 patients seen at medical outpatient department, surgical outpatient department and medical and surgical wards of Aminu Kano Teaching
Hospital, Kano. There were 157 episodes of ISA infection among the patients studied. The periodic prevalence of ISA infection among adults seen at Aminu Kano Teaching Hospital during the study period was 40 cases per 10,000 patients seen.
28
4.1 PATIENT CHARACTERISTICS
4.1.1 AGE AND SEX DISTRIBUTION
The ages of the patients ranged from 18-85 years with a mean age of 40.74 (standard deviation
15.60). There were 82 (58.6%) males and 58 (41.4%) female with a male to female ratio of
1.41. The age group most affected is 25-34 years.
29
FIGURE 1: AGE (IN YEARS) AND SEX DISTRIBUTION OF PATIENTS
0
5
10
15
20
25
30
≤ 24 25-34 35-44 45-54 55-64 ≥ 65
8
27
14
19
8
6
7
18 13
9
3
8
Male Female
30
4.2 PATTERN OF PRESENTATION
Out of 140 patients 79 (56.4%) were inpatients. There were 157 episode of ISA infection (Table
1). Seventeen patients had secondary bacteraemia; out of which 9 had line associated infection,
1 had endocarditis, 1 had meningitis, 2 had pneumonia, 3 had SSTIs and 1 had both pneumonia and SSTIs. The number of patients with community acquired infections were 94/140 (67.1%).
Patients with bacteraemia and line associated infection were more likely to present with
Hospital acquired infections than Community acquired infections (p = 0.001), while patients with SSTIs were more likely to present with Community acquired infection than Hospital acquired infection (p = 0.001) (Table 1).
31
TABLE 1: DIAGNOSES IN 140 PATIENTS WITH INVASIVE STAPHYLOCOCCUS
AUREUS INFECTION
*Statistically significant P value ≤ 0.05 using Chi-Square test
+
: Central catheter infection 7(46.7%); Cannula infection 8(53.3%)
**: 17 patients with bacteraemia had more than one ISA infection
Diagnosis N (%) Mean Age Community
Acquired
Infection
Hospital
Acquired
Infection p value Pneumonia 15 (10.7%) 34.47 13 (86.7%) 2 (13.3%) 0.144
Meningitis 1 (0.7%) Not applicable
0 (0.0%) 1 (100.0%) 0.329
**Bacteraemia 17 (12.1%) 39.47 3 (17.6%) 14 (82.4%) 0.001*
+
Line associated infections
15 (10.7%) 39.13 0 (0.0%) 15 (100.0%) 0.001*
Infective
Endocarditis
1 (0.7%) Not applicable
0 (0.0%) 1 (100.0%) 0.329
SSTIs 108 (77.1%) 41.36 81 (75.0%) 27 (25.0%) 0.001*
Sum 157
32
4.2.1 CLINICAL FEATURES
Fifty-three (49.1%) of the patients with skin and soft tissue infection were admitted while 10
(66.7%) and 14 (93.3%) patients with Pneumonia and intravascular catheter infection respectively were also admitted. All patients with bacteraemia, meningitis and endocarditis were admitted. The mean duration of symptoms was 8.8 ± 5.8 days, with a range of 2-40 days.
Fever was present in 59 (42.1%) patients and 51 (36.4%) had sepsis.
33
TABLE 2: DISTRIBUTION OF CLINICAL FEATURES OF PATIENTS WITH ISA
INFECTION
CLINICAL
FINDINGS n (%) ISA INFECTIONS
Pneumonia
(n=15)
Skin and
Soft
Tissue
Infections
(n=108)
Meningitis
(n=1)
Bacteremia
(n=17)
Line associated infection
(n=15)
Endocarditis
(n=1)
Fever 13 (86.7%) 30 (27.8%) 1 (100%) 17 (100%) 14 (93.3%) 1 (100%)
Tachycardia 11 (73.3%) 20 (18.5%) 1 (100%) 17 (100%) 12(80.0%) 1 (100%)
Hypotension 1 (6.7%) 2 (1.9%) 0 (0.0%) 5 (29.4%) 3 (20.0%) 0 (0.0%)
Hepatomegaly 0 (0.0%) 0 (0.0%) 0 (0.0%) 6 (35.3%) 7 (46.7%) 1 (100%)
Splenomegaly 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (11.8%) 5 (33.3%) 0 (0.0%)
Sepsis 6 (40.0%) 30 (27.8%) 1 (100%) 15 (88.2%) 13 (86.7%) 1 (100%)
Altered level of consciousnes s
1 (6.7%) 0 (0.0%) 1 (100%) 4 (23.5%) 3 (20.0%) 0 (0.0%) Duration of
Symptoms
(Mean ± SD)
6.2 ± 4.3 9.5 ± 6.0 19.00 8.1 ± 4.2 6.3 ± 3.3 5.00
34
4.3 AGE GROUP BY ISA INFECTION
Skin and soft tissue infection (SSTIs) and Pneumonia were the commonest forms ISA infection in the young and middle aged patients while Bacteraemia is commoner among age groups 15 -24 years 5 (33.3%) and ≥ 65 years 4 (28.6%) (Table 3). Among patients with SSTIs, the age group most commonly affected was 25-34 years 39 (36.1%), p value 0.041. The age group most commonly affected among patients with bacteraemia was 18-24 years 5 (33.3%), p value
0.034.
