Diseases, Disorders information

Antifungal antibiotics. There are just buckets of these. I would comment on a couple of things. First of all, amphotericin B is a very toxic drug when you have to give it IV. It’s nephrotoxic. It causes hypokalemia. It causes a syndrome we call “shake and bake” which is chills or shakes and fever.

There are newer products available that are lipid complexes. Abelcet and Amphotec and AmBisome. These will cut down on the nephrotoxic reactions and will cut down on the intolerance of the drug but they are more than 20 times more expensive than amphotericin B. So when you can use amphotericin B continue to use it. For those patients who have renal impairment or are intolerant of amphotericin B, these may very well be useful.

Flucytosine may be useful in some fungal infections. However, there are others that have largely replaced it. Ketoconazole may be useful for mucocutaneous candidiasis and some other infections. There are a whole bunch of drug interactions with these products and they can cause disulfiram-like reactions.

Fluconazole or Diflucan is often preferable to Ketoconazole when that might be used. It can be used single dose for vaginal candidiasis. It is the drug of choice for coccidioidal mycosis. It can be used for cryptococcosis. It does have some hepatotoxic reactions. It can be teratogenic so you would want to be careful about using that drug during pregnancy.

Itraconazole or Sporanox can be useful in things like blasto- and histoplasmosis. It’s the drug of choice for that indication. It may be useful in aspergillosis and nail infections, mucosal candidiasis.

There are two different forms of this product out there. One is a capsule and one is a suspension. Be aware that the capsule should be given with meals but the suspension should be given between meals.

Terbinafine or Lamisil is another product that has been marketed. It may be useful in treating nail infections. The usual treatment course is six to twelve weeks. It costs less than itraconazole so it might be a reasonable substitute. The other drugs have been around forever.

Miconazole IV is not usually a preferred drug but I put it on for completeness and no doubt you’ve seen more nystatin in your life than you’d care to ever see.

Sulfas. Major uses. These can be used in urinary tract infections. They can be used in combination therapy for otitis media. Be aware that allergic reactions and blood dyscrasias are problems. These drugs can cause literally any kind of skin rash known to mankind.

Gantrisin or sulfisoxazole has been used in otitis media prophylaxis. I presume you’ve had your pediatrics lecture by now?

Cotrimoxazole. This is Bactrim or Septra. This is used for things like otitis media and pneumocystis carinii prophylaxis and treatment. The problems with these drugs are mainly related to sulfa although trimethoprim can cause some bone marrow suppression.

It’s for that reason that some patients who are immunosuppressed may occasionally be put on Bactrim or Septra three times a week, Monday, Tuesday, Wednesday or something like that. Basically that is to suppress pneumocystis. Pneumocystis is a fairly slow growing organism. It only requires occasional exposure to the drug to be able to suppress it or to keep it from growing. So if we gave it every day in somebody with bone marrow suppression, we might be further suppressing the bone marrow with the trimethoprim and that’s the reasoning for that. It’s not that somebody has made a mistake.

Cefotetan or Cefotan is another product very similar to cefoxitin in its uses. It is used less often, once a day or twice a day, so this may be preferable in some circles if you want to use a cephalosporin for anaerobes.

Cefmetazole can cause some reactions. Bleeding, disulfiram or Antabuse-like reactions with alcohol. We really don’t see a unique use for this product so we tend not to talk very much about it.

Similarly, cefonicid is marketed as Monocid. It has more activity against H. flu but it is less active against Gram positives. So, again, we don’t see a really unique place where this drug should be used and it’s one that I don’t see a particular amount of use for.

Now, if I need to stick a stick in a hornet’s nest and shake it up, this is the one drug that I will potentially create controversy with and that’s cefaclor or Ceclor. This drug is way overused. It is a very palatable drug. Children will take it. But it is not that effective. It has been shown that tissue levels may be lower than with other oral cephalosporins. Serum sickness is possible with repeat use, much more so than with any of the other cephalosporins and actually the cost of this drug, even though it is now available in generic form, is only about $5 for a prescription less than some of the new second and third generation cephalosporins. So this really is a drug that possibly you could forget about and there are plenty of other good drugs available that are going to cause a lot fewer calls in the middle of the night because of treatment failures or adverse reactions.

