Assessment of Tigecycline Prescription and Patients’ Outcomes at Three Different Hospitals in Saudi Arabia

Purpose: To investigate tigecycline prescription and patient outcomes in the Kingdom of Saudi Arabia (KSA). Methods: A retrospective observational study was conducted in three KSA government hospitals, between January, 2013 and May, 2014. The patients were identified from electronic prescription records; data were retrieved by trained researchers. Results: Thirty-seven patients who received tigecycline were included (mean age, 52.5 years; range, 17 92); 51.4 % were female. Tigecycline was prescribed for sepsis (59.5 %), pneumonia (21.6 %), and/or intra-abdominal infections (13.5 %). The majority of the patients (86.5 %) were prescribed tigecycline in intensive care unit (ICU) and the remaining patients were in the general medical ward. APCHE II score at the beginning of treatment was 16.8 ± 4.3, indicating severe disease. Susceptibility testing revealed 22 different bacterial pathogens, most commonly Acinetobacter baumannii (20 patients) and Klebsiella pneumoniae (14 patients). A significant proportion (56.7 %) was polymicrobial and 16.2 % involved suspected resistant pathogens. Sixteen patients recovered (5 on tigecycline alone, 5 with additional antimicrobials, and six switched to alternatives) while 21 patients died (nine on tigecycline alone, 12 with additional antimicrobials). Conclusions: The study revealed that tigecycline prescription was conducted according to marketing authorizations and national guidelines. Infection severity/stage and comorbidities may influence patients’ response, and explain some of the poor outcomes.


INTRODUCTION
Bacterial infections present an increasing and well-recognized challenge to clinical practice for several reasons: the rapid emergence of resistant strains [1]; medication over-prescription in all healthcare settings [2,3]; and ethical issues, for example inappropriate patient demands [4].Furthermore, the empirical antibacterial therapy without sufficient intelligence in relation to pathogen susceptibility has been linked to increased fatality in patients with sepsis [5].The discovery and development of truly novel antibacterials by the pharmaceutical industry has declined markedly, primarily due to scientific complexity and resource implications [6].Tigecycline is one of the very few unique agents launched in the last decade, with initial introduction in the United States (US) in 2005 [7].The US Food and Drug Administration (FDA) licensed tigecycline for the treatment of patients with skin and soft tissue infections, complicated intra-abdominal infections, and communityacquired pneumonia [8]; followed by the European Medicine Agency (EMA) licensing in 2006 [9].Tigecycline circumvents mechanisms of bacterial resistance via a modification of the central structure of minocycline by the addition of a 9-tbutyl-glycylamido side chain.This renders tigecycline effective against a wide range of gram-positive and gram-negative organisms, notably highly resistant pathogens such as methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, vancomycinresistant Enterococcus species, extended spectrum β-lactamase producers (ESBL), Clostridium difficile and many carbapenemaseproducing Enterobacteriaceae; however, it has no activity against Proteus or Pseudomonas species [10,11].It exhibits a linear pharmacokinetic profile, a large volume of distribution Vd (7 10 L), a half-life of 37 -67 h, and clearance of 0.2 -0.3 L/h/kg [12,13].In adults, it is administered intravenously as a loading dose of 100 mg, followed by 50 mg every 12 h, with dose-reduction recommended in cases of sever hepatic impairment as in Child-Pugh Class C. Adverse drug reactions include: nausea (26 %), vomiting (18 %), diarrhea (12 %), abdominal pain (6 %), headache (6 %), and increased serum glutamic pyruvic transaminase levels (< 2 %) [14].
Two main concerns of tigecycline have become apparent recently: the emerging clinical resistance [15] and life-threatening adverse events [16] which have been confirmed by independent meta-analyses of all-cause mortality data [17,18].Studies conducted in Europe [19] and Taiwan [20] have demonstrated largely, an appropriate use of tigecycline in terms of its licensed indications and dosage, highlighting the need to balance patients' risks and benefits.Tigecycline was introduced to the Saudi market in 2008 to treat skin, soft-tissue, and intraabdominal infections.In August, 2011, the Saudi Food and Drug Authority (SFDA) issued a safety notification advising that tigecycline should only be prescribed for licensed indications and as a last resort, where alternative antimicrobials were deemed inappropriate [21].

Study design
A retrospective observational study was conducted in several hospitals.This study was approved by the Ethical Committee of the Ministry of Health Research Centre in Jeddah, KSA.All the three hospitals must comply with local prescription guidelines for tigecycline: the prescription should be initiated by a medical consultant; pathogen susceptibilities should be determined by laboratory analyses; and the prescription should be authorized by an infectious diseases physician, a microbiologist, and a pharmacist.

Study setting and participants
The study was conducted in three main KSA governmental hospitals: King Fahad Hofuf Hospital (KFHH); King Fahad Jeddah Hospital (KFJH); and King Fahad Specialist Hospital (KFSH), located in the regional provinces of Makkah, Al-Ahsa, and Qassim, respectively.Each hospital has 500-900 beds and mainly serves adult patients.All patients prescribed tigecycline between January 2013 and May 2014 were included in the study, with no exclusions.