35
TABLE 3: AGE GROUP BY ISA INFECTION
Age group
SSTIs
N=108
Pneumonia
N=15
Bacteraemia
N=17
Line associated infection
N=15
Infective endocarditis
N=1
Meningitis N=1
≤ 24 7 (6.5%) 4 (26.7%) 5 (33.3%) 3 (20.0%) 1 (100%) 0 (0.0%)
25-34 39 (36.1%) 5 (33.3%) 4 (23.5%) 2 (13.3%) 0 (0.0%) 0 (0.0%)
35-44 20 (18.5%) 3 (20.0%) 2 (11.8%) 4 (26.7%) 0 (0.0%) 0 (0.0%)
45-54 24 (22.2%) 1 (6.7%) 2 (11.8%) 3 (20.0%) 0 (0.0%) 0 (0.0%)
55-64 7 (6.5%) 1 (6.7%) 0 (0.0%) 3 (20.0%) 0 (0.0%) 0 (0.0%)
≥ 65 11 (10.2%) 1 (6.7%) 4 (23.5%) 0 (0.0%) 0 (0.0%) 1 (100%)
P value 0.041* 0.395 0.034* 0.096 0.476 0.457
*Statistically significant (i.e p value ≤ 0.05) using Chi-Square test
36
4.4 RISK FACTORS
The patients studied have one or more recognized risk factors for ISA infection. Only 56 patients consented to HIV screening, out of which 7 were positive. In patients with (SSTIs) 5
(4.6%) had HIV infection, 31 (28.7%) had diabetes mellitus and 1 (0.9%) was on steroids. The patient with Meningitis had a foreign body (shunt), intravenous (IV) canulation and was admitted in ICU. Among patients with bacteraemia 13 (76.5%) had IV canulation, 4 (23.5%) had diabetes mellitus, 7 (41.2%) had CKD, 5 (29.4%) were in ICU. HIV and ICU admission account for 2 (13.3%) each of patients with pneumonia. Eleven patients with CKD 11/16
(68.6%) were on haemodialysis out of which 8/11 (72.7%) had central line infection.
37
TABLE 4: DISTRIBUTION OF RISK FACTORS AT PRESENTATION
RISK
FACTORS
ISA INFECTION
Pneumonia n=15
Skin and
Soft
Tissue Infections n=108
Meningitis n=1
Bacteremia n=17
Line associated infections n=15
Endocarditis n=1
HIV Infection 2 (13.3%) 5 (4.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Malignancy 1 (6.7%) 5 (4.6%) 0 (0.0%) 2 (11.8%) 1 (6.7%) 0 (0.0%)
CLD 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (13.3%) 0 (0.0%)
HHD 1 (6.7%) 4 (3.7%) 0 (0.0%) 6 (35.3%) 7 (46.7%) 0 (0.0%)
Diabetes
Mellitus
0 (0.0%) 31 (28.7%) 0 (0.0%) 4 (23.5%) 5 (33.3%) 0 (0.0%)
Intravenous cannulation
0 (0.0%) 0 (0.0%) 0 (0.0%) 13 (76.5%) 12 (80.0%) 0 (0.0%)
CKD 0 (0.0%) 0 (0.0%) 0 (0.0%) 7 (41.2%) 8 (53.3%) 1 (100%)
Foreign body 0 (0.0%) 0 (0.0%) 1 (100%) 1 (5.9%) 0 (0.0%) 0 (0.0%)
ICU 2 (13.3%) 1 (0.9%) 1 (100%) 5 (29.4%) 2 (13.3%) 0 (0.0%)
Steroids 0 (0.0%) 1 (0.9%) 0 (0.0%) 2 (11.8%) 1 (6.7%) 0 (0.0%)
Dialysis 0 (0.0%) 3 (2.8%) 0 (0.0%) 6 (35.3%) 8 (53.3%) 0 (0.0%)
38
4.5 ANTIBIOTIC SUSCEPTIBILITY PATTERN OF THE ISOLATES Eighty-two (52.2%) of the Staphylococcus aureus isolates were MSSA and 75 (47.8%) were
MRSA (Table 5). Cases of CA-MRSA were 31/94 (32.9%) of community acquired infections while cases with HA-MRSA were 32/46 (69.6%) of hospital acquired infections.