Cefprozil is Cefzil. This is a product that is given once or twice a day as an oral tablet or suspension. It can be used for otitis media and soft tissue infections although this is not a drug of first choice usually. It certainly is a reasonable alternative particularly in patients who have trouble tolerating some of the drugs that we will mention to you later.

Cefuroxime is marketed as a parenteral product – Zinacef – and also as an oral tablet or suspension as Ceftin. While it used to be used in meningitis, it is no longer recommended for use because it is not as effective as the third generation agents. It does have good activity against many of the common infecting organisms that cause soft tissue infections and pneumonias. It is a good empiric therapy, for example, in a pediatric pneumonia because it covers most of the common infecting organisms unless you think there is a meningitis present.

The problem with cefuroxime is that it is very bitter. The suspension needs to be given with food. Regardless, it tastes bad. Kids under three don’t seem to mind that terribly and that’s a prime age group for using this drug, for example, in acute otitis media and I will mention another drug that is very similar to this in a few minutes. But it is less expensive than the third generation cephalosporins so it may have some cost advantage unless you’re worried about meningitis.

Third generation cephalosporins generally have an increased Gram negative spectrum with decreased Gram positive activity generally. They are considered third generation based on a broader Gram negative spectrum. Some people think of these as being third generation because of anti-Pseudomonal activity but frankly none of the oral third or fourth generation agents have Pseudomonas coverage.

CSF levels with many of these parenteral products are adequate to treat meningitis. In fact, several of these drugs are considered drugs of choice for meningitis now. Be aware though that these drugs have poor coverage of Listeria and poor coverage of Enterococcus so you can get overgrowth of these particular organisms. For example, in a neonatal intensive care unit you may see ampicillin being added to Claforan in a child with sepsis to cover the possibility of Listeria.

Cefotaxime is Claforan. This is probably the most useful of the third generation cephalosporin parenteral products. It is given parenterally usually every six hours. It is a drug of choice for neonatal sepsis and meningitis and is a drug for meningitis in general in pediatrics. It is useful in gonorrhea especially in young children and in CNS Lyme disease. It has minimal effects on bowel flora and that fact is going to come back as we talk about several of the other products in terms of being a unique advantage for this product.

Ceftizoxime is Ceftizox. This particular product is like Claforan or cefotaxime but it is given every eight hours. However, we don’t have a great deal of experience with this in children and the literature generally has not adapted this instead of cefotaxime. Cefotaxime continues to be the preferred drug.

Ceftriaxone is Rocephin. This particular product is just as good as Claforan against meningitis. The advantage here is that it is given once a day. The problem here, though, is that this drug has a much greater effect on suppressing bowel flora than does cefotaxime. It’s for that reason that we would prefer to use cefotaxime or Claforan for IV therapy in institutionalized patients and switch to Rocephin or ceftriaxone when we switch to IM therapy or for home therapy. There is no sense in inducing pseudomembranous colitis or other severe diarrheas with a drug when we have an alternative drug that is only a little more expensive that is available and that is the reasoning behind the use of that. However, that said, this is a very good drug for treating gonorrhea. It’s a good drug for treating serious Lyme disease and it is especially useful for IM therapy.

Cephalosporins. There are now four generations of cephalosporins. The third and fourth generation cephalosporin differences are fairly minor and we will treat those as a group. First generation cephalosporins and second generation cephalosporins do not cross the blood-brain barrier in adequate quantities to be able to use those for any CNS infections. So none of these would be recommended for treating a meningitis, for example. The first generation agents generally cover Gram positives including Staph aureus to about the same extent as the penicillinase resistant penicillins. So these are good drugs to use instead of the drugs like oxacillin.

The cephalosporins, as a group, may be useful in penicillin allergic patients but the general rule of thumb should be if they had an anaphylactoid reaction to penicillin, avoid cephalosporins if you can. If they have a rash with penicillin, there is probably about a 5% incidence of cross-reactivity but that’s not too much higher than the 3% background rate of rash that you are going to get anyway. So most clinicians would suggest that it is safe to use these provided you counsel the patient about stopping the drug and contacting you if a rash develops.

A major use for the first and second generation agents is in surgical prophylaxis, particularly the first generation agents. Gram negative spectrum with the first generation agents is quite spotty. We do not suggest that they be used for Gram negative infections. As I mentioned earlier, these are very useful and probably actually are the preferred drugs for treating non-methicillin resistant Staph aureus infections where a liquid is needed.

