Online Canadian Pharmacy Blog

Azlocillin is like piperacillin in its spectrum and its uses. It basically is essentially as good as piperacillin and I would suggest that whichever one you use depends on which one your institution can get the least expensively. You do not need to have both azlocillin and piperacillin in a given hospital.

Penicillin H resistant penicillins are useful for Staph aureus infections. That is essentially the only reason that these should be used because they are significantly more expensive and more toxic for other uses. Therefore, they should be limited to treatment of suspected or proven Staph aureus. These should not be used for methicillin resistant Staph aureus and I might point out that methicillin resistant Staph aureus is a misnomer. These are not only methicillin resistant, they are also beta-lactam resistant, so they are unlikely to be susceptible to any of the penicillins or the cephalosporins.

One other thing that you need to consider when you are prescribing these products is that most of the oral liquids of these products are literally unpalatable. I don’t know if you have ever tasted oxacillin or dicloxacillin liquid but in taste tests with children, we routinely find that these products end up at the very bottom in terms of acceptability. If you have used these over the years and you went back and talked to your patients and they were honest with you, they might have taken one or two doses and refused to take anymore. There are some alternatives that I will be talking about in a minute but I would strongly encourage you wherever possible to stay away from using the oral liquids of these products.
Antibiotics
Methicillin, too, is probably a product that has fallen by the wayside in terms of its use because it is the most nephrotoxic of this group. While it is the least highly protein bound and should achieve the highest blood levels of free drug, it also is the most nephrotoxic. So most institutions that I am aware of no longer have this on their formulary.

Nafcillin is a parenteral product that has some Staph that are susceptible to it that are not to others in this group. So in terms of the most effective of these drugs, this is the most effective. But the IV dosage form is very irritating. Many hospitals have switched to syringe pump administration systems because a syringe costs 50 cents and a piggy back costs a patient $5 and so it is more economical to do it that way. But when we put this drug in a syringe pump and run it in over 20 minutes, it is more concentrated than it would have been in a piggy back and it can lead to major venous irritation, phlebitis and loss of IV sites. Regardless, the oral dosage form should not be used. Oral nafcillin is too unpredictable in terms of its bioavailability so I would strongly encourage you to forget that oral nafcillin even exists.

The alternative to nafcillin IV is oxacillin and many institutions use that. That is the product that we use here as our penicillinase resistant parenteral penicillin because we use a syringe pump system.

Oral oxacillin, cloxacillin and dicloxacillin. In the solid dosage forms, you may be able to get a patient to take it but (1) They need to all be given on an empty stomach. Hopefully the pharmacist will tell them that but it is probably best to prescribe them that way. (2) There is confusion and controversy about which of these is the best one to use. Cloxacillin is better absorbed than oxacillin. It is monochlorinated oxacillin. Dicloxacillin is dechlorinated oxacillin. It’s the best absorbed of the three. I will give you that. But it’s also the most highly protein bound. There is nearly twice as much free drug with oxacillin than there is with dicloxacillin. The bottom line then is that you probably should be using whichever one of these three is the least expensive for your institution to purchase. Dicloxacillin is really not that much better.

Ticarcillin is also a penicillin derivative but its major activity, rather than being Gram positive, is Pseudomonas. That is the principal use of ticarcillin. We give it IV in large doses. It is impractical to give this product IM. It contains about 5 milliequivalents of sodium per gram and we give big doses. So we potentially could be running the equivalent of two-thirds or a full liter of normal saline into our patient with the sodium content of this product. So you can get into sodium overload problems. You can also, in patients who are predisposed to bleeding, run into problems with this because it can interfere with platelet adhesiveness and directly with the coagulation sequence. In most normal patients that is not a concern but if you have someone with a preexisting severe nutritional deficiency or coagulopathy, you probably should be careful about using this particular product.

Carbenicillin indanyl sodium used to be available parenterally. It is no longer available that way. It is only available in an oral tablet that can be useful in urinary tract infections and prostatitis. It is a big pill. It is very bitter. It is very hard to get some people to take it and please don’t ask them to crush it. If you crush it and try to mix it with something, it tastes like rotten eggs. Fortunately, we have other drugs such as the fluoroquinolones that are effective instead of this drug in prostate problems so it’s not as necessary as it once was.