Resistance to antibiotics among isolates was as follows: Cloxacillin 123/157 (78.3%),
Amoxicillin/clavulanate 101/157 (64.3%), cephalexin 93/157 (59.2%), Ceftriazone 93/157
(59.2%), cotrimoxazole 110/157 (70.1%), tetracycline 48/157 (30.6%), clindamycin 53/157
(33.8%), erythromycin 49/157 (31.2%), ciprofloxacin 47/157 (29.9%), gentamicin 66/157
(42.0%) (Table 6).
In patients with pneumonia 8 (53.3%) isolates were MRSA. The number of MRSA isolates from SSTIs were 46 (42.6%) while MRSA isolates from line associated infections were 7
(46.7%). Both isolates from meningitis and endocarditis were MRSA (Table 5).
MRSA isolates were more susceptible tetracycline (64%) and ciprofloxacin (64%) (Table 6).
While MSSA isolates were more susceptible to macrolides (erythromycin and clindamycin) and cephalosporins (Ceftriazone and cephalexin) (Table 6).
39
Table 5: ANTIBIOTIC RESISTANCE OF STAPHYLOCOCCUS AUREUS
ISOLATES BY ISA INFECTION .
MRSA MSSA TOTAL P value
Pneumonia 8 (53.3%) 7 (46.7%) 15 0.787
Bacteraemia 12 (70.6%) 5 (29.4%) 17 0.070
Meningitis 1 (100%) 0 (0.0%) 1 0.477
Endocarditis 1 (100%) 0 (0.0%) 1 0.477
Line associated infection
7 (46.7%) 8 (53.3%) 15 1.000
SSTIs 46 (42.6%) 62 (57.4%) 108 0.059
TOTAL 75 82 157
Statistically significant P value ≤ 0.05 40
TABLE 6: RESISTANT PROFILE OF MSSA AND MRSA AGAINST OTHER
ANTIBIOTICS
Antibiotics
Number of
MRSA
Isolates n= 75
Number of
MSSA
Isolates n= 82
Total
P value
Amoxycillin/clavulanate 75 (74.3%) 26 (25.7%) 101 *< 0.001
Cloxacillin 75 (61.0%) 48 (39.0%) 123 *< 0.001
Cotrimoxazole 63 (57.3%) 47 (42.7%) 110 *0.004
Erythromycin 31 (63.3%) 18 (36.7%) 49 *0.010
Clindamycin 35 (66.0%) 18 (34.0%) 53 *< 0.001
Ciprofloxacin 27 (57.4%) 20 (42.6%) 47 0.120
Ceftriazone 75 (80.6%) 18 (19.4%) 93 *< 0.001
Gentamicin 40 (60.6%) 26 (39.4%) 66 *0.009
Tetracycline 27 (56.3%) 21 (43.7%) 48 0.169
Cephalexin 75 (80.6%) 18 (19.4%) 93 *< 0.001
*Statistically significant P value ≤ 0.05 using Fischer exact test
41
4.6 LABORATORY RESULTS
Leucocytosis and neutrophilia was found in 6/15 (40%) of patients with Pneumonia. The commonest radiologic finding in pneumonia is consolidation seen in 11/15 (73.3%). Only 1/15
(6.7%) patient has cavitation. Leucocytosis was also the commonest finding in SSTIs, bacteraemia, meningitis and catheter infection. Echocardiography detected vegetation in one patient with bacteraemia. Many patients with bacteraemia and line associated infection have elevated urea and creatinine.
42
TABLE 7: LABORATORY RESULTS FINDINGS
LABORATORY
FINDINGS n (%)
DIAGNOSIS
Pneumonia n=15
Skin and
Soft
Tissue
Infections n=108
Meningitis n=1
Bacteremia n=17
Line associated
Infections n=15
Endocarditis n=1
Leucocytosis
Neutrophilia
6 (40.0%)
6 (40.0%)
28 (25.9%) 28 (25.9%)
1 (100%)
1 (100%)
15 (88.2%)
15 (88.2%)
12 (80.0%)
12 (80.0%)
1 (100%)
1 (100%)
Thrombocytosis 1 (6.7%) 2 (1.9%) 0 (0.0%) 2 (11.8%) 2 (13.3%) 0 (0.0%)
Thrombocytopenia 0 (0.0%) 1 (0.9%) 0 (0.0%) 1 (5.9%) 2 (13.3%) 0 (0.0%)
ALT elevated 0 (0.0%) 1 (0.9%) 0 (0.0%) 1 (5.9%) 0 (0.0%) 0 (0.0%)
AST elevated 0 (0.0%) 1 (0.9%) 0 (0.0%) 1 (5.9%) 0 (0.0%) 0 (0.0%)
Albumin low 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (5.9%) 2 (13.3%) 0 (0.0%)
Elevated Urea 0 (0.0%) 8 (7.4%) 0 (0.0%) 4 (23.5%) 8 (53.3%) 0 (0.0%)
Elevated
Creatinine
0 (0.0%) 8 (7.4%) 0 (0.0%) 4 (23.5%) 7 (46.7%) 0 (0.0%)
Vegetation on
Echo
0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (5.9%) 0 (0.0%) 1 (100%)
No vegetation on
Echo
0 (0.0%) 0 (0.0%) 0 (0.0%) 9 (52.9%) 0 (0.0%) 0 (0.0%)
Consolidation 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Effusion 5 (33.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Cavitation 1 (6.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
43
4.7 CLINICAL OUTCOME Out of 140 patients that participated in this study, 13 (9.3%) were lost to follow-up. The overall mortality was 25 (19.7%) at one month follow up for 127 patients.
