Rheumatoid Arthritis

Prevalence: 1 in 100, 75% women
Sx: progressive disability, systemic complications, early death

Dx: Anti-citrullinated protein antibody
Rx: initial aggressive therapy. Escalate based on disease intensity. Goal: remission.

COMBO DMARD plus prednisone/infliximab

DMARDs:
Methotrexate
Jakvinus (Tofacitinib) (JAK inhibitor class)

The endemic mycoses compared

Histoplasmosis:
Prevalence: Most common
Sx:Caves. Small yeast forms in neutrophils, patients on TNF-alpha inhibitors, hypoadrenalism. Pancytopenia, tongue ulcer,
Dx: Urinary antigen, narrow-based multiple budding reproduction.
Tx: Itraconazole, but beware of heart failure, in which case, or in pregnancy, use Amphotericin B.


Coccidioidomycosis:
Prevalence: 150,000 cases a year, Second Most common
Sx: mucosal lesions in 25% of cases, "Valley fever", "desert bumps" =  erythema nodosum, most often in anterior tibia region
Dx: with serology, biopsy with granulomas, no budding reproduction, CS fluid shows high eosinophils, pathognomonic.
Tx: 1 month fluconazole and serial serology q2-4 months, for meningitis requires life-long fluconazole for prophylaxis: Relapse extremely common. Amphotericin 2nd line and for pregnant.


Blastomycosis:
Prevalence: Third most common
Sx: Ohio River Valley, acute PNA, miliary lung lesions, affects skin, bone, GU tract, prostatitis, verrucous lesions in head/neck region.
Dx: with culture. broad-based single budding reproduction.


Paracoccidiomycosis:
Prevalence: 80% cases in Brazil.
Dx: Captain's wheel on microscopy


Generally (except yeast), mold in cold (environment), yeast in heat (host organism).

Always: Mold-hyphae, yeast-spherical unicellular

Disorders of Structure

Marfan's Syndrome (Autosomal Dominant)
Prevalence:
Defect: Fibrillin
Symptoms: tall stature, arachnodactyly, prone to ascending aortic aneurysm, ligamentous laxity, pectus excavatum, myopia, scoliosis

Osteogenesis Imperfecta (Autosomal Dominant)
Prevalence: 1 in 7,000 in USA
Defect: Type I Collagen
Symptoms: prone to fracture, hearing loss later in life.

Ehlers-Danlos Syndrome (variable inheritance)
Prevalence: 1 in 5,000 worldwide
Defect: Type III Collagen
Symptoms: Hyperflexible joints, fragile joints, early onset Osteoarthritis, Easy bruising, extra skin folds, Livedo reticularis, piezogenic papules, Raynaud's phenomenon, Valvular heart disease, Hiatal hernia, GERD, Gorlin's sign (can touch tongue to nose), sleep apnea

Types of Arm Somatic Dysfunctions

Anterior Radial Head: Falls backwards onto a supinated arm

Posterior Radial Head: Falls backwards onto a pronated arm

Lateral epicondylitis (Tennis elbow): Repetitive stress to extensor carpi radialis (brevis: deep radial nerve, longus: radial nerve). Chronic injury.

Medial epicondylitis (Golfer's elbow): Repetitive stress to the flexor carpi ulnaris (ulnar nerve)

Subluxation of radial head (nursemaid's elbow): arm pulled up suddenly. Common in children.
Tx: Manual reduction by supinating arm held at 90 degrees of flexion.

Subluxation of ulnar head: uncommon in fall on outstretched hand (FOOSH) often with frx.

Common Rash Diseases of Childhood

Spanish

Spanish Phrases » Online exam software

APGAR Scoring

`If baby has apnea, cyanosis, poor muscle tone, and bradycardia (<100bpm) during first minute of life, positive pressure ventilation on room air is warranted.

Oxygen may also be titrated to achieve SpO2 of 90%.

Anatomical impairments of the fetal/neonatal brain

Hydranencephaly: fluid filled cavity where cerebral hemispheres should be, seen with ultrasound.

Lissencephaly: Lack of gyri on cerebrum, "smooth brain", accompanied by severe retardation, seen with ultrasound.

Schizencephaly: Fluid-filled clefts that communicate with the lateral gyri, seen with ultrasound.

Teratoma: Mass in brain that often causes macrocephaly, seen on ultrasound. Usually fatal/stillbirth.