Ticarcillin clavulanate is Timentin. This is a parenteral product that may be useful when Ticar effectiveness is being reduced by beta-lactamase production. However, there are other single entity antibiotics that are equally effective and possibly less expensive. So we haven’t found a lot of use for this particular drug but it is certainly one that is out there that may occasionally be useful.

Also we don’t use mezlocillin a great deal but mezlocillin is better than ticarcillin against Pseudomonas. It’s not quite as good, though, as piperacillin or azlocillin and rather than having a whole number of antibiotics with similar spectrum on our formulary we choose not to have this particular product.

Piperacillin is sort of the top of the line of the anti-Pseudomonal penicillins. It is better than ticarcillin against Pseudomonas but it is significantly more expensive. It doesn’t have the significant bleeding problems. It has less sodium although sometimes it can be enough to get you into trouble. It is also available as Zosyn as a parenteral product combined with Tazobactam. Again, the Tazobactam is useful in preventing beta-lactamase induced destruction. It probably should be restricted to resistant organisms or treatment failures. Please note that the dose of piperacillin contained in this, if you are dosing it properly, is considered inadequate to treat Pseudomonas. So this is not a supercharged anti-Pseudomonal med but rather using Zosyn may extend the spectrum against some other Gram negative organisms which may be beta-lactamase producers.

Penicillin resistant Pneumococcus and other bacterial resistance have become a rapidly increasing problems. So we have to be careful with the way we use antibiotics as we do any other drug. Some resistant mechanisms work by competitive antagonism. The sulfas are folic acid synthesis inhibitors. Those bacteria that are obligate folate synthesizers are inhibited because there are non-utilizable forms of folate that are synthesized when the sulfas are present. Some others are cell wall inhibitors. For example, penicillins and cephalosporins will cause defects in the formation of the cell walls. Essentially it’s like taking the cement out from between the bricks. The cell membrane may, too, be interfered with. The antifungals very often will align themselves between the lipid and protein complexes and interfere with the metabolic functions of the cell membrane in fungi. Some will inhibit protein synthesis. For example, erythromycin, tetracycline and chloramphenicol will basically stop protein synthesis. They are therefore considered bacteriostatic drugs.

Others will cause protein synthesis to be altered. For example, the aminoglycosides like tobramycin or gentamicin cause the formation of non-utilizable proteins. So the bacteria go on trying to grow and yet the proteins which are critical to their structural integrity – enzymes, etc – are no longer there. Lastly, nucleic acid interference includes drugs like ciprofloxacin, which is a DNA gyrase inhibitor.

Penicillins. That is typically where most antibiotic lectures start. A reminder that if someone is truly allergic to one penicillin, they should be considered allergic to all other penicillins. But penicillins in general are fairly low in toxicity other than allergic reactions. You can occasionally get into electrolyte overload with some of the parenteral forms. Most of them contain either potassium or sodium and if you have a patient who has electrolyte disturbances, you might get into trouble with sodium or potassium overload.

Penicillin G is the first drug that we will basically talk about. It is useful in a number of Gram positive infections. It is relatively nontoxic. It is cheap. If you give it IM, though, it is painful and you have to give it frequently. IV, if you order aqueous penicillin G or penicillin G K or crystalline penicillin, the pharmacy will send you the potassium salt. Now, that contains about 1.8 milliequivalents of potassium per million units and if you are giving large doses, for example, in treating SBE, you might very well be giving 30 or 40 milliequivalents of unanticipated potassium each day and you could get into trouble with that. There is also a sodium salt available. If that is the situation you might switch to the sodium salt or in some cases we may even have to alternate the sodium and potassium every other dose.

Phenoxymethyl penicillin is oral penicillin. There is no longer oral penicillin G on the market. That has been taken off the market. Penicillin V would be used when oral penicillin is indicated. Procaine penicillin gets around the problem of pain on IM injection of aqueous penicillin by complexing it with procaine. Obviously the patient history needs to include inquiry about both the history of penicillin allergy and a history of local anesthetic or procaine allergy. If this drug is given IV, it is neurotoxic and will cause hallucinations and delirium. It has a duration of 12-24 hours and may be useful when moderately high blood levels of penicillin are acceptable. You don’t get very high levels with procaine penicillin.