Among patients with more than one form of ISA infection; 5/9 (55.5%) patients with line associated infection and bacteraemia died, 1/2 (50%) of patient with pneumonia and bacteraemia died while the other one was lost to follow up, 2/3 patients with SSTIs and bacteraemia died. The patient with SSTIs and pneumonia died. The differences in outcome for patients with SSTIs and those with more than one ISA infection is statistically significant (p =
< 0.001) (Table 8).
44
TABLE 8: CLINICAL OUTCOME AND DIAGNOSIS
ISA
INFECTION
OUTCOME
Cured Died Recurren ce
Amputa tion
Lost to follow up
Total
Pneumonia 9 (75%) 2 (16.7%) 0 (0.0%) 0 (0.0%) 1 (8.3%) 12
SSTIs 71 (67.6%) 8 (7.6%) 10 (9.5%) 5 (4.8%) 11 (10.4%) 105
Line associated infections
2 (33.3%) 4 (66.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 6
More than one
ISA infection
5 (29.4%) 11 (64.7%) 0 (0.0%) 0 (0.0%) 1 (5.9%) 17
Total 87 25 10 5 13 140 45
4.7.1 CLINICAL OUTCOME AND COMORBIDITIES
The commonest comorbidity among the patients is Diabetes Mellitus 36/140 (25.7%).
Mortality is highest in patients with CKD 9/25 (36.0%) and Diabetes mellitus 8/25 (32.0%).
Patients with Hospital Acquired infections account for 19/25 (76%) of the number of dead.
46
TABLE 9: CLINICAL OUTCOME AND COMORBIDITIES
COMORBIDITIES OUTCOME
DEAD ALIVE P value
HIV Infection 2 (28.6%) 5 (71.4%) 0.097
CKD 9 (60.0%) 6 (40.0%) *0.001
HHD 7 (58.3%) 5 (41.7%) *0.002
Diabetes mellitus 8 (22.2%) 28 (77.8%) 0.630
CLD 2 (100%) 0 (0.0%) *0.037
Malignancy 5 (62.5%) 3 (37.5%) *0.008
*Statistically significant p value ≤ 0.05 using Fisher exact test
47
4.7.2 MORTALITY AND ANTIBIOTIC RESISTANCE BY ISA
INFECTION
When outcome of patients was compared between MRSA and MSSA infections, the overall mortality was found to be higher in patients with MRSA infection p value 0.003 (OR 4.15,95%
CI:1.590-10.85) (Table 11). Mortality is as well higher in patients with Invasive MRSA infection for all the ISA infections, however only the differences in the outcome for bacteraemia is statistically significant (p value 0.013) (Table 10). The mortality rate for MRSA and MSSA was 18/57 (31.6%) and 7/70 (10%) respectively.
48
TABLE 10: MORTALITY AND ANTIBIOTIC RESISTANCE BY ISA INFECTION
ISA
INFECTION OUTCOME OR/95% CI P value
Dead Alive
SSTIs
MRSA 7/10 (70%) 34/87 (39.1%)
MSSA 3/10 (30%) 53/87 (60.9%) 3.637/0.8794-15.04 0.090
Pneumonia
MRSA 4/4 (100%) 3/9 (33.3%)
MSSA 0 (0.0%) 6/9 (66.7%) 16.71/0.6824-409.4 0.070
Bacteraemia
MRSA 10/11 (90.9%) 1/5 (20.0%)
MSSA 1/11 (0.09%) 4/5 (80.0%) 40.00/1.981-807.7 0.013
Line associated infections
MRSA 5/9 (55.6%) 2/6 (33.3%)
MSSA 4/9 (44.4%) 4/6 (66.7%) 2.50/0.29-21.41 0.608
* Statistically significant P value ≤0.05 using Fischer’s exact test
49
TABLE 11: MORTALITY AND ANTIBIOTIC RESISTANCE
OUTCOME OR/95% CI p value
Dead
N=25
Alive
N=102
MRSA 18 (72.0%) 39 (38.2%) 4.154/1.590-10.85 0.003*
MSSA 7 (28.0%) 63 (61.8%)
*Statistically significant P value ≤0.05 using Fisher exact test.