Autosomal Recessive Diseases of Childhood

Phenylketonuria (Autosomal Recessive)
Prevalence: 1 in 10,000 Caucasians
Def. enzyme: phenylalanine hydroxylase, or lack of its cofactor, tetrahydrobiopterin.
Build-up: Phenylalanine
Symptoms: Phenylpyruvate in urine (metabolized from phenylalanine), severe mental retardation, often light colored hair and skin
Rx: Kuvan (sapropterin), low protein diet, Most US facilities recommend that phenylalanine levels be maintained in the range of 2-6 mg/dL (120-360 µmol/L).

Alkaptonuria (Autosomal Recessive)
Prevalence: 1 in 100,000
Def. enzyme: homogentisate 1,2 dioxygenase
Build-up: Phenylalanine and Tyrosine which leads to toxic build-up of homogentisate.
Symptoms: Dark urine from protein build-up when left to stand, NOT immediately; "black bones", osteoporosis, increased pigmentation in cartilage of ear, valvular heart and aortic disease, hearing loss after age 40.
Rx: In the past Hi Dose Vit C and protein restriction, but recent studies have shown not effective. Possible new treatment is nitisinone, but this will cause tyrosine build-up, effects unknown.

Maple Syrup Urine Disease (Autosomal Recessive)
Prevalence: 1 in 200,000
Def. enzyme: alpha-ketoacid dehydrogenase
Build-up: Isoleucine, Leucine, Valine (Mnemonic: I Like Vermont Maple Syrup)
Symptoms: Ketoacidosis, Neuro symptoms, Sweet smelling, normal-looking urine
Rx: Restrict Branch chain AA consumption

Hyperprolinemia (Autosomal Recessive)
Prevalence: 1 in 200,000 in the US
Def. enzyme: proline oxidase
Build-up: proline in blood, urine, CSF
Symptoms: seizures, intellectual dysfunction, schizophrenia
Rx: None

Homocystinuria (Autosomal Recessive)
Prevalence: 1 in 300,000
Def. enzyme: Cystathionine Beta Synthase (see diagram)
Build-up: Homocysteine
Symptoms: Lens dislocation leading to near-sight, high stroke risk, thromboembolic risk, osteoporosis, learning disability, pectus carinatum/excavatum
Rx: High dose Vit. B6, Betaine (Cystadene) to clear Homocysteine, low protein (low methionine) diet.

Ectopic pregnancy management

Salpingotomy

or

Methotrexate if Beta HCG is below 5000.

Classic Triads

Ectopic Pregnancy: Vaginal Bleeding, Amenorrhea, Abdominal pain.

Reiter's syndrome Triad: Reactive arthritis, uveitis, urethritis

Asthma is defined by a triad that includes airway inflammation, airway hyperresponsiveness, and reversible airflow obstruction. 

Charcot's Triad: For ascending cholangitis: RUQ pain, fever, jaundice.

MEN-1. One of these, involving the alpha cells, causes over-secretion of glucagon, resulting in a classic triad of high blood glucose levels (hyperglycemia), a rash called necrolytic migratory erythema, and weight loss. 

Normal Pregnancy Weight Gain

Normal weight gain is 25 to 35 pounds in the entire pregnancy. 3 to 6 in the first trimester followed by 0.5 to 1 pound per week in second and third trimesters.

PAP Smear Algorithm

PAP Results

Normal --> see you in 12 months (sy)

ASCUS --> HPV Test, if negative, sy. If positive, E6, E7. If neg, reassess in 6 months. If, positive, treat like Low Grade Dysplasia.

Low Grade: colposcopy every 6 months for 18 months, then at physician's discretion.

High Grade: LEEP procedure.

Pregnancy Screening Guidelines for Nova Clinic

Initial Visit:

Social, Family, Medical History

Complete Physical Exam (with Breast, Cervical, Pelvic Exam)
Labs: H/H, Blood type, Ab screen, Rhesus type, PAP smear, genetic screen if high risk (e.g. CF,
 SCA)

Urine: UA and Urine Cx

Infections: Rubella status, Syphilis Screen (RPR), Hep B surface antigen, HIV counseling and testing, Chlamydia, Gonorrhea (GCC), TB if high risk.