Cefazolin is Kefzol. You’ll notice I don’t have cephalothin or Keflin on this. Cephalothin had to be given every six hours. It caused a lot of IM pain. Cefazolin is given every eight hours. It causes less IM pain and really in most hospitals has replaced cephalothin and therefore that’s the only one I have listed here. So this would be the parenteral drug that usually would be used. Cephapirin or Cefadyl is another drug that is very much like cefazolin and has similar uses.

For the oral cephalosporins, actually these drugs may be quite useful in Staph aureus infections particularly as the liquids. Liquid Keflex of cephalexin. One of the products is bubble gum flavored. It’s quite well tolerated by children. It’s not terribly expensive so this may be a preferred product.
Antibiotics
Our experience here has been that cephalexin is the product we prefer in preadolescent children when we are trying to treat a Staph infection or we want to use an oral first generation cephalosporin. For adolescents and adults, we often would use cefadroxil. Cefadroxil does come in a liquid dosage form and is given less often so that should improve compliance. But our experience with trying to use cefadroxil in younger children, we found that we were having more treatment failures than when we had been using cephalexin so we switched back. So, in general, I would suggest the use of cephalexin or Keflex in younger children and in adolescents and adults use cefadroxil.

Dosing of lithium

Dose-response relationships of lithium and other proposed mood-stabilizing agents have not been investigated extensively. Most studies have considered the daily minimum or trough serum levels of lithium (ca. 12 hrs after the last dose), which were introduced initially to provide protection from overdosing with this agent of very low therapeutic index (only about 3-fold ratio of toxic to therapeutic levels). Levels of about 0.50-1.25 mEq/L cover the therapeutic range; levels below 0.5 mEq/L are less effective, while levels above 1.0 mEq/L probably provide limited additional benefit but increase side effects and are best reserved for acute mania, rapid cycling, or treatment-resistant cases. Tolerability and compliance may be enhanced by long-term use of relatively moderate doses of lithium (providing levels at 0.6–0.8 mEq/L), as is standard in European clinical practice. Based on animal experimentation and limited and inconsistent clinical data, it has been suggested that once or twice daily dosing with ordinary lithium carbonate may reduce renal side effects, particularly polyuria and nocturia, and increase compliance; however, in view of the narrow margin of safety of his agent, and the risk of CNS intoxication with high peak plasma concentrations (which can be at least 2-3x trough levels), especially in elderly patients, and the limited risk of significant, irreversible, nephrotoxicity of lithium, as well as trivial average reductions in 24-hour urine volumes, once-daily dosing is not recommended as a routine practice. Sustained-release lithium carbonate may limit CNS intoxication risks but can increase GI distress. Many patients are now reluctant to accept lithium treatment owing to popular views of its alleged toxicity or lack of efficacy, as well as issues of stigmatization and denial of illness. Moreover, adherence to long-term lithium treatment is often variable, and requires constant encouragement in order to maximize protective benefits.
Antidepressants
Adverse effects of lithium

Adverse effects of lithium include frequent initial polyuria and thirst and 10%-20% risk of later persistent (but usually reversible), clinically significant diabetes insipidus, associated with elevated circulating levels of antidiuretic hormone (ADH) and unresponsiveness to exogenous synthetic antidiuretic peptides (such as desmopressin). High 24-hr urine volumes (5 L) have been associated with elevated risk of histopathological changes in renal biopsies suggestive of chronic granulomatous, nephron-distorting, inflammation. Nevertheless, irreversible azotemic renal failure due to lithium treatment is rare and is sensitively and simply detected by quarterly or semiannual monitoring of serum creatinine concentrations, watching for gradually rising trends rather than any single abnormal value.

Weight-gain and dermatological disorders (severe acne, worsening of psoriasis, mild alopecia) are common reasons for discontinuing lithium. However, subtle neurological or cognitive effects are among leading reasons to resist or discontinue long-term lithium therapy. These include a high risk of mild resting tremor and impaired handwriting (often responsive to reduced dose or use of propranolol), as well as varying degrees of subjective cognitive impairment, mild mental confusion and even low-grade delirium, which can occur even at trough plasma concentrations in a nominally therapeutic range, particularly in elderly or neurologically impaired patients.