But you get even lower blood levels with benzathine penicillin. This is another IM suspension marketed as Bicillin L-A where the release is extremely slow. You get very low blood levels so we would use this for rheumatic fever prophylaxis or for treatment of very susceptible infections like susceptible Strep throats where we don’t think compliance is going to be very good. The problem with this is that it hurts. Many patients will complain of pain for three days or so after they get a shot of benzathine penicillin.

There is also a Bicillin C-R on the market. That is Bicillin Controlled-Release, if you will. That is a 50/50 mixture of procaine and benzathine penicillin. The procaine gives a moderately high blood level for the first day. After that, the benzathine is there to help eradicate what is left of the infection. The problem with this is that some infectious disease people didn’t think that that was quite enough benzathine penicillin and suggested a different mix – that is, Bicillin C-R 900/300, which contains 75% of the slow release or the benzathine and 25% of the faster release procaine penicillin.

The bottom line, though, regardless of which you choose, Bicillin L-A, the C-R or the C-R 900/300, make sure you are giving enough of the benzathine to eradicate the infection because within 24 hours the procaine component is gone.
Antibiotics. Ampicillin. Amoxicillin.

Alternative applications of “antidepressants”

Although the evidence of efficacy of antidepressants, as a class, is not as convincing as for other types of drugs, there is growing clinical and research evidence to support a widening range of potential indications of these drugs. The partial success of the SSRIs as a group in ameliorating

OCD is encouraging, as is the utility of TCAs (especially imipramine) and MAO inhibitors (less so fluoxetine, not bupropion) in blocking the episodic, acute autonomic expression of panic. The range of disorders suspected of being related to OCD and in which serotonin-enhancing treatments are being explored, includes eating disorders, hair-pulling (trichotillomania) and other repetitive habits, compulsive gambling, kleptomania, premenstrual dysphoria, and perhaps body dysmorphic disorder. Antidepressants have a scientifically demonstrated but incompletely defined place in the overall management of patients with bulimia nervosa and may have an adjunctive role in anorexia nervosa. Some chronic pain syndromes (particularly with tertiary-amine TCAs in moderate doses), chronic fatigue, and sleep apnea may be helped with an antidepressant, and narcolepsy may be benefited by certain antidepressants (clomipramine) as well as stimulants. Attention deficit-hyperactivity disorder (ADHD) also responds to antidepressants (desipramine or imipramine, probably nortriptyline, possibly bupropion), whereas the record of effectiveness of antidepressants in pediatric depression is less convincing, and for unclear reasons that do not include doses, blood levels, or strong placebo response. Antidepressants (nortriptyline, desipramine) as well as stimulants (methylphenidate) may be useful in mild dementia-depression syndromes of the elderly, but benefits of the safer SSRIs in the elderly is less clear.

Adverse effects of antidepressants

Characteristic side effects of antidepressant drugs, as a group, include annoying and sometimes dangerous autonomic effects. Some of these (especially xerostomia, defective visual accommodation, acute glaucoma, mild tachycardia, constipation, urinary retention, and confusion) have been ascribed to the appreciable antimuscarinic actions of most TCAs, especially the tertiaryamine subgroup, which also carry elevated risks of sedation and postural hypotension. On the other hand, sexual dysfunction (especially ejaculatory incompetence) is routine with most SSRIs and can also occur occasionally with TCAs and with agents virtually without anticholinergic-parasympathetic activity (MAO inhibitors, and especially phenelzine in commonly used doses >45 mg/day), possibly due to a shift toward adrenergic-sympathetic dominance; priapism associated with trazodone may be due to antiadrenergic actions. TCAs and MAO inhibitors are associated with weight gain, which can become a significant medical problem and often leads to discontinuation of treatment; some relatively stimulating antidepressants (bupropion, fluoxetine) have a low risk of weight gain but may tend to induce agitation and insomnia. Risk of life-threatening cardiac arrhythmias with clinical doses of antidepressants is greatly exaggerated, although these can occur in acute overdoses on the order of one or two weeks supply; the quinidine-like actions of most TCAs contraindicate their use with other cardiac depressants. Sustained, usually mild, elevation of diastolic blood pressure has been found with TCAs and MAO inhibitors. Some of the newer antidepressants (bupropion, SSRIs, nefazodone) are much less likely than TCAs to induce life-threatening toxic cardiovascular effects or delirium on acute overdoses; indeed, the SSRIs have largely displaced the TCAs for use in cardiac patients. Nevertheless, most SSRIs (less with sertraline and venlafaxine) inhibit hepatic microsomal cytochrome-P450 oxidases, to interact with and increase circulating concentrations of many other drugs, with an increased risk of toxic effects. Bupropion, clomipramine and maprotiline carry a dose-dependent risk of inducing epileptic seizures.