6-8 Weeks:

History and Physical: BP, Wt, BMI
Fetal Heart Tones.
Labs: Ab Screen if not done at initial, Genetic screen if not done at initial
Urine Dipstick
Ultrasound (Crown-Rump Length)

10-12 Weeks:

Chorionic Villus Sampling (if high risk)

16-18 Weeks:

History and Physical: BP, Wt, Fundal Ht, Fetal Heart Tones
Lab: Urine Dipstick, US (BPD, HC, FL, AC)
Amniocentesis if high risk
Pentascreen

26-28 Wks:

History and Physical: BP and Wt, Fundal Ht, Fetal Position and FHTs
Lab: H/H, Gestational DM screen, Ab Screen and Rhogam IF RH NEG.
Urine: Dipstick, UA and Urine Cx

32 Weeks:

History and Physical: BP, Wt, Fundal Ht, Fetal Position and FHTs
Urine Dipstick

36 Weeks:

History and Physical: BP and Wt, Fundal Ht, Fetal Position and FHTs
Labs: CBC
Urine Dipstick
Infections: HIV, Syphilis (RPR), HB Surface Ag, Chlamydia/Gonorrhea (GCC), GBS Culture

38 Weeks:

History and Physical: BP and Wt, Fundal Ht, Fetal Position and Fetal Heart Tones
Labs: H/H
Urine: Dipstick

39 Weeks (Term as of 2017):

History and Physical: BP and Wt, Fundal Ht, Fetal Position and FHT
Urine Dipstick

40 Wks:

History and Physical: BP and Wt, Fundal Ht, Fetal Position and FHT
Urine Dipstick

Sexual Genetic Deviations

Klinefelter Syndrome: XXY with small testes and increased height, usually impotent.

Turner Syndrome: X0 with short stature webbed neck and breasts facing laterally, impotent.

Swyer Syndrome: Genotypically male, phenotypically female due to Y chromosome mutation. Never go through puberty. Need to remove their gonadal streaks to prevent malignancy, impotent.

(Asherman Syndrome: secondary amennorhea 2/2 aggressive dilation and curettage.)

Hyperemesis gravidarum versus Physiologic Nausea and Vomiting of Pregnancy

Need to treat asymptomatic bacteriuria in pregnant patients

Haemophilus ducreyi

Cause of chanchroid sexually transmitted disease
Usually symptomatic in men (women usually carriers)
In about 2 weeks papule forms, evolves to pustule, to very painful ulcer
Usually seen with lymphadenopathy, may progress to bubos
Causes painful wide 10-20mm ulcerations
Seen as gram negative rod on gram stain of pustules.
Rx:

• Preferred:
  
  • Azithromycin 1 g PO as a single dose
  • Ceftriaxone 250 mg IM as a single dose
• Alternatives:
• Ciprofloxacin 500 mg PO twice daily x 3d
• Erythromycin base 500 mg PO four times a day x 7d

Fluctuant inguinal lymph nodes should be incised and drained.

Metronidazole Drug Profile

INDICATIONS

FDA

• Anaerobic infections: intra-abdominal infections, skin and skin structure infections, bone and joint infections
• Bacterial septicemia; endocarditis (caused by Bacteroides spp.)
• Gynecologic infections (endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection)
• Lower respiratory tract infections (in combination with another agent with activity against microaerophilic Streptococcus)
• Adjunct treatment for gastritis and duodenal ulcer associated with Helicobacter pylori
• CNS infections (meningitis and brain abscess)
• Treatment of acute intestinal amebiasis and amebic liver abscess
• Treatment of symptomatic and asymptomatic trichomoniasis
• Bacterial vaginosis (vaginal gel)
• Acne rosacea (topical gel)

NON-FDA APPROVED USES

• Colitis, antibiotic-associated including C. difficile
• Treatment of giardiasis and dracunculiasis
• Periodontal disease
• Elective colorectal surgery (classified as contaminated or potentially contaminated)

FORMS

brand name	preparation	manufacturer	route	form	dosage^	cost*
Flagyl	Metronidazole	Pfizer and generic manufacturers	oral	tablet	250 mg	$3.42
			oral	cap	375 mg	$5.24
			oral	tablet	500 mg	$6.12
			IV	minibag	500 mg	$9.42
Metrocream; Metrolotion	Metronidazole	Galderma	topical	cream	0.75% (45 g)	$72.00
			topical	gel	0.75% (70 g)	$36.00
MetroGel (Vaginal)	Metronidazole	Prasco	topical	gel	0.75% (70 g)	$33.71
MetroGel	Metronidazole	Galderma; Taro	topical	gel	0.75% (1.5 oz)	$65.89
			topical	gel	1% (60 g)	$193.70
Flagyl ER	Metronidazole	Pfizer	oral	extended release tab	750 mg	$12.70