Clinical myxedema is unusual during lithium therapy, diffuse, nontoxic, and non-precancerous goiter can occur, sometimes with a lowering of serum thyroid hormone indices into the low-normal or subnormal range, with elevated TSH as an early harbinger; some clinicians believe that adding supplemental thyroid hormone not only can reduce goiter, but may also contribute to minimizing depression and slowing rapid cycling.

There probably is moderately increased risk of major cardiovascular malformations during the first trimester of pregnancy during lithium use (most commonly, Ebstein’s tricuspid/septal malformations, at 2-5 times above the spontaneous base rate of ca. 1/20,000 live births). Lithium can also induce hypotonia in the newborn, and elimination and tolerance of lithium typically decrease sharply soon after delivery. These risks have strongly encouraged avoiding pregnancy during lithium treatment. Nevertheless, recurrence risks in pregnancy, and especially the neonatal period, are high when lithium is discontinued early in pregnancy (similar to that in nonpregnant women), and particularly rapidly. Sudden discontinuation of lithium (eg, due to pregnancy or other medical contraindications), even in patients who have been euthymic for several years, carries a high risk of early relapse which can be minimized by slowly tapered dosing (over at least one month). While mood-stabilizing anticonvulsants can not be considered safe during pregnancy (mainly owing to spina bifida in >1/100 cases), cautious use of neuroleptics or antidepressants in low-effective doses can be considered when necessary, and ECT is safe and effective in mania or depression during pregnancy. For some high-risk patients, lithium is being used in middle or late pregnancy and the neonatal period to avoid potentially dangerous and life-threatening (suicide, infanticide) recurrences of manic-depressive illness (as many cases of “post-partum psychosis” probably are).

Efficacy of lithium salts

Lithium salts (carbonate or citrate) are relatively specific for the treatment of mania but their onset of useful action is slow (5-10 days). For this reason, and due to the limited margin of safety (therapeutic index) of lithium in acutely disturbed, poorly cooperative, and metabolically compromised patients, many are not treated immediately or primarily with lithium in acute mania. Instead, they are treated temporarily with an antipsychotic agent (often more dramatically effective in mania than in schizophrenia) or a sedative (usually a high-potency benzodiazepine, such as lorazepam [Ativan] or clonazepam [Klonopin]). Lithium salts can then be added safely in gradually increasing doses. Short-term effectiveness in mania is best established in young adults (in whom placebo response rates are surprisingly high: 30%-40%), almost certainly extends to adolescents, is poorly studied in children, and may be less effective and is less well tolerated in the elderly. Lithium is particularly useful for continuation treatment in the months following clinical recovery from an acute episode of mania, and for long-term maintenance treatment aimed at minimizing risk or severity of future recurrences of mania or bipolar depression in cases with severe or multiple episodes. In maintenance treatment, lithium appears to be more effective against hypomanic > manic > depressive phases in bipolar disorder; it is very effective in Type II bipolar disorder (episodic major depression with hypomania or cyclothymia). Lithium probably is also effective adjunctively in nonbipolar depression, including cases of apparent antidepressant unresponsiveness or tolerance (best tested with TCAs), and as an adjunct in recurring major depression, although the place of routine lithium treatment in nonbipolar major depression is less secure and not currently included in FDA-approved guidelines. Poor response to lithium can be anticipated in patients who present with mixed, agitated, or psychotic bipolar states; those presenting depression before mania may do less well than those who present with mania first (D-M-I vs. M-D-I syndrome, in which I = euthymic interval), but rapid-cycling (>4 episodes in any year), and prolonged latency from illness onset to the start of treatment do not necessarily predict a poor response to lithium.

Evidence for efficacy of lithium in acute nonbipolar depression is much weaker than for bipolar depression. Some beneficial effects of lithium in depression may be due to underdiagnosis of bipolar disorder and related conditions, or the possibility that some cases of apparent nonbipolar depression may be phenotypic variants of bipolar disorder (”pseudounipolar” depression hypothesis). It is also very likely that recurring depressive illness can be worsened with excessive antidepressant treatment (rapid cycling, agitation, mixed states, mania or psychosis); such cases may include apparently “treatment-resistant” depression, and less aggressive antidepressant treatment or adding lithium may be useful in their management. Lithium salts (and antimanic anticonvulsants) also may have a place in some other conditions, including cases of secondary bipolar disorder associated with neurological disorders (particularly in the elderly), as well as episodes of aggressive outbursts, even in persons without clear evidence of a primary mood disorder. Other potential medical applications of lithium, as in hyperthyroidism and leukopenia, lacks substantial support.