Treatment-resistance

The problem of apparent “treatment-resistance” in depression requires further study, but many cases respond when a patient actually is willing to follow a previously recommended treatment, or high doses are accepted and pursued for at least 6-8 weeks. Some cases may represent destabilizing effects of overly aggressive antidepressant treatment of patients with overlooked bipolarity, but many others are truly treatment-unresponsive unipolar depressions. In cases of convincing treatment resistance, or loss of response over time (tolerance), evidence that important gains are to be found in exploring a series of similar agents is lacking. It may be useful to try an agent of a dissimilar type, and the most encouraging experience has been reported in adding lithium (while considering previously overlooked, subtle bipolarity and even use of mood-stabilizer therapy alone), changing from a TCA to an MAO inhibitor, or use of ECT (especially in severe, psychotic, or acutely suicidal cases). If severe agitation or psychotic features are present, temporary addition of an antipsychotic (avoiding long-term use of typical neuroleptics due to increased risk of TD in depression), or use of ECT is indicated, and bipolarity should be reconsidered. Most alternative applications of polypharmaceutical treatments are either unconvincing as to added efficacy (eg, supplemental thyroxin), poorly investigated (eg, mixing a TCA with an atypical agent), have not been shown superior to aggressive monotherapy (eg, TCA + MAO inhibitor or stimulant), or are not safe (eg, fluoxetine + any MAO inhibitor). Sometimes combining an SSRI cautiously with a stimulant or bupropion (avoiding high doses due to increase seizure risk with SSRIs) may be helpful.

Long-term treatment

Long-term maintenance treatment of recurrent unipolar major depression with antidepressants has a complex body of research findings. Continuation of such agents in nearly full doses as are given short-term is probably effective in preventing early relapse in the 6-12 months following apparent recovery from an acute episode, and this is a widely accepted clinical practice. However, studies of more prolonged prophylactic benefit over several years of maintenance treatment are limited and suggest diminishing evidence of efficacy with duration of follow-up, perhaps in part due to limited compliance with generally poorly tolerated TCAs. An influential study in which compliance with high doses (ca. 200 mg of imipramine daily) and blood TCA concentrations of imipramine was assured, there was convincing evidence of benefit over a placebo in outpatients treated up to 5 years, whereas (possibly inadequately vigorous) psychotherapy added little. Several recent trials provide support for long-term use of SSRIs. Long-term use of antidepressants is more secure with more previous episodes, and even in dysthymia or chronic depression. Rapid dose-reduction or discontinuation of maintenance antidepressant treatment appears to carry a high risk of early recurrence of depression, particularly within six months, and even following several years of stable mood (as well as nonspecific physiological withdrawal symptoms). The post-discontinuation recurrence effect raises questions about the contribution of drag discontinuation itself to early relapse risk in drug vs. placebo maintenance studies; relapse risk may actually be quite similar on drug or placebo beyond the initial several months after discontinuing an antidepressant. It is uncertain whether slow tapering off an antidepressant can spare early post-discontinuation relapse risk (as it does with lithium in bipolar disorders, and perhaps with antipsychotics in schizophrenia), though this is a sound general practice whenever feasible. From a practical perspective, tolerability of most antidepressants limits their long-term acceptance, particularly in high doses, by many patients. In addition, many physicians may be reluctant to use antidepressants aggressively (particularly older TCAs and MAOIs), due to their exaggerated reputation for cardiotoxicity, formerly common involvement in suicidal overdoses, and limited acceptability by patients. Recent surveys of the recognition and treatment of major depression strongly suggest that both are seriously inadequate, and that the diagnosis of major depression and its treatment with 150 mg IMI-eq daily doses for at least four weeks occur in fewer than half of such patients, and possibly fewer than one-quarter.