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

• Susceptible anaerobic infections:
  • Traditional dosing:
    • Oral: 250-500 mg q8h
    • Parenteral: 500 mg IV q6h (manufacturer’s recommendation)
  • Dosing based on PK data
    • Oral 0.5-1 gm q12h
    • Parenteral: 0.5-1 gm q12h
      • Consider a loading dose of 1 gm for severe infections.
• C. difficile colitis: 500 mg PO q8h or 250 mg PO four times a day x 10-14 d.
• Bacterial vaginosis: 500 mg twice daily PO x 7d or Flagyl ER 750 mg PO once daily x 7d.
• Trichomoniasis: single 2 gm x 1 dose or 500 mg PO twice-daily x 7 d (more effective).
• Amebiasis: 750 mg PO q8h x 5-10 d.
• Giardiasis: 250 mg PO q8h x 5-10 d.

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

• Neonates (Neofax dosing):
  • Loading dose: 15 mg/kg/dose IV or PO x 1
  • Maintenance dose: 7.5 mg/kg/dose IV or PO

Metronidazole Dosing Interval Chart

Post-menstrual age (weeks)	Post-natal age (days)	Dosing interval (hours)
≤ 29 weeks	0-28 days >28 days	q48h q24h
30 to 36 weeks	0-14 days >14 days	q24h q12h
37 to 44 weeks	0-7 days >7 days	q24h q12h
≥ 45 weeks	ALL	q8h

• Neonates: (Cohen-Wolkowiez 2012[3] and 2013[2]*). 
  
  • Loading dose: 15 mg/kg/dose IV or PO x 1
  • Maintenance dose based on PMA:
    • 7.5 mg/kg/dose IV or PO q12h if PMA < 34 weeks
    • 7.5 mg/kg/dose IV or PO q8h if PMA 34-40 weeks
    • 7.5 mg/kg/dose IV or PO q6h if PMA > 40 weeks
    • *NOTE: this dosing achieves much higher concentrations when compared to Neofax dosing. Consider this dosing regimen for serious anaerobic infections like meningitis.

• Infants/Children:
  • Intra-abdominal infections: 30-40 mg/kg/day IV divided q6-8h; max 1500mg/day
  • Clostridium difficile infection (CDI): 30 mg/kg/day PO divided q6h; max 500mg/dose
  • Amebiasis: 35-50 mg/kg/day PO divided q8h; max 750mg/dose
  • Giardiasis: 15 mg/kg/day PO divided q8h; max 250mg/dose
  • Trichomoniasis: 15 mg/kg/day PO divided q8h; max 2000mg/day

Acknowledgement: Pediatric dosing information authored by Alice Jenh Hsu Pharm.D. BCPS

PEDIATRIC RENAL DOSING

• No renal dosage adjustment necessary.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual dose.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Usual dose.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

Usual dose.

DOSING IN HEMODIALYSIS

Usual regimen.

DOSING IN PERITONEAL DIALYSIS

Usual regimen.

DOSING IN HEMOFILTRATION

No data. Usual dose likely.

ADVERSE DRUG REACTIONS

COMMON

• GI intolerance
• Metallic taste
• Headache
• Dark urine (harmless)

OCCASIONAL

• Peripheral neuropathy (with prolonged use, usually reversible)
• Phlebitis at injection sites
• Disulfiram-like reaction with alcohol
• Insomnia
• Stomatitis

RARE

• Neuro: seizures, encephalopathy, aseptic meningitis, optic neuropathy, dysarthria
• Stevens-Johnson Syndrome

DRUG INTERACTIONS

• Barbiturates: may decrease metronidazole levels.
• Disulfiram: contraindicated.
• Ethanol: nausea, vomiting, headache, abdominal cramps, and flushing. Acute of psychosis or confusional state may also occur (avoid co-administration). Alcohol should be avoided and disulfiram should be discontinued 2 wks prior to use of metronidazole.
• Lithium: lithium levels may be increased.
• Lopinavir liquid: disulfiram-like reaction (avoid co-administration).
• Phenytoin: phenytoin levels may be increased.
• RTV liquid: due to the alcohol content in the RTV liquid formulation, a disulfiram-like reaction may occur (avoid co-administration).
• Tipranavir capsule: disulfiram-like reaction (avoid co-administration).
• Warfarin: INR may be increased.