Surprisingly, lithium is the only form of maintenance treatment in recurring major affective disorders with substantial evidence of reduced suicidal risk (including anticonvulsants, antidepressants, ECT, and psychotherapy, but perhaps not clozapine which has reduced suicide risk in schizophrenia, at least). Recent direct comparisons of lithium with TCA maintenance in unipolar depression and carbamazepine in bipolar cases found more protection against suicide attempts with lithium. It is not clear whether this is a specific effect or a reflection of long-term protection against depression by lithium. Suicide risk is at least six-fold lower on lithium, and may increase over time-on-treatment. Stopping lithium is followed by sharply increased, largely time-limited, risks of recurrences of mania and depression and also suicide attempts and deaths, with evidence that slow discontinuation can reduce this risk. Mortality rates are further elevated in bipolar disorders due to comorbid medical disorders (particularly stress-related cardiovascular and pulmonary diseases) and complications of substance abuse, and treatment may reduce overall mortality risk.

Approach to acute pelvic pain with a positive pregnancy test

In a female patient of reproductive age, presenting with acute pelvic pain, the first distinction is whether the pain is pregnancy-related or non-pregnancy-related on the basis of a serum pregnancy test.
In the patient with acute pelvic pain associated with pregnancy, the next step is localization of the tissue responsible for the hCG production.
Transvaginal ultrasound should be performed to identify an intrauterine gestation. Ectopic pregnancy is characterized by a noncystic adnexal mass and fluid in the cul-de-sac.
If a gestational sac is not demonstrated on ultrasonography, the following possibilities exist:
Ectopic pregnancy
Very early intrauterine pregnancy not seen on ultrasound
Recent abortion
Management of patients when a gestational sac is not seen with a positive pregnancy test
Diagnostic laparoscopy is the most accurate and rapid method of establishing or excluding the diagnosis of ectopic pregnancy.
Examination of endometrial tissue. For pregnant patients desiring termination, and for those patients in whom it can be demonstrated that the pregnancy is nonviable, suction curettage with immediate histologic examination of the curettings is a diagnostic option. The presence of chorionic villi confirms the diagnosis of intrauterine pregnancy, whereas the absence of such villi indicates ectopic pregnancy.

Management of the ectopic gestation

Two IV catheters of at least 18 gauge should be placed and 1-2 L of normal saline infused.
Laparoscopy or laparotomy with linear salpingostomy or salpingectomy should be accomplished in unstable patients. An HCG level should be checked in one week to assure that it is declining.
Methotrexate. Stable patients can be treated with methotrexate in a single intramuscular dose of 50 mg per meter2. Treatment response should be assessed by serial HCG measurements made until the hormone is undetectable.

Approach to acute pelvic pain in non-pregnant patients with a negative HCG
Acute PID is the leading diagnostic consideration in patients with acute pelvic pain unrelated to pregnancy. The pain is usually bilateral, but may be unilateral in 10%. Cervical motion tenderness, fever, and cervical discharge are common findings.
Acute appendicitis should be considered in all patients presenting with acute pelvic pain and a negative pregnancy test. Appendicitis is characterized by leukocytosis and a history of a few hours of periumbilical pain followed by migration of the pain to the right lower quadrant. Neutrophilia occurs in 75%. A slight fever exceeding 37.3EC, nausea, vomiting, anorexia, and rebound tenderness may be present.
Torsion of the adnexa usually causes unilateral pain, but pain can be bilateral in 25%. Intense, progressive pain combined with a tense, tender adnexal mass is characteristic. There is often a history of repetitive, transitory pain. Pelvic sonography often confirms the diagnosis. Laparoscopic diagnosis and surgical intervention are indicated.
Ruptured or hemorrhagic corpus luteal cyst usually causes bilateral pain, but it can cause unilateral tenderness in 35%. Ultrasound aids in diagnosis.
Endometriosis usually causes chronic or recurrent pain, but it can occasionally cause acute pelvic pain. There usually is a history of dysmenorrhea and deep dyspareunia. Pelvic exam reveals fixed uterine retrodisplacement and tender uterosacral and cul-de-sac nodularity. Laparoscopy confirms the diagnosis