Data collection and analysis
The patients prescribed tigecycline were identified from electronic prescription data.A data collection template was developed and piloted to record the following: patient demographics (age, sex, weight, hospital); past medical history; adverse drug reactions, allergies, medication history (including current medication); reason for admission to hospital (signs, symptoms); Acute Physiology and Chronic Health Evaluation (APACHE II) disease severity score [22]; tigecycline indication and regimen (dose, route, duration); documented adverse events; renal and hepatic function; microbiological analyses of pathogen susceptibility; ongoing monitoring (documented clinical response); and clinical safety endpoints (documented recovery, surgery, readmission).The data were entered into SPSS (SPSS Inc., Cary, NC version 22.0) and analyzed using descriptive statistics.Missing data were recorded for all variables considered.Three hospital pharmacists attended researcher training sessions to receive information about the purpose of the research and the data collection process.The data were collected from the patients' electronic medical records in KFSH and KFHH, and from paper-based medical records in Trop J Pharm Res, October 2015; 14(10): 1921 KFJH, where electronic records had not been fully implemented at the time of this study.

RESULTS
Thirty-seven patients were included: 18 in KFHH; 11 in KFJH; and 8 in KFBH.The mean patient age was 52.5 years (SD ± 21.4, range 17 92) and 19 (51.4 %) were female.The demographics at the start of tigecycline therapy, disease severity scores, and comorbidities, as shown in Table 1.Thirty-two patients (86.5 %) were   treated with tigecycline in the intensive care unit (ICU) and the remaining proportion of patients were in the medical wards.Biochemical monitoring prior to commencing tigecycline, identified three patients with impaired renal function; there was no evidence of impaired hepatic function.
The documented indications for tigecycline are given in Table 2, with some patients having more than one indication.None of the patients had been treated previously for similar infections.

DISCUSSION
Tigecycline is a very few unique antimicrobial agents which was launched in the last decade, with initial introduction to the US in 2005.Two main concerns of tigecycline have become apparent since its launch; emerging clinical resistance and life-threatening adverse events.Tigecycline was introduced to the KSA market in 2008.
This study showed that tigecycline prescription patterns within these hospitals in the KSA were mostly in line with the guidelines [7,9]; it was reserved and prescribed for clearly defined indications at appropriate initiation and maintenance doses [7,11,22].This is in line with the previous studies in Taiwan [19] and Europe [20].Tigecycline was initiated under the instruction of a consultant in according to the recommended dosing schedule of 100 mg intravenously initially, followed by 50 mg every 12 hours (except one patient with renal insufficiency received 50 mg followed by 25 mg every 12 h).The treatments and patients' outcomes are shown in Figure 1.
However, we identified tigecycline usage for some unapproved indications that both the SFDA and FDA have issued warnings against; these included diabetic foot, urinary tract infections, undefined pneumonia, and septic shock.
These dangerous pathogens are acknowledged to pose the greatest therapeutic challenges and, while often drug-resistant, may respond to tigecycline [23,24] Tigecycline's adverse events include: nausea and vomiting (n = 4); diarrhea (n = 2); and hypotension (n = 1).These mostly appeared on the first or second day of tigecycline treatment.None of these adverse drug reactions led to tigecycline discontinuation or treatment change.Patients' clinical outcomes varied and were extremely difficult to associate with tigecycline efficacy because of the influences of confounding factors, including severity and stage of infection, comorbidities, and concurrent antimicrobial therapy.The documented adverse events were of low prevalence and severity, and were similar to those reported previously [6,14].While lifethreatening adverse events have been noted with tigecycline [16,18] and have resulted in safety warnings, it is unlikely that the high mortality observed in this study was directly attributable to tigecycline.Many patients included in this study died, irrespective of treatment, and few patients continued on tigecycline as the sole antimicrobial.

Limitations of the study
The small dataset and the potential reporting bias due to the reliance on case notes; are the major two limitations.It is possible that drug adverse events were underreported.Even when tigecycline is mostly prescribed in line with the relevant marketing authorizations, patient outcomes are complex and influenced by many confounding factors and may not necessarily be generalizable to the entire KSA.

CONCLUSION
The study revealed that tigecycline prescription was in line with the marketing authorizations and national guidelines.While many patients had poor outcomes, these could not be attributed solely to a lack of tigecycline efficacy or toxicity; confounding factors, including infection severity/stage and comorbidities may influence patients' outcomes.

Table 1 :
Summary of patients' characteristics and reasons for tigecycline use regurgitation; NA, not available; PD, Parkinson's disease; PE, pulmonary edema; RA, rheumatoid arthritis; SCA, sickle-cell disease; SLE, systemic lupus erythematosus; TB, tuberculosis.a Improvement was defined as a clinical cure or response without additional antibiotic.b Death was defined as failure or no improvement with additional antibiotic.c Patients could have more than one reason.d Previous therapy included all treatments that were given prior to tigecycline

Table 4 :
Indication, treatment, and outcomes of patients commenced and continued on tigecycline (n = 10)