SPECTRUM

Trichomonas vaginalis; Giardia lambia; Entamoeba histolytica

Spectrum of Activity

Pathogen	Line
Anaerobic gram-positive bacilli
Clostridium difficile	1st line
Clostridium species	2nd line
Anaerobic gram-positive cocci
Peptostreptococcus spp.	2nd line
Aerobic gram-negative bacilli
Helicobacter pylori	1st line
Anaerobic gram-negative bacilli
Prevotella bivia (Bacteroides)	1st line
Bacteroides distasonis	1st line
Bacteroides fragilis	1st line
Bacteroides ovatus	1st line
Bacteroides thetaiotamicron	1st line
Bacteroides vulgatus	1st line
Prevotella intermedius	1st line
Fusobacterium necrophorum	1st line
Prevotella melaninogenicus	1st line

RESISTANCE

• H. pylori resistance rate up to 20-30%. High metronidazole doses (1.5g/d) may overcome resistance.

PHARMACOLOGY

MECHANISM

Exact mechanism not fully elucidated, but reduction of metronidazole may lead to a polar metabolite that disrupts DNA and inhibits nucleic acid synthesis.

PHARMACOKINETIC PARAMETERS

Absorption

90% absorbed with oral administration (IV only if oral administration is contraindicated).

Metabolism and Excretion

Hepatic hydroxylation, oxidation and glucuronide conjugation to an active metabolite (2-hydroxy metronidazole) accounts for 30-60% of administered dose. 77% of the dose excreted in urine and 14% in feces as unchanged drug and metabolites within 5 days.

Protein Binding

20%.

Cmax, Cmin, and AUC

20-25 mcg/mL after 500 mg PO or IV dose administration.

T1/2

6-14 hrs.

Distribution

Distributed to saliva, bile, seminal fluid, bone, liver, and liver abscesses, lungs, vaginal secretions. Good CSF penetration (30-100% of serum levels attained in the CSF).

DOSING FOR DECREASED HEPATIC FUNCTION

Decreased dose in severe hepatic impairment.

PREGNANCY RISK

Category B: animal (rodents) data show risk of carcinogenicity. The use of metronidazole in pregnancy is controversial, reports in humans have arrived at conflicting data (but most studies show no risk). The manufacturer and CDC consider metronidazole to be contraindicated in the first trimester.

BREAST FEEDING COMPATIBILITY

Excreted in breast milk. American Academy of Pediatrics recommends using metronidazole with caution, discontinuation of breast feeding for 12-24 hrs recommended to allow excretion of the drug.

COMMENTS

• Metronidazole is the gold standard anti-anaerobic agent. Generally active against almost all anaerobes with exception of actinomyces, Propionibacterium acnes, and Lactobacillus spp.
• Some Bacteriodes spp. with resistance described (e.g., B. thetaiotaomicron).
• Additional antibiotic coverage needed for combined aerobes/anaerobes infections (metronidazole only active against anaerobes).
• First line agent for giardiasis, trichomoniasis, and amebiasis.
• Oral vancomycin and metronidazole are equivalent in the treatment of MILD (but not severe; oral vancomycin preferred) C. difficile associated colitis with comparable rates of response and relapse.

