Drug-induced gingival enlargement

Introduction

Drug-induced gingival enlargement is classified by the American Academy of Periodontology as a dental plaque-induced gingival disease,  as evidence suggests that existing gingival inflammation may be necessary for its development and that proper plaque control and effective oral hygiene can lessen its severity or potentially prevent its occurrence altogether. 2 Currently, there are over 20 medications from three pharmaceutical categories including anticonvulsants, calcium channel blockers and immunosuppressants that are associated with gingival enlargement.4  It is the responsibility of the dental practitioner to recognize the potential of these medications to contribute to gingival enlargement and to provide the proper prophylactic care or appropriately refer the patient for periodontal therapy.  A team approach involving a consultation with a periodontist and the patient’s physician is a critical step in successful treatment.

Risk factors

During a course of treatment with a medication implicated in the pathogenesis of drug-induced gingival enlargement, poor plaque control is the most significant risk factor associated with its development.  The severity of enlargement is often proportional to the amount of gingival inflammation present and not the dosage of medication.  Overall, males tend to be affected three times as often as females and age is inversely correlated with likelihood of occurrence.

Medication

Prevalence of gingival enlargement with phenytoin (Dilantin®) use has been shown to be up to 50%, while other anticonvulsants such as valproic acid, Phenobarbital® and Tegretol® have been shown to be rarely associated with the disorder.  Of the calcium channel blockers, nifedipine (Adalat®, Procardia®) and diltiazem (Cardizem®) are the most likely to cause gingival enlargement (5-20%) while amlodipine (Lotrel®, Norvasc®), felodipine (Aggon®, Plendil®) and verapamil (Calan®, Covera®) are far less likely to be implicated.  Cyclosporin A, an immunosuppressant commonly used in organ transplant patients, has been shown to be associated in 25-30% of adult patients and over 70% in children, while tacrolimus has a significantly lower association at 14%.

Pathogenesis

While the physiology behind drug-induced gingival enlargement has not been definitively elucidated, histopathologic studies have shown that the gingival tissue volume increase is due to an excessive accumulation of extracellular matrix proteins including collagen and ground substance with a predominance of plasma cells.  Hence, the increase in tissue volume is primarily a connective tissue response and not epithelial.  Recent evidence suggests that this overgrowth could occur not from over-production of collagen, but rather through prolonged cell life of keratinocytes.  Another hypothesis is that fibroblasts in susceptible patients are sensitive to the medication in question, causing increased protein, and hence collagen, production.

Clinical presentation

Clinically, gingival enlargement frequently appears within 1-3 months of the initiation of treatment with the offending medication. The facial surfaces of the gingiva in anterior sextants are often most severely involved, and the patient may present with inflamed, fibrotic masses spreading from the interdental papillae to the attached gingiva that may interfere with mastication, speech and esthetics.  Due to discomfort secondary to inflammation and the physical topography of the enlarged gingiva, oral hygiene may be impaired and diet can be adversely affected.  This can lead to a host of other problems including caries, periodontal disease and immunosuppression secondary to malnutrition.

Treatment and prevention

Meticulous oral hygiene and plaque control combined with the removal of local factors are essential for any patient taking drugs associated with gingival enlargement.  A three-month periodontal maintenance interval is strongly recommended as well.  While excellent oral hygiene and professional plaque control can potentially prevent or lessen the severity of the condition, they often are insufficient for reversing the process once established.  It is therefore prudent to consult the patient’s physician to discuss potential drug substitutions that may result in regression of the lesions with proper supportive periodontal care and oral hygiene.  After drug substitution or withdrawal, evidence suggests that gingival lesions may resolve in 1-8 weeks in some patients.In transplant patients, however, drug substitution or cessation may not be an option due to the risk of transplant rejection.  Treatment of gingival enlargement in patients taking cyclosporin A should focus on their chronically immunosuppressed state.  In these patients, evidence suggests that topical antifungal treatment such as Nystatin lozenges, chlorhexidine rinses or a short course of azithromycin (3-5 days; 200-500 mg/day) can be effective.  There is evidence that systemic azithromycin remains effective in reducing gingival overgrowth from three months to two years after treatment, but this data is controversial.  A topical treatment including scaling and root planing in conjunction with an azithromycin-containing toothpaste used twice daily for one month has been shown to be effective in reducing gingival overgrowth as well, but the long-term efficacy of this treatment is unclear.