50
4.7.3 MORTALITY BY AGE GROUP The age groups with the highest mortality rate are 55-64 years (45.5%) and 65 years and above (28.6%).
51
FIGURE 2: MORTALITY BY AGE GROUP (IN YEARS)
80.0%
88.9%
77.8%
92.9%
54.5%
71.4%
20.0%
11.1%
22.2%
7.1%
45.5%
28.6%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
≤ 24 25-34 35-44 45-54 55-64 ≥ 65
Alive Dead 52
4.8 PREDICTORS OF MORTALITY
In a univariate analysis, all covariates that were significantly associated with mortality at 5% or lower, were entered into multiple logistic regression analysis where only sepsis and infection with MRSA were significant independent predictors of mortality after adjusting all other confounders and covariates.
53
TABLE 12: UNIVARIATE ANALYSIS TO DETERMINE THE PREDICTORS OF
MORTALITY IN PATIENTS WITH INVASIVE STAPHYLOCOCCUS AUREUS
INFECTION
VARIABLES COEFFICIENT p value OR 95% CI for OR
Lower Upper
Fever 2.036 <0.001* 7.657 2.648 22.142
Hypotension 2.957 0.010* 19.238 2.046 80.919
Tachycardia 1.775 <0.001* 5.903 2.286 15.240
Low GCS 22.883 0.999 97.778 0.165 2.864
Meningitis 22.650 0.999 68.657 7.546 20.352
Sepsis 2.358 <0.001* 10.571 3.618 30.886
Bacteremia 2.724 <0.001* 15.243 4.607 50.429
Pneumonia 0.677 0.296 1.968 0.553 7.005
Line associated infections
2.197 <0.001* 9.000 2.819 28.729
Skin and Soft
Tissue
Infections
-2.163 <0.001* 0.115 0.044 0.303
Infective Endocarditis
22.650 0.999 77.480 4.546 48.920
CKD 2.197 <0.001* 9.000 2.819 28.729
HHD 2.021 0.002* 7.544 2.55 26.413
DM 0.218 0.651 1.244 0.483 3.204
HIV 0.523 0.547 1.687 0.308 9.250
ICU 22.883 0.999 86.725 0.623 3.793
MRSA 1.424 0.004* 4.154 1.590 10.849
OR: Odds ratio of Mortality; CI: Confidence interval; *: Statistically significant (i.e p value ≤
0.05)
54
TABLE 13: MULTIVARIATE LOGISTIC REGRESSION ANALYSIS TO
DETERMINE THE PREDICTORS OF MORTALITY IN PATIENTS WITH
INVASIVE STAPHYLOCOCCUS AUREUS INFECTION
VARIABLES COEFFICIENT p value OR 95% CI for OR
Lower Upper
Fever 0.489 0.601 1.631 0.261 10.197
Hypotension 1.290 0.408 3.635 0.170 77.496
Bacteremia 0.649 0.463 1.914 0.338 10.844
Catheter infection -0.504 0.632 0.604 0.077 4.757
Sepsis 1.906 0.016* 6.723 1.431 31.585
Tachycardia -0.887 0.339 0.412 0.067 2.534
Skin and Soft tissue infections
-1.805 0.052 0.165 0.027 1.014
CKD 1.386 0.159 4.000 0.581 27.566
HHD 0.092 0.932 1.096 0.133 9.053
MRSA 1.709 0.010* 5.523 1.506 20.250
OR: Odds ratio of Mortality; CI: Confidence interval; *: Statistically significant (i.e p value ≤ 0.05) 55
CHAPTER FIVE
5.0 DISCUSSION
There is paucity of data on ISA infection in Nigeria. There are few studies on epidemiology of
ISA infection. Most of the studies are limited either by including only selected patients with
ISA or by failure to provide relevant clinical information.
This study has provided a comprehensive evaluation of the epidemiology, clinical and microbiologic profile, and outcome of patients with ISA infection as observed in a Teaching
Hospital in North-west Nigeria. It shows that ISA infection is an important cause of morbidity and mortality in Aminu Kano Teaching Hospital, Kano. It also shows high prevalence of
MRSA and Nosocomial infections.
The periodic prevalence of ISA infection among the patients studied is 40 per 10,000. There is paucity of local data on ISA infection. However Jacobsson et al (4) in Sweden reported annual incidence of 33.9 cases per 100,000 population.
In this study most of the clinical isolates were recovered from middle age group (45-64 years).
This differs from report by Bisi-johnson et al(72) in Ile-Ife where they recovered most isolates from age group (20-45 years). However, their study included children and isolates from both clinical samples and healthy carriers. The median age of the patients in this study was 38.0 years which is similar to findings by Nickerson et al (63) in Thailand where 39 years was reported as the median age. The lower prevalence among those aged 65 years and above compared to 45-64 years in this study may be explained by the low life expectancy in Nigeria with fewer people above 65 years.