References

1. Boyanova L, Kolarov R, Mitov I: Recent evolution of antibiotic resistance in the anaerobes as compared to previous decades. Anaerobe May 26  [PMID:24875330]
   Comment: Resistance is increasingly described with metronidazole to Bacteroides/Parabacteroides spp. Historically, resistance was nil, reports starting in ~2000 through 2010 in Urope, USA and Middle East place rates of resistance from 0.06% (USA) to 4.0% (Spain).
   Rating: Important
2. Cohen-Wolkowiez M et al: Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants. Pediatr Infect Dis J 32:956, 2013  [PMID:23587979]
   Comment: Multicenter PK study of metronidazole in premature infants < =32 weeks gestation demonstrating that a simplified dosing scheme based on PMA would be able to achieve targetted troughs in >80% of infants. 
3. Cohen-Wolkowiez M et al: Population pharmacokinetics of metronidazole evaluated using scavenged samples from preterm infants. Antimicrob Agents Chemother 56:1828, 2012  [PMID:22252819]
   Comment: PK study of metronidazole in preterm infants < =32 weeks gestation and < 120 days old evaluated the probability of achieving metronidazole troughs of >8 mcg/mL using three different dosing recommendations, and found that a simplified dosing scheme based on PMA was best at achieveing targetted troughs. 
4. Bartlett JG: Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 145:758, 2006  [PMID:17116920]
   Comment: C. difficilehas been more frequent, more severe, more refractory to standard therapy, and more likely to relapse. This pattern is wildly distributed in the US, Canada, and Europe and is now attributed to a new strain of C. difficiledesignated BI, NAP1, or ribotype 027 (which are synonymous terms). This strain appears more virulent, possibly because of production of large amounts of toxins, and fluoroquinolones are now major inducing agents along with cephalosporins, which presumably reflects newly acquired in vitro resistance and escalating rates of use. The recent experience does not change principles of management of the individual pt, but it emphasizes the need for better diagnostics, early recognition, improved methods to manage severe disease and relapsing disease, and greater attention to infection control and antibiotic restraint. 
5. Czeizel AE, Rockenbauer M: A population based case-control teratologic study of oral metronidazole treatment during pregnancy. Br J Obstet Gynaecol 105:322, 1998  [PMID:9532994]
   Comment: Use of oral metronidazole during pregnancy presents no clinically important association with congenital abnormalities. Risk of metronidazole exposure in pregnancy has been ongoing controversy since It showed positive results in the Ames test and fetal toxicity in rodent studies. Nevertheless, FDA pregnancy class is B and most recommend avoidance in first trimester. 
6. Misra PK et al: A comparative clinical trial of albendazole versus metronidazole in children with giardiasis. Indian Pediatr 32:779, 1995  [PMID:8617554]
   Comment: Both metronidazole and albendazole can be effective in the treatment of giardiasis. Represents a new use for albendazole. 
7. Joesoef MR, Schmid GP: Bacterial vaginosis: review of treatment options and potential clinical indications for therapy. Clin Infect Dis 20 Suppl 1:S72, 1995  [PMID:7795111]
   Comment: 2002 CDC guidelines for management of STDs (MMWR 2002;51(RR-6):1-78) recommend: metronidazole 500 mg twice daily x 7 d, clindamycin 2 gm intravaginal x 7 d or metronidazole gel 0.75% intravaginal twice daily x 5 d. Oral metronidazole is most cost effective regimen for treatment of bacterial vaginosis. 
8. Teasley DG et al: Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 2:1043, 1983  [PMID:6138597]
   Comment: Study criticized as inconclusive because most of the pts had mild disease that may have responded to single withdrawal of the inducing agent. A subsequent comparison included more seriously ill pts (the majority had endoscopy confirmed PMC) and showed equivalence. Most authorities accept oral vancomycin and metronidazole as equivalent with comparable rates of response and relapse. Major advantages to metronidazole are cost (AWP=$214 per 10 day course of vancomycin vs. $2.40 for metronidazole) and avoidance of vancomycin abuse. 
9. Perlino CA: Metronidazole vs clindamycin treatment of anerobic pulmonary infection. Failure of metronidazole therapy. Arch Intern Med 141:1424, 1981  [PMID:7025777]
   Comment: This is 1 of 3 reports with total of 51 pts showing nearly 50% failure rate with metronidazole. Presumed explanation is lack of activity vs aerobic and microaerophilic streptococci that are often concurrently present and clinically important. May be used for anaerobic lung infections if combined with PCN. 
10. Chaudhry R et al: Emergence of metronidazole-resistant Bacteroides fragilis, India. Emerg Infect Dis 7:485, 2001 May-Jun  [PMID:11384542]
    Comment: Multiple studies have shown increasing resistance of B. fragilisto beta-lactams and clindamycin, but metronidazole appears to have consistent activity against virtually all strains (Antimicrob Agents Chemother 1999;43:2417; Int J Antimicrob Agents 2000;15:1). This is the fifth report of a single strain of B. fragilis resistant to metronidazole (Others are J Infect 1992;25:211; J Infect 1990;20:129; J Antimicrob Chemother 1989;23:660; J Antimicrob Chemother 1986;18:642; Lancet 1995;345:1275). 
11. Metronidazole. In: Neofax(R). Truven Health Analytics, Inc. Greenwood Village, CO. http://neofax.micromedexsolutions.com/ . Accessed June 10, 2014.
    Comment: Neofax dosing recommendations for metronidazole based on post-menstrual and post-natal age.