If the patient has gingival overgrowth and is currently taking:	Discuss the following substitution with the primary care provider:
Nifedipine (6-15%)	Isradipine, Amlodipine, Verapamil, Felodipine
Phenytoin (50%)	Carbamazepine, Valproic Acid, Vigabatrin, Phenobarbitone
Cyclosporin A (Adults 25-30%, Children >70%)	Tacrolimus

Note: incidence of gingival enlargement in parentheses.  Table adapted from Dongari-Bagtzoglou 2004.

While non-surgical therapy and, if possible, drug substitutions should be attempted first, surgery is often necessary to fully correct the esthetic and functional impairment encountered in this disorder.  Surgical excision has been successful in non-responding nifedipine cases when combined with good oral hygiene as well as in cases associated with verapamil and diltiazem, but it does tend to recur.A classic external bevel gingivectomy is an option to reduce redundant tissue.  An internal gingivectomy approach, however, has been advocated due to its ability to provide primary closure and reduce the incidence of postoperative bleeding, discomfort and infection.  Due to its technical difficulty, this procedure may be best referred to a periodontist.  Another surgical option is the CO₂ laser due to its decreased surgical time, rapid hemostasis and its compatibility with a host of underlying medical conditions.

Recurrence

Eighteen months after surgical therapy, the recurrence rate of gingival overgrowth in patients taking cyclosporin A or nifedipine was 34% in a study of 38 individuals.  Age, gingival inflammation and attendance at recall visits are all significantly related to recurrence.  To help prevent recurrence post-surgically, chlorhexidine rinse twice daily is recommended.

Conclusion

Drug-induced gingival enlargement is a common sequela to treatment with anticonvulsants, calcium channel blockers and immunosuppressants.  Evidence suggests that gingival inflammation is critical in its pathogenesis.  While it may be prevented through meticulous periodontal maintenance and home care, it is essential for the dentist to work together with the patient’s physician and periodontist in order to successfully treat this condition once it occurs.

Oral Health and Pregnancy

What is the public health issue?

Oral disease, particularly periodontal (gum) disease, may be related to premature and low birth-weight babies. Pregnant women with periodontal disease may be seven times more likely to have a baby that's born too early and too small, which can result in serious health problems that can be life-long. The exact connection between periodontal disease and preterm birth is unknown, but it might be due to inflammation (swelling) inside the body, the transfer of bacteria from the mouth into the placenta or amniotic fluid, or the release of a particular chemical that stimulates contractions (prostaglandin) from the mouth into the body. Pregnant women should take good care of their teeth and gums by brushing two times every day for two minutes, and flossing daily. They are at an increased risk for gum problems, as almost half of pregnant women in their second or third month of pregnancy get pregnancy gingivitis—this causes gum swelling, pain, and bleeding. In some cases, gums swollen by pregnancy gingivitis can form large growths, called “pregnancy tumors.” They are not cancerous and generally painless. However, if a tumor does not go away, it may need to be removed by a dentist. Pregnant women should also be educated about protecting their new baby’s oral health. Bacteria that cause tooth decay can spread from Mother and Child, and this increases the child’s risk for tooth decay in the future. Mothers should avoid sharing forks, spoons, and drinks with their babies.

Pregnency and oral health

Oral Health Before and During Pregnancy

• Drink fluoridated water
• Brush your teeth and gums twice a day with a fluoride toothpaste and floss each day
• Make an appointment for an exam with a dentist
• Make good nutritional choices; limit sweet drinks and avoid sugar
• Include Vitamin C and Calcium in your daily diet
• Do not smoke
• Get plenty of rest
• Learn how to take care of the baby’s gums and teeth even before birth

Infant and Toddler Oral Health Tips

• Consult a pediatrician or family physician on the best water to use with infant formula.
• Start oral care early. Begin by wiping the baby’s gums with a cloth or gauze after feeding.
• Start brushing as soon as the first tooth appears.
• When the child can brush on his or her own, supervise brushing to make sure fluoride toothpaste is not being used in large amounts and swallowed by the child.
• Try to schedule the child’s first dental visit around his or her first birthday.

NOSOCOMIAL INFECTIONS (HOSPITAL ACQUIRED INFECTIONS)

Definition of NOSOCOMIAL INFECTIONS (NI) 

Infection acquired in relation to hospital stay, not present at the time of admission.