The study found more males than females with ISA infection which is similar to findings of
Bisi-johson et al and Nickerson et al(12,72). However, the higher female to male ratio observed in patients more than 64 years is likely because women live longer than men this age group.
56
Skin and soft tissue infections, bacteraemia and pneumonia are the commonest forms of ISA infections(75). This is similar to findings in this study where SSTIs accounts for 108 (77.1%) cases, bacteraemia 17 (12.1%) and pneumonia 15 (10.7%). While SSTIs is a disease of the young(15) , Staphylococcal pneumonia is mainly a disease of the elderly, immunosuppressed and patients with chronic debilating illnesses (46,47,). This study found the age group 25-34 as the most commonly affected among patients with SSTIs. However, patients with pneumonia are younger with 12/15 (80%) within the age group 18-44 years. This is due to the high number of patients with CA-MRSA pneumonia 6/15 (40%) which is a disease of young healthy adults(77). Other risk factors for Staphylococcal pneumonia for this age group in this study include HIV infection accounting for 2/15 (13.3%) and Hypertensive heart disease accounting for 1/15 (6.7%). CA-MRSA pneumonia follows infection with influenza virus(38). In a study by Dalhatu et al, the peak period of influenza activity in Nigeria is between November and
March(78). This may account for the high number of patients with CA-MRSA pneumonia in this study since the study was carried out within this period. Patients with SSTIs are likely to have CA-MRSA, while patients with bacteraemia and intravascular catheter infection are likely to have HA-MRSA. This is similar to findings by Diekema et al(75). Staphylococcus aureus is among the most common significant blood culture isolate in hospitalized patients(79). This is similar to findings in this study where all the cases of bacteraemia were inpatients and 14/17
(82.4%) had hospital acquired infection. Consistent with the findings in other studies(2,59,81) the commonest identifiable foci for bacteraemia were intravascular catheter infection 9/17
(52.9%) and SSTIs 3/17 (17.6%). Though staphylococcus aureus bacteraemia is an independent risk factor and a leading cause of IE in many regions of the world (81), only one case of IE in patients with staphylococcal bacteraemia 1/17 (5.9%) was found in this study , probably due to low sensitivity of transthoracic echocardiography used in this study compared to transesophageal echocardiography(82) and probably due to low intravenous drug use in our
57 setting compared with United States and Europe where IV drug use is a common risk factor(83). Bacterial meningitis caused by staphylococcus aureus is not common(5) and neurosurgery is a risk factor in most patients(54). Only one patient had meningitis secondary to shunt infection in this study.
The clinical manifestations of ISA infection include those of the primary site of infection and fever which was found in all patients with bacteraemia, meningitis and IE and in 14 (93.3%) and 13 (86.7%) of patients with intravenous catheter infection and pneumonia respectively.
Only 30 (27.8%) of patients with SSTIs had fever. There were 51 (36.4%) episodes of sepsis in this study with highest incidence among patients with bacteraemia and intravenous catheter infection 15 (88.2%) and 13 (86.7%) respectively. Similar findings were noted by Jacobsson
(30).
The mean duration of symptoms was 8.8 days, it accounts for time lag between symptoms evolution and seeking medical attention.
Several conditions have been identified as risk factors for ISA infections, they include diabetes mellitus, HIV infection, cancer, intravenous drug use, foreign bodies and dialysis(1,5,12).
Patients at risk of ISA also have high rate of colonisation by Staphylococcus aureus (4,5). The commonest recognised risk factor in the patients studied was Diabetes Mellitus. This is a source of concern due to the fact that diabetes mellitus is associated with poor outcome in ISA infection(56). The high number of cases of central line infection and bacteraemia in patients undergoing haemodialysis in this study suggest high colonisation of these patients by the organism and probably poor implementation of infection control policies. Patient with meningitis had a ventriculoperitoneal shunt. HIV is a risk factor in 2 (13.3%) patients with pneumonia and 5 (4.6%) of patients with SSTIs. Since HIV infection is a risk factor for both
MRSA carriage and infection(84), the number of cases with ISA infection and HIV may be
58 higher than observed if all patients were screened for HIV infection. Intravenous canulation and ICU admission are major risk factor among the patients studied.
The prevalence of MRSA was lower than 50% in most of the African countries, although it appears to have risen since 2000 in many African countries, except for South Africa(85).
In Nigeria, several studies conducted in different parts of the country between 1998 and 2013 found a rising prevalence of MRSA ranging from 9% to 47%(18,34,86,87). Prevalence was greater in northern part of Nigeria(85). This may explain the high prevalence of MRSA infection at 47.8% in this study. MRSA was initially known to be a hospital pathogen, causing infection in hospitalised patients but since the mid-1990s rising cases of CA-MRSA infection have increasingly being reported(88). This study demonstrated high number of cases CA-MRSA infection 31/63 (49.2%) with majority of cases from SSTIs 25/31 (80.6%).