Antidepressants
Types of antidepressants

Antidepressants currently fall into five major categories: [1] tertiary amine tricyclics (amitriptyline, clomipramine, doxepin, imipramine, trimipramine), secondary amine tricyclics (amoxapine, desipramine, maprotiline, nortriptyline, protriptyline); [2] monoamine oxidase (MAO) inhibitors (phenelzine, tranylcypromine, selegiline [(-)-deprenyl], and experimental short-acting MAO-A inhibitors (eg,, moclobemide [Manerex], marketed in Canada); [3] serotonin-reuptake inhibitors: (SSRIs) clomipramine, citalopram, [±]-fluoxetine, fluvoxamine, sertraline, paroxetine, and the mixed 5-HT/NE uptake inhibitor venlafaxine (plus the withdrawn zimelidine; [4] stimulant-like dopaminergic as well as noradrenergic agents: bupropion (and the withdrawn nomifensine); [5] the atypical antidepressant mirtazapine (Remeron; a sedating antidepressant chemically related to mianserin, with indirect adrenergic and serotonergic actions as an a2 and serotonin 5-HT2 and 5-HT3 antagonist that enhances release of both NE and 5-HT) and [6] sedative-anxiolytics: including the triazolopyridines trazodone and nefazodone, but probably not high-potency benzodiazepines. The tricyclic antidepressant (TCA) group is usefully subdivided into the tertiary and secondary amine types; they are about equi effective, but the tertiary amines are less selectively pharmacologically (interact with NE, 5-HT, ACh, histamine), have important anticholinergic-autonomic and sedative side effects, and are somewhat less potent, while the secondary amines are somewhat more potent, less sedating, have longer plasma half-life, and are somewhat less anticholinergic. Newer agents, particularly the SSRIs, now dominate clinical practice, due principally to safety and tolerability, and range of uses, though their efficacy is not superior to older agents. There is a lingering clinical suspicion that TCAs (particularly nortriptyline or desipramine) may be somewhat superior agents for severe depression, particularly in the elderly, including postmenopausal women, and perhaps in men, when they can be tolerated, and they are superior for some chronic pain syndromes.

Efficacy of antidepressants
The evidence of antidepressant efficacy of most antidepressants is much less compelling than most other classes of psychotropic agents. Indeed, virtually all types have outperformed a placebo in only about 60%-70% of comparisons. In part, this limited evidence of efficacy reflects ambiguities surrounding currently broad definitions of depressive syndromes, particularly the relatively loose contemporary category of “major” depression, such that rates of response to a placebo may be as high as 20%-40% and that to other relatively nonspecific treatments (including sedative-anxiolytics) is even higher (40%-50%), while typical responses to an antidepressant range from 50%-75%, with best responses found in the presence of classic melancholic features, absence of psychotic symptoms, moderate but not extreme severity, and absence of comorbidity. Inclusion of mild depression within the “major” depression syndrome encourages development of agents with questionable efficacy in severe, melancholic depression (eg, the triazolopyridine trazodone [its congener nefazodone may be more effective, even in panic disorder], potent triazolo-benzodiazepines, buspirone and other experimental azaspirones) which may have a place in the treatment of anxious and mildly depressed outpatients, but marginal or uncertain efficacy in severe depression. While the ethics of placebo-controlled (or dose-stratified) antidepressant trials and inclusion of severely depressed melancholic patients are debated, the limited evidence of efficacy of this class of agents requires continued consideration of such rigorous testing or, at least, caution in generalizing about the spectrum of clinical utility of innovative antidepressants. Testing of cognitive-behavioral (CBT) and interpersonal (IPT) psychotherapies in major depression shows encouraging benefits in milder depression, but remains untested in severe depression, despite broad empirical clinical application of various forms of psychotherapy in various forms of depression.