Important complications of the hospital care with multiple negative impacts:

• worsen prognosis of the patient principal illness
• increase mortality
• prolong the hospital stay
• worsen the patients´ quality of life
• demand expensive investigation, treatment and control measures – increase the cost of care

NI = complicated interaction between the population of susceptible individuals with often serious illnesses and specific hospital environment.

Factors predisposing to hospital infection:

• Pre-existing condition
• Need for invasive devices ( IV, U, ET)
• Effect of surgery (skin wound, tissue trauma, opening colonized viscus, immobilization, implants of foreign material (joint prostheses, arterial graft)
• Effect of antibiotic treatment (colonization by resistant bacteria and fungi)
• Effect of immunosupressive treatment (corticosteroids, cancer chemotherapy, radiotherapy, transplant immunosupression)
• Exposure to health care workers and other pts. who may transmit pathogens
• Exposure to pathogens in the hospital environment

Patients in the intensive care units are particularly susceptible to infection for several reasons:

• underlying disease is more severe = more disturbing their immune responses
• recently underwent anaesthesia and surgery
• often had got previous (multiple) antibiotics
• barriers to infection are breached by catheterization ant intubation

Epidemiology:

- 10 % of pts. admitted to hospital

EPIIC Study (European Prevalence of Infection in Intensive Care) Study 1995 - prevalence and epidemiology of intensive care-related infections – single day study:

10038 pts. hospitalized at ICUs in 17 Europian countries

20,6 % of patients had an intensive care-related infection:

1. pneumonia                                   46,9 %
2. other respiratory tract infection     17,8 %
3. urinary tract infection                    17,6 %
4. catheter-related infection              12 %
5. surgical site infection                     6,9 %

The most frequent pathogens were Staphylococcus aureus, enterobacteria, Pseudomonas aeruginosa, Acinetobacter spp., coagulase-negative staphylococci, enterococci and candida.

Main groups of NI: catheter-related infections

• pneumonia
• respiratory tract infections other than pneumonia
• surgical site infections
• urinary tract infections
• gastrointestinal infections
• central nervous system infections
• Intravascular catheter-related infections

Localised - peripheral thrombophlebitis, absces

Systemic – bacteraemia, sepsis, endocarditis, metastatic infection

Source of infection:

• contamination during insertion of catheter or cannula
• later contamination from the skin along the catheter
• contamination of catheter hub,taps,line during manipulation
• contaminated IV fluids
• hematogenous spread from another focus of infection

Influencing factors:

• Insertion site: subclavian x jugular x femoral
• Catheter characteristics:
• Type: central tunnelled, Portacath x central x peripheral
• Material: teflon, silicon, polyurethan x PVC, polyethylene surface impregnated with silver, antibiotics

• Number of lumen: single-luminar x multiple-luminar
• Usage: drugs x nutrition x blood

Microbiology:

coagulase-negative staphylococci (S. epidermidis), S. aureus, Candida spp., Enterococcus spp., gramnegative rods

Clinical features:

• local signs of inflammation at the site of entry – redness, tenderness, swelling, slight purulent exudate – prominent in peripheral lines, less in central lines
• systemic signs – fever, rigors and no other source of fever
• clinical improvement after catheter removal
• elevated inflammatory markers, typical pathogens in blood culture

Management of line-related sepsis:

• Blood culture: 1. catheter, 2. peripheral – colonization x catheter-related bacteraemia
• Catheter removal, culture of the tip – semiquantitative > 15 CFU = infection
• (insertion of a new catheter not immediately)
• Antibiotics, if symptoms did not resolve after removal, guided by culture results
• Long-time catheters (Broviac, Hickman) – catheter treatment, ATB locks

Prevention and control:
Choice of catheter and insertion site

• Aseptic and atraumatic insertion (skin disinfection, barrier precautions), fixation to the skin
• TPN (all-in-one bags) prepared in the pharmacy under sterile precautions
• Minimimize opening of the IV set for additive drugs, every opening strictly aseptic!
• Maintaining adequate hygiene and dressing of the insertion site and regular review of insertion site
• Replacing giving set and catheter at appropriate intervals
• giving set every 72 hours, if lipid emulsions or blood products – 24 hours
• catheter – peripheral 48 h, central 7 days, tunnelled line much longer
• removal of catheter if not longer necessary

IV teams in hospitals in the USA insert and take care of IV catheters following a strict protocol, and thus minimize the incidence of catheter-related infections.

Hospital – acquired, nosocomial pneumonia

• Pneumonia occurring at least 48 h after admission.
• The leading hospital acquired infection in ICU, associated with increased morbidity, prolonged mechanical ventilation and ICU-stay, higher antibiotic use and attributable mortality.
• Affect 5 % of all hospitalized pts, 25 % of ICU pts, 30 % of mechanically ventilated pts.
• Mortality 30-50 %, highest in the elderly and ventilated pts.

Risk factors: age, underlying chronic/acute illness, thoracic or abdominal surgery, immobility, reduced level of consciousness, dysphagia, use of broad-spectrum ATB, mechanical ventilation.

Endotracheal tubes and tracheostomies bypass host respiratory tract defense mechanisms and allow bacteria to be deposited directly into the LRT. Secretions may pool in the subglottic area above the endotracheal cuff and slowly leak into the LRT.

Etiology:  in 50 % mixed infection

early onset  2-5days - similar to CAP – S.pneum., H.infl. S.aureus, anaerobes

late onset > 5d – gramnegative bacteria – Enterobacteriacae, S.aureus, other gramnegatives, Pseudomonas, anaerobes, rarely Legionella sp.

Clinics: fever, purulent respiratory secretions, respiratory symptoms

Diagnosis: new X-ray signs, leukocytosis, neutrophilia, CRP,sputum and blood culture

Ventilator associated pneumonia (VAP) – particular subgroup.

Pseudomonas, Acinetobacter, Klebsiella, S.aureus, Enterococcus, resistant!            

Source of infection:

endogenous:

GIT:         
a) retrograde colonization of the upper GIT and pharynx by intestinal flora, facilitated by decreased stomach acidity
b) translocation of bacteria through intestinal wall during gut ischaemia

hematogenous spread from a distant focus

exogenous:

hands of hospital personnel, tap water, ventilator circuit, nebulizers

Diagnosis is difficult:

• purulent secretion = infection x local irritation
• tracheal aspirate culture = infection x colonization x tracheobronchitis
• fever and leukocytosis = pneumonia x other reasons (pneumonia with no fever and leukocytosis)

• X-ray infiltrate = pneumonia x embolia x edema in CHF x malignancy

Microbiology:

- tracheal aspirate widely used for detection of eti, doubtful value?quantitative bacteriology- cut-off 10⁵ - 10⁶  /ml

- bronchoscopy with bronchoalveolar lavage 10⁴ or protected bronchial brush specimen 10³ /mL

Studies: correlation 70%, no mortality advantage, more ATB changes.

Endotracheal aspiration with quantification is the simplest and most cost effective method of diagnosing etiology of VAP.

- blood culture, pleural fluid culture

Treatment:
Antibiotic:

early onset and non-ventilated – empirical ATB covering the possible pathogens

late and VAP – guided by culture and sensitivity results, if empirical, then covering the problem pathogens Pseudomonas, Acinetobacter, with respect to the microbiology of the environment

Respiratory support, physiotherapy

Treatment of underlying conditions (CHF, diabetes,...)

Prevention:
Postoperative patients: cough and deep-breathing exercises, patient positioning and early mobilization, effective analgesia
VAP:
Infection control strategies: hand washing, exchange of ventilator circuits, sterile equipment, nontraumatic sterile suctioning
Decrease URT colonization and aspiration of upper GIT contents:

• oral cavity hygiene
• positioning – upper part elevation
• maintain stomach acidity (pH < 4) – prevent stress ulcer with sucralfate rather than antacids and H₂ antagonists, acidificated feeding, good splanchnicus O₂ supply (oxygenation, blood pressure), jejunostomy tubes for long-term feeding
• keep appropriate integrity and function of GIT mucosa - early enteral feeding, intermittent vs. continuous, glutamin enriched f., appropriate O₂ supply, prokinetic drugs
• improved endotracheal tubes

Antimicrobial prophylaxis – studies with conflicting results (incidence VAP, no influence on mortality, ↑ ATB resistance):
selective digestive tract decontamination (SDD) – polymyxinE + tobramycin + amphotericin B
local prophylaxis with polymyxin B decreased P.aeruginosa infection, but fatal pneumonias caused by resistant pathogens occured
systemic prophylaxis

Other respiratory tract infections – tracheobronchitis, sinusitis – frequent in mechanically ventilated pts., risk factor for development NP and sepsis.

Urinary tract infections = urinary catheter-related infections

Prolonged hospital stay and raised expenses, low impact on mortality.

Etiology:

• gramnegatives – E.coli, Klebsiella pn., Pseudomonas, Proteus spp.
• enterococci
• Candida spp.
• Ascending extraluminal or intraluminal route of infection.

Risk factors: length of catheterization (5 %/day), opened drainage system, diabetes, female sex, age above 50 y.
Colonization is often asymptomatic, but there is a risk of ascending infection – pyelonephritis, bacteraemia, sepsis.
Diagnosis:
pyuria - > 5 leukocytes per high-power field
urine culture – significant bacteriuria ≥ 10⁵ CFU/mL
Treatment:
catheter removal or change
antibiotics in symptomatic UTI
Prevention:
catheterization only when necessary
sterile, atraumatic insertion
closed sterile drainage
maintenance of good patient hygiene
replacing catheter at appropriate intervals
ICU – bacteriological screening – urine culture at appropriate intervals

Surgical site infections (SSI)
infections in the site of surgery and related bacteraemias.

CDC classification:
Superficial SSI – skin and subcutaneous tissue involved
Deep SSI – deep soft tissue, fascia, muscles
Organ SSI – organs, cavities
Microbiology:

S.aureus, coagulase-negative staphylococci, enterococci, E.coli, Pseudomonas, Enterobacter

Factors influencing SSI: patient, operation, antimicrobial prophylaxis,  surgical team, postoperative care.

Patient: underlying disease (diabetes, malignancy, multiple trauma), immunosupression, malnutrition, obesity. Minimizing the time between admission and surgery will limit the opportunity to acquire resistant hospital pathogens. Preexisting infection should be treated before surgery.

Classification of operations for the purpose of ATB prophylaxis:

• Clean - in normally sterile tissue - orthopaedics, neurosurgery, cardiovascular, SSI incidence < 2% (staphylococci), antimicrobial prophylaxis is not indicated.

The exception is insertion of prosthetic device, infection may have catastrophic consequences, antimicrobial prophylaxis is indicated. The other prophylactic measures: filtered air to OR, impermeable suits for surgeons, antibiotic-impregnated orthopaedic cement, antibiotic-impregnated intravascular prostheses.

Neurosurgical operations on opened meninges carry a risk of meningitis, S.aureus or gramnegatives, esp. Pseudomonas.

• Contaminated – GIT, RT and UT surgery and endoscopy. Antimicrobial prophylaxis is indicated.

• Infected (dirty) – infection already exists - drainage of abscess, excision of perforated bowel. Appropriate antimicrobial therapy rather than prophylaxis is necessary.

Antibiotic prophylaxis:
ATB bactericidal, effective against considered pathogens, with respect to local resistance, not betalactamases inducers
Short course of prophylaxis – first dose IV at induction of anesthesia, second dose if surgery > 3hours
Prevention of SSI:
Preoperative

• minimizing the preoperative hospital stay  
• cutting > shaving of surgical site 
• ATB prophylaxis, if indicated 
• surgical team clothing and washing

Intraoperative: 

• regardful (tissue-saving) operation technique 
• bleeding control 
• excision of foreign bodies and devitalised tissue 
• isolation of incised bowel 
• minimizing of surgical staff and their movement

Postoperative:  aseptic care of the site, sterile covering

Gastrointestinal infections
Antibiotic-associated colitis
Precipitated by previous antibiotic treatment, mainly lincosamides, ampicillins, cephalosporins.
Clostridium difficile toxin A (enterotoxin), toxin B (cytotoxin)
Transmission via spores may cause hospital epidemics.

postantibiotic diarhea, simple colitis

pseudomembranous colitis

toxic megacolon

Diagnosis:

• clinical: diarhea, fever, abdominal pains, vomiting, related to antibiotic treatment
• laboratory: Cl.difficile toxin detection - ELISA
• antigen detection - latexagglutination
• (stool culture on selective agar, cytotoxicity test on tissue culture = „gold standard“, rarely available)
• colonoscopy –   typical morphology with pseudomembranes typical histology in biopsy specimens

Treatment:

• stop precipitating ATB
• rehydration, diet

ATB:

• p.o. metronidazol 3-4x 500mg p.o.  or vancomycin 4 x 125-250mg
• if no peristalsis, give i.v. metronidazol
• treat at least 7 days
• probiotic drugs, colestipol
• no inhibitors of peristalsis
• toxic megacolon - colectomy

Central nervous system infections

CSF shunt-related, rare occurence, mostly Staph. aureus and Pseudomonas, often serious course (nosocomial ventriculitis) and high mortality.