Overcrowding, poor hygiene, and inadequate water supply may contribute to the high number of cases of SSTIs due to CA-MRSA infection found in this study.
Staphylococcus aureus has developed resistance to wide range of antibiotics making the treatment of infections difficult, especially in developing countries like Nigeria where drugs for the treatment of MRSA infections like vancomycin, linezolid and tigecycline are not commonly available and determination of methicillin resistance is not routinely done in our laboratories. Resistance of isolates to cotrimoxazole in this study was high 110/157 (70.1%).
This is slightly lower than findings in previous Nigerian studies by Shittu et al from eight hospitals in South-west, North-central and North-eastern Nigeria(18) and Nwakwo et al in
Kano (89) where resistance to cotrimoxazole was reported to be 72% and 84.5% respectively.
The high resistance rate is probably due to misuse or overuse of this drug due to its wide clinical application. It is relatively cheap, orally administered and available over the counter even without prescription. In this study, the resistance of MRSA and MSSA isolates to cotrimoxazole was 84.1% and 57.3% respectively. However findings by Shittu et al (90) is
59 slightly higher where resistant was reported to be up to 86.7% and 80.6% for MRSA and MSSA respectively.
This study has found about 30% of isolates to be resistant to ciprofloxacin. The resistant to ciprofloxacin of MRSA and MSSA isolates were 36.0% and 24.3% respectively. This may be due to abuse of this drug in treating febrile illnesses presumably believed to be caused by typhoid fever. In a previous study in Kano by Kumurya et al (91) resistant to ciprofloxacin for
MRSA and MSSA were 20.9% and 9.8% respectively.
Macroside-Lincosamide-Streptogramin B antibiotics are alternative antibiotics used in the treatment of mild to moderate infection caused by CA-MRSA. In this study, MRSA strains show higher resistance to this class of antibiotics than MSSA strains: erythromycin (41.3% vs
22%), clindamycin (46.6% vs 22%). Among MRSA strains resistance is lowest to tetracycline and ciprofloxacin which is 36.0% for both antibiotics. This study found mortality rate of 19.7%. This figure is similar to reports by Jacobsson et al,
Laupland et al and Song et al (5,62,92) where mortality at one month was reported to be 19.1%,
19.0% and 25.6% respectively. Kang et al (15) reported mortality at one month of 22.7% and
8.7% for elderly and younger patients respectively. This is reflected by the findings of this study where the mortality rate in those aged 65 years and above was 28.6%.
Mortality in ISA infection varies according to the type of ISA infection. Staphylococcus aureus bacteraemia has been reported to be associated with mortality rate of 10-53.2% (2,12,56,80).
In this study, patients with bacteraemia have the highest mortality 11/25(44%).
Recurrence occurred among patients with SSTIs10/97 (10.3%). Among patients with SSTIs 5
(5.2%) had lower limb amputation due to Diabetes mellitus foot syndrome.
In this study, there was a statistically significant increase in mortality in patients with infection due to MRSA (p value 0.003). Similar finding was reported by Kang et al(15) and Nickerson
60 et al (63). However Song et al (92) did not find any association between MRSA infection and
30 day mortality.
A statistically significant increase in mortality for patients with Methicillin-resistant
Staphylococcus aureus bacteraemia was found in this study (p value 0.013). This is in keeping with reports in studies by Nickerson et al, Cosgroove et al and Price et al (12,93,80). Mortality was also found to be higher in MRSA infections, though not statistically significant.
Factors reported as predictors of mortality in ISA infection include age > 65 years, severe sepsis, low systolic blood pressure, underlying cardiac diseases, respiratory infections, immunosuppression, diabetes mellitus and MRSA infection(16,94,93,95,96). In this study,
MRSA infection and sepsis were identified as independent predictors of mortality using logistic regression.
61
CHAPTER SIX
6.0 CONCLUSION
1. This study demonstrates that the burden of ISA infection is high in Nigeria.
2. It affects both young and old patients with co-morbidities and immunosuppressed individuals.
3. The predominant syndrome in ISA infection is SSTIs, followed by Bacteraemia.
Pneumonia and line associated infection. Cases of meningitis and Endocarditis are rare.
4. The commonest form of CA-MRSA infection is SSTIs and the commonest form of HA-MRSA is Bacteraemia
5. There is high prevalence of MRSA. High level of resistance to Macrolides
(erythromycin), Lincosamides (clindamycin) and cotrimoxazole was also found and
Staphylococcus aureus is most susceptible to ciprofloxacin.
6. Staphylococcus aureus bacteraemia has poorer outcome. MRSA infection and sepsis were recognized as independent risk factors for mortality.
62
6.1 LIMITATIONS OF THE STUDY
1. Failure to do molecular studies to determine the serotype and to confirm Methicillin-resistance.
2. Failure to do D-test to determine inducible clindamycin resistance
3. Sample size was calculated using the prevalence of staphylococcus aureus due to lack of local data on ISA infection
4. Duration of the study did not capture year round potential seasonal pattern of presentation
5. Skin and soft tissue infection included wound infection which was defined based on isolation of staphylococcus aureus from wound swab
6. Staphylococcus aureus bacteraemia was define based at least one positive blood culture from at least one venipuncture site
7. Staphylococcal pneumonia was defined based on isolation of the organism from an appropriately collected (ideal) sputum sample instead of from culture of lung tissue.
63
6.2 RECOMMENDATIONS
1. Staphylococcus aureus should be considered for empiric therapy in all patients with
SSTIs, line associated infections, hospital acquired pneumonia, bacteraemia with no focus and ventriculoperitoneal shunt. 2. Quinolones should be considered as empiric therapy for patients with mild to moderate community acquired SSTIs.
3. In vitro testing for Methicillin resistance should be done as a routine for isolates of staphylococcus aureus.
4. Infection control programs should be implemented in order to reduce the transmission in this organism
5. Severely ill patients at risk of ISA infection should be decolonized
6. Antibiotic use policy for Nigeria should be developed
64
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6.4 APPENDIX 1
CLINICAL PROFILE AND OUTCOME OF PATIENTS WITH INVASIVE
STAPHYLOCOCCUS AUREUS INFECTIONS
1-PERSONAL DATA
Sex Male [ ] Female [ F ]
Age [ ] year Marital status………………..
Religion…………………….…. Occupation………… Educational Status………..…….
Address…………………………..…..
2-CLINICAL DETAILS
Duration of symptoms [ ] Days
Clinical presentation Pneumonia [ ] Meningitis [ ] Skin and soft tissue infection:
Cellulitis ( ), Ulcer/wound ( ), Abscess ( ), Pyomyositis ( )
Bacteraemia [ ] Septic arthritis [ ] other [ ] specify
Temperature………………………………Cyanosis…………………………………………
Pulse rate………………………………..Blood pressure……………………………
Hepatomegaly………. Splenomegaly……..
Glasgow coma score………………
Outcome: Cured [ ] Died [ ] Recurrence
Morbidity [ ] specify ______
Duration of hospital stay…………………………. Risk Factors: HIV: positive [ ] Negative [ ] not known [ ]
Malignancy [ ] specify…………………….
CLD [ ] HHD [ ]
Alcohol [ ] Diabetes [ ]
IV canulation [ ] Renal failure [ ]
Foreign body [ ] ICU [ ] Sc.D. [ ]
Number of hospitalization in the last 12 month [ ]
78
Prior antibiotic use [ ] specify------Steroid [ ] Chemotherapy [ ] ARV [ ]
Specify…
…………………………………
…………………………………
Prescribed antibiotic(s):
3-LABORATORY AND X-RAY DETAILS
Specimen Blood [ ] URINE [ ] Pus [ ] Aspirates [ ] CSF [ ]
Sputum [ ] Others------specify…
Full Blood Count [ ] Differentials: N….…. L….…. B….…. E……..M……..
PCV………… PLATELETS…………….
ALT mmol/l [ ] AST mmol/l…… Albumin g/l……..
Urea mmol/l [ ] Creatinine micmol/l [ ]
CXR:
2D Echo:
CT scan:
Antibiotic susceptibility for MSSA: Amoxyclav [ ] Cloxacillin [ ] Cotrimoxazole [ ]
Erythromycin [ ] Tetracycline [ ]
Clindamycin [ ] Ciprofloxacin [ ] Cephalexin [ ]
Gentamicin [ ] Ceftriazone [ ]
Antibiotic susceptibility for MRSA: Amoxyclav [ ] Cloxacillin [ ] Cotrimoxazole [ ]
Erythromycin [ ] Tetracycline [ ] Clindamycin [ ] Ciprofloxacin [ ] Cephalexin [ ] Gentamicin [ ] Ceftriazone [ ]
S--- Sensitive
R—Resistant
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6.5 APPENDIX TWO
CONSENT FORM
I am Dr. S.H TAMBUWAL, a resident doctor with the department of medicine Aminu Kano
Teaching Hospital Kano conducting a study on clinical profile and outcome of patients with invasive staphylococcus aureus infection.
I will be very grateful if you will agree to participate in the project as a participant. All that is required of you is that, you will be examined and samples such as blood, sputum, CSF, joint aspirate or wound swab will be taken for analysis. A questionnaire will also be administered.
You will be followed up at one month.
Kindly sign in the space below if you are willing to participate. Participation is entirely voluntary, and refusal to participate will not affect you in any way. Those who are found to have risk factors will be referred to a specialist for proper evaluation and treatment. Information obtained in this study will be treated with utmost confidentiality.
Thank you.
Name of client:
Sign/thumbprint:
Date:
Name of researcher:
Sign